StemCell Therapy

This article is a non-technical introduction to the subject. For the main encyclopedia article, see Genetics.

A long molecule that looks like a twisted ladder. It is made of four types of simple units and the sequence of these units carries information, just as the sequence of letters carries information on a page.

They form the rungs of the DNA ladder and are the repeating units in DNA. There are four types of nucleotides (A, T, G and C) and it is the sequence of these nucleotides that carries information.

A package for carrying DNA in the cells. They contain a single long piece of DNA that is wound up and bunched together into a compact structure. Different species of plants and animals have different numbers and sizes of chromosomes.

A segment of DNA. Genes are like sentences made of the "letters" of the nucleotide alphabet, between them genes direct the physical development and behavior of an organism. Genes are like a recipe or instruction book, providing information that an organism needs so it can build or do something - like making an eye or a leg, or repairing a wound.

The different forms of a given gene that an organism may possess. For example, in humans, one allele of the eye-color gene produces green eyes and another allele of the eye-color gene produces brown eyes.

The complete set of genes in a particular organism.

When people change an organism by adding new genes, or deleting genes from its genome.

An event that changes the sequence of the DNA in a gene.

Genetics is the study of genes what they are, what they do, and how they work. Genes are made up of molecules inside the nucleus of a cell that are strung together in such a way that the sequence carries information: that information determines how living organisms inherit phenotypic traits, (features) determined by the genes they received from their parents and thereby going back through the generations. For example, offspring produced by sexual reproduction usually look similar to each of their parents because they have inherited some of each of their parents' genes. Genetics identifies which features are inherited, and explains how these features pass from generation to generation. In addition to inheritance, genetics studies how genes are turned on and off to control what substances are made in a cell - gene expression; and how a cell divides - mitosis or meiosis.

Some phenotypic traits can be seen, such as eye color while others can only be detected, such as blood type or intelligence. Traits determined by genes can be modified by the animal's surroundings (environment): for example, the general design of a tiger's stripes is inherited, but the specific stripe pattern is determined by the tiger's surroundings. Another example is a person's height: it is determined by both genetics and nutrition.

Genes are made of DNA, which is divided into separate pieces called chromosomes. Humans have 46: 23 pairs, though this number varies between species, for example many primates have 24 pairs. Meiosis creates special cells, sperm in males and eggs in females, which only have 23 chromosomes. These two cells merge into one during the fertilization stage of sexual reproduction, creating a zygote in which a nucleic acid double helix divides, with each single helix occupying one of the daughter cells, resulting in half the normal number of genes. The zygote then divides into four daughter cells by which time genetic recombination has created a new embryo with 23 pairs of chromosomes, half from each parent. Mating and resultant mate choice result in sexual selection. In normal cell division (mitosis) is possible when the double helix separates, and a complement of each separated half is made, resulting in two identical double helices in one cell, with each occupying one of the two new daughter cells created when the cell divides.

Chromosomes all contain four nucleotides, abbreviated C (cytosine), G (guanine), A (adenine), or T (thymine), which line up in a particular sequence and make a long string. There are two strings of nucleotides coiled around one another in each chromosome: a double helix. C on one string is always opposite from G on the other string; A is always opposite T. There are about 3.2 billion nucleotide pairs on all the human chromosomes: this is the human genome. The order of the nucleotides carries genetic information, whose rules are defined by the genetic code, similar to how the order of letters on a page of text carries information. Three nucleotides in a row - a triplet - carry one unit of information: a codon.

The genetic code not only controls inheritance: it also controls gene expression, which occurs when a portion of the double helix is uncoiled, exposing a series of the nucleotides, which are within the interior of the DNA. This series of exposed triplets (codons) carries the information to allow machinery in the cell to "read" the codons on the exposed DNA, which results in the making of RNA molecules. RNA in turn makes either amino acids or microRNA, which are responsible for all of the structure and function of a living organism; i.e. they determine all the features of the cell and thus the entire individual. Closing the uncoiled segment turns off the gene.

Heritability means the information in a given gene is not always exactly the same in every individual in that species, so the same gene in different individuals does not give exactly the same instructions. Each unique form of a single gene is called an allele; different forms are collectively called polymorphisms. As an example, one allele for the gene for hair color and skin cell pigmentation could instruct the body to produce black pigment, producing black hair and pigmented skin; while a different allele of the same gene in a different individual could give garbled instructions that would result in a failure to produce any pigment, giving white hair and no pigmented skin: albinism. Mutations are random changes in genes creating new alleles, which in turn produce new traits, which could help, harm, or have no new effect on the individual's likelihood of survival; thus, mutations are the basis for evolution.

Genes are pieces of DNA that contain information for synthesis of ribonucleic acids (RNAs) or polypeptides. Genes are inherited as units, with two parents dividing out copies of their genes to their offspring. This process can be compared with mixing two hands of cards, shuffling them, and then dealing them out again. Humans have two copies of each of their genes, and make copies that are found in eggs or spermbut they only include one copy of each type of gene. An egg and sperm join to form a complete set of genes. The eventually resulting offspring has the same number of genes as their parents, but for any gene one of their two copies comes from their father, and one from their mother.[1]

The effects of this mixing depend on the types (the alleles) of the gene. If the father has two copies of an allele for red hair, and the mother has two copies for brown hair, all their children get the two alleles that give different instructions, one for red hair and one for brown. The hair color of these children depends on how these alleles work together. If one allele dominates the instructions from another, it is called the dominant allele, and the allele that is overridden is called the recessive allele. In the case of a daughter with alleles for both red and brown hair, brown is dominant and she ends up with brown hair.[2]

Although the red color allele is still there in this brown-haired girl, it doesn't show. This is a difference between what you see on the surface (the traits of an organism, called its phenotype) and the genes within the organism (its genotype). In this example you can call the allele for brown "B" and the allele for red "b". (It is normal to write dominant alleles with capital letters and recessive ones with lower-case letters.) The brown hair daughter has the "brown hair phenotype" but her genotype is Bb, with one copy of the B allele, and one of the b allele.

Now imagine that this woman grows up and has children with a brown-haired man who also has a Bb genotype. Her eggs will be a mixture of two types, one sort containing the B allele, and one sort the b allele. Similarly, her partner will produce a mix of two types of sperm containing one or the other of these two alleles. When the transmitted genes are joined up in their offspring, these children have a chance of getting either brown or red hair, since they could get a genotype of BB = brown hair, Bb = brown hair or bb = red hair. In this generation, there is therefore a chance of the recessive allele showing itself in the phenotype of the children - some of them may have red hair like their grandfather.[2]

Many traits are inherited in a more complicated way than the example above. This can happen when there are several genes involved, each contributing a small part to the end result. Tall people tend to have tall children because their children get a package of many alleles that each contribute a bit to how much they grow. However, there are not clear groups of "short people" and "tall people", like there are groups of people with brown or red hair. This is because of the large number of genes involved; this makes the trait very variable and people are of many different heights.[3] Despite a common misconception, the green/blue eye traits are also inherited in this complex inheritance model.[4] Inheritance can also be complicated when the trait depends on interaction between genetics and environment. For example, malnutrition does not change traits like eye color, but can stunt growth.[5]

Some diseases are hereditary and run in families; others, such as infectious diseases, are caused by the environment. Other diseases come from a combination of genes and the environment.[6]Genetic disorders are diseases that are caused by a single allele of a gene and are inherited in families. These include Huntington's disease, Cystic fibrosis or Duchenne muscular dystrophy. Cystic fibrosis, for example, is caused by mutations in a single gene called CFTR and is inherited as a recessive trait.[7]

Other diseases are influenced by genetics, but the genes a person gets from their parents only change their risk of getting a disease. Most of these diseases are inherited in a complex way, with either multiple genes involved, or coming from both genes and the environment. As an example, the risk of breast cancer is 50 times higher in the families most at risk, compared to the families least at risk. This variation is probably due to a large number of alleles, each changing the risk a little bit.[8] Several of the genes have been identified, such as BRCA1 and BRCA2, but not all of them. However, although some of the risk is genetic, the risk of this cancer is also increased by being overweight, drinking a lot of alcohol and not exercising.[9] A woman's risk of breast cancer therefore comes from a large number of alleles interacting with her environment, so it is very hard to predict.

The function of genes is to provide the information needed to make molecules called proteins in cells.[1] Cells are the smallest independent parts of organisms: the human body contains about 100 trillion cells, while very small organisms like bacteria are just one single cell. A cell is like a miniature and very complex factory that can make all the parts needed to produce a copy of itself, which happens when cells divide. There is a simple division of labor in cells - genes give instructions and proteins carry out these instructions, tasks like building a new copy of a cell, or repairing damage.[10] Each type of protein is a specialist that only does one job, so if a cell needs to do something new, it must make a new protein to do this job. Similarly, if a cell needs to do something faster or slower than before, it makes more or less of the protein responsible. Genes tell cells what to do by telling them which proteins to make and in what amounts.

Proteins are made of a chain of 20 different types of amino acid molecules. This chain folds up into a compact shape, rather like an untidy ball of string. The shape of the protein is determined by the sequence of amino acids along its chain and it is this shape that, in turn, determines what the protein does.[10] For example, some proteins have parts of their surface that perfectly match the shape of another molecule, allowing the protein to bind to this molecule very tightly. Other proteins are enzymes, which are like tiny machines that alter other molecules.[11]

The information in DNA is held in the sequence of the repeating units along the DNA chain.[12] These units are four types of nucleotides (A,T,G and C) and the sequence of nucleotides stores information in an alphabet called the genetic code. When a gene is read by a cell the DNA sequence is copied into a very similar molecule called RNA (this process is called transcription). Transcription is controlled by other DNA sequences (such as promoters), which show a cell where genes are, and control how often they are copied. The RNA copy made from a gene is then fed through a structure called a ribosome, which translates the sequence of nucleotides in the RNA into the correct sequence of amino acids and joins these amino acids together to make a complete protein chain. The new protein then folds up into its active form. The process of moving information from the language of RNA into the language of amino acids is called translation.[13]

If the sequence of the nucleotides in a gene changes, the sequence of the amino acids in the protein it produces may also change - if part of a gene is deleted, the protein produced is shorter and may not work any more.[10] This is the reason why different alleles of a gene can have different effects in an organism. As an example, hair color depends on how much of a dark substance called melanin is put into the hair as it grows. If a person has a normal set of the genes involved in making melanin, they make all the proteins needed and they grow dark hair. However, if the alleles for a particular protein have different sequences and produce proteins that can't do their jobs, no melanin is produced and the person has white skin and hair (albinism).[14]

Genes are copied each time a cell divides into two new cells. The process that copies DNA is called DNA replication.[12] It is through a similar process that a child inherits genes from its parents, when a copy from the mother is mixed with a copy from the father.

DNA can be copied very easily and accurately because each piece of DNA can direct the creation of a new copy of its information. This is because DNA is made of two strands that pair together like the two sides of a zipper. The nucleotides are in the center, like the teeth in the zipper, and pair up to hold the two strands together. Importantly, the four different sorts of nucleotides are different shapes, so for the strands to close up properly, an A nucleotide must go opposite a T nucleotide, and a G opposite a C. This exact pairing is called base pairing.[12]

When DNA is copied, the two strands of the old DNA are pulled apart by enzymes; then they pair up with new nucleotides and then close. This produces two new pieces of DNA, each containing one strand from the old DNA and one newly made strand. This process is not predictably perfect as proteins attach to a nucleotide while they are building and cause a change in the sequence of that gene. These changes in DNA sequence are called mutations.[15] Mutations produce new alleles of genes. Sometimes these changes stop the functioning of that gene or make it serve another advantageous function, such as the melanin genes discussed above. These mutations and their effects on the traits of organisms are one of the causes of evolution.[16]

A population of organisms evolves when an inherited trait becomes more common or less common over time.[16] For instance, all the mice living on an island would be a single population of mice: some with white fur, some gray. If over generations, white mice became more frequent and gray mice less frequent, then the color of the fur in this population of mice would be evolving. In terms of genetics, this is called an increase in allele frequency.

Alleles become more or less common either by chance in a process called genetic drift, or by natural selection.[17] In natural selection, if an allele makes it more likely for an organism to survive and reproduce, then over time this allele becomes more common. But if an allele is harmful, natural selection makes it less common. In the above example, if the island were getting colder each year and snow became present for much of the time, then the allele for white fur would favor survival, since predators would be less likely to see them against the snow, and more likely to see the gray mice. Over time white mice would become more and more frequent, while gray mice less and less.

Mutations create new alleles. These alleles have new DNA sequences and can produce proteins with new properties.[18] So if an island was populated entirely by black mice, mutations could happen creating alleles for white fur. The combination of mutations creating new alleles at random, and natural selection picking out those that are useful, causes adaptation. This is when organisms change in ways that help them to survive and reproduce.

Since traits come from the genes in a cell, putting a new piece of DNA into a cell can produce a new trait. This is how genetic engineering works. For example, rice can be given genes from a maize and a soil bacteria so the rice produces beta-carotene, which the body converts to Vitamin A.[19] This can help children suffering from Vitamin A deficiency. Another gene being put into some crops comes from the bacterium Bacillus thuringiensis; the gene makes a protein that is an insecticide. The insecticide kills insects that eat the plants, but is harmless to people.[20] In these plants, the new genes are put into the plant before it is grown, so the genes are in every part of the plant, including its seeds.[21] The plant's offspring inherit the new genes, which has led to concern about the spread of new traits into wild plants.[22]

The kind of technology used in genetic engineering is also being developed to treat people with genetic disorders in an experimental medical technique called gene therapy.[23] However, here the new gene is put in after the person has grown up and become ill, so any new gene is not inherited by their children. Gene therapy works by trying to replace the allele that causes the disease with an allele that works properly.

Read more here:
Introduction to genetics - Wikipedia, the free encyclopedia

Have people ever said to you, "It's in your genes"? They were probably talking about a physical characteristic, personality trait, or talent that you share with other members of your family.

We know that genes play an important role in shaping how we look and act and even whether we get sick. Now scientists are trying to use that knowledge in exciting new ways, such as treating health problems.

To understand how genes work, let's review some biology basics. Most living organisms are made up of cells that contain a substance called deoxyribonucleic (pronounced: dee-AHK-see-rye-bow-noo-klee-ik) acid (DNA).

DNA contains four chemicals (adenine, thymine, cytosine, and guanine called A, T, C, and G for short) that are strung in patterns on extremely thin, coiled strands in the cell. How thin? Cells are tiny invisible to the naked eye and each cell in your body contains about 6 feet of DNA thread, for a total of about 3 billion miles of DNA inside you!

So where do genes come in? Genes are made of DNA, and different patterns of A, T, G, and C code for the instructions for making things your body needs to function (like the enzymes to digest food or the pigment that gives your eyes their color). As your cells duplicate, they pass this genetic information to the new cells.

DNA is wrapped together to form structures called chromosomes. Most cells in the human body have 23 pairs of chromosomes, making a total of 46. Individual sperm and egg cells, however, have just 23 unpaired chromosomes. You received half of your chromosomes from your mother's egg and the other half from your father's sperm cell. A male child receives an X chromosome from his mother and a Y chromosome from his father; females get an X chromosome from each parent.

Genes are sections or segments of DNA that are carried on the chromosomes and determine specific human characteristics, such as height or hair color. Because you have a pair of each chromosome, you have two copies of every gene (except for some of the genes on the X and Y chromosomes in boys, because boys have only one of each).

Some characteristics come from a single gene, whereas others come from gene combinations. Because every person has about 25,000 different genes, there is an almost endless number of possible combinations!

Continue reading here:
The Basics on Genes and Genetic Disorders - KidsHealth

Genetics Colloquium - Spring 2016

Wednesdays, 3:30 PM, Auditorium (Room 1111) of the Genetics/Biotech Building

Jan 27

Kate O'Connor-Giles, UW-Madison, Dept. of Genetics Genetic Dissection of Synapse Form and Function

Feb 3

Nitin Phadnis, University of Utah (Pool) "Selfish Genes and Speciation in Drosophila"

Feb 10

Nader Sheibani, UW-Madison, Dept. of Ophthalmology & Visual Sciences (Aki Ikeda) "Thrombospondin-1 and Pathogenesis of Diabetic Retinopathy"

Feb 17

Lauren McIntyre, University of Florida (O'Connor-Giles) "Regulation of Gene Expression in Drosophila"

Feb 24

Aaron Hoskins, UW-Madison, Department of Biochemistry (Pelegri) "Mechanisms of pre-Spliceosome Assembly and Dysfunction in Blood Cancers"

March 2

Reid S. Alisch, UW-Madison, Department of Psychiatry (Aki Ikeda) "Defining the Epigenetic Origins of Mental Illness"

March 9

Christopher Bradfield, UW-Madison, Department of Oncology (Pelegri) "Dioxins, Clocks and Oxygen: Prototype Signals of a Nuclear Sensor Family"

March 16

Jean-Michel Ane, UW-Madison, Department of Bacteriology (Pelegri) "Strange bedfellows: symbiotic signaling between land plants and their microbial symbionts"

March 23

Spring Break - No Colloquium

March 30

Jim Cheverud, Loyola University (Payseur) "Context-dependent gene effects on complex traits"

April 6

Alejandro Snchez-Alvarado, Stowers Institute for Medical Research (Skop) "The Reproductive and Developmental Plasticity of Planarians"

April 13

Steve Henikoff, University of Washington (Rupa Sridharan)

April 20

Mark D. Rausher, Duke University (Hittinger)

April 27

John Yin, UW-Madison (Doebley) "The Chemical Origins Of Life (COOL) Project"

May 4

Mike Eisen, University of California-Berkley (Melissa Harrison)

Read the original:
Colloquium | Laboratory of Genetics | University of Wisconsin ...

Mar. 7, 2016 Sometimes, a nematode worm just needs to take a nap. In fact, its life may depend on it. New research has identified a protein that promotes a sleep-like state in the nematode Caenorhabditis elegans. ... read more Mar. 3, 2016 Researchers have identified a common ancestral gene that enabled the evolution of advanced life over a billion years ... read more Mar. 2, 2016 Scientists have solved the structure of a key protein in HKU1, a coronavirus identified in Hong Kong in 2005 and highly related to SARS and MERS. They believe their findings will guide future ... read more Mar. 2, 2016 A faster, less expensive method has been developed and used to learn the DNA sequence of the male-specific Y chromosome in the gorilla. The research reveals that a male gorilla's Y chromosome is ... read more Mar. 2, 2016 DNA does not always adopt the form of the double helix which is associated with the genetic code; it can also form intricate folds and act as an enzyme: a deoxyribozyme. Scientists have solved the ... read more Mar. 2, 2016 Every cell in our bodies has its proper place, but how do they get there? A research group has discovered the mechanism for a mosaic pattern formation of two different cell types. Their discovery has ... read more Need for Better Characterized Genomes for Clinical Sequencing Mar. 1, 2016 Challenges in benchmarking difficult, but clinically important regions of the genome have been reported. The results underscore the need to extend benchmarking references against which sequencing ... read more Mar. 1, 2016 This is a story about spit. Not just any spit, but the saliva of cyst nematodes, a parasite that literally sucks away billions in profits from soybean and other crops every year. Scientists find how ... read more Mar. 1, 2016 Our innate immune system uses two mechanisms. The first kills foreign bodies within the phagocyte itself. The second kills them outside the cell. Microbiologists have discovered that a social amoeba ... read more Preserved Siberian Moose With the DNA of Ancient Animal Discovered Mar. 1, 2016 Scientists have found preserved moose in Western Siberia that have unique features of DNA structure. This discovery will help determine the origin and path of moose movement in the last few tens of ... read more Female Fertility Is Dependent on Functional Expression of the E3 Ubiquitin Ligase Itch Feb. 29, 2016 Protein ubiquitination is known to result in its proteasomal degradation or to serve as a signal for tissue-specific cellular functions. Here it is reported that mice with a mutant form of the E3 ... read more Cell Biology: Nuclear Export of Opioid Growth Factor Receptor Is CRM1 Dependent Feb. 29, 2016 The opioid growth factor receptor (OGFr) interacts with a specific opioid growth factor ligand (OGF), chemically termed [Met5]-enkephalin, to maintain homeostasis in a wide variety of normal and ... read more Feb. 29, 2016 DNA is made from four nucleosides, each known by its own letter -- A, G, C, and T. However, since the structure of DNA was deciphered in 1953, scientists have discovered several other variants that ... read more Feb. 29, 2016 Microsatellites are a key tool for researchers working to understand the genetic diversity and evolutionary dynamics of organisms. A recent study offers a deeper understanding of the utility and ... read more Watching New Species Evolve in Real Time Feb. 29, 2016 Sometimes evolution proceeds much more rapidly than we might think. Genetic analysis makes it possible to detect the earliest stages of species formation. For example, a new study investigating rapid ... read more Blood Vessels Sprout Under Pressure Feb. 29, 2016 It is blood pressure that drives the opening of small capillaries during angiogenesis. A team of researchers has observed the process for the first ... read more Feb. 29, 2016 A team of researchers has identified a new mechanism that regulates the effect of the satiety hormone leptin. The study identified the enzyme HDAC5 as key factor in our control of body weight and ... read more Making Better Enzymes and Protein Drugs Feb. 29, 2016 Natural selection results in protein sequences that are only soluble to the level that is required to carry out its physiological function. However, in biotechnological applications, we need these ... read more Feb. 29, 2016 The development of every animal in the history of the world began with a simple step: the fusion of a spermatozoon with an oocyte. Despite the ubiquity of this process, the actual mechanisms through ... read more Feb. 29, 2016 When venom from animals such as spiders, snakes or cone snails is injected via a bite or harpoon, the cocktail of toxins delivered to its victim tends to cause serious reactions that, if untreated, ... read more

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Genetics News -- ScienceDaily

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Link:
Laser Genetics - Night Vision, Green Lasers for Law ...

Genetic tests are done by analyzing small samples of blood or body tissues. They determine whether you, your partner, or your baby carry genes for certain inherited disorders.

Genetic testing has developed enough so that doctors can often pinpoint missing or defective genes. The type of genetic test needed to make a specific diagnosis depends on the particular illness that a doctor suspects.

Many different types of body fluids and tissues can be used in genetic testing. For deoxyribonucleic acid (DNA) screening, only a very tiny bit of blood, skin, bone, or other tissue is needed.

For genetic testing before birth, pregnant women may decide toundergo amniocentesis or chorionic villus sampling. There is also a blood test available to women to screen for some disorders. If this screening test finds a possible problem, amniocentesis or chorionic villus sampling may be recommended.

Amniocentesis is a test usually performed between weeks 15 and 20of a woman's pregnancy. The doctor inserts a hollow needle into the woman's abdomen to remove a small amount of amniotic fluid from around the developing fetus. This fluid can be tested to check for genetic problems and to determine the sex of the child. When there's risk of premature birth, amniocentesis may be done to see how far the baby's lungs have matured. Amniocentesis carries a slight risk of inducing a miscarriage.

Chorionic villus sampling (CVS) is usually performed between the 10th and 12th weeks of pregnancy. The doctor removes a small piece of the placenta to check for genetic problems in the fetus. Because chorionic villus sampling is an invasive test, there's a small risk that it can induce a miscarriage.

A doctor may recommend genetic counseling or testing for any of the following reasons:

Although advances in genetic testing have improved doctors' ability to diagnose and treat certain illnesses, there are still some limits. Genetic tests can identify a particular problem gene, but can't always predict how severely that gene will affect the person who carries it. In cystic fibrosis, for example, finding a problem gene on chromosome number 7 can't necessarily predict whether a child will have serious lung problems or milder respiratory symptoms.

Also, simply having problem genes is only half the story because many illnesses develop from a mix of high-risk genes and environmental factors. Knowing that you carry high-risk genes may actually be an advantage if it gives you the chance to modify your lifestyle to avoid becoming sick.

As research continues, genes are being identified that put people at risk for illnesses like cancer, heart disease, psychiatric disorders, and many other medical problems. The hope is that someday it will be possible to develop specific types of gene therapy to totally prevent some diseases and illnesses.

Gene therapy is already being studied as a possible way to treat conditions like cystic fibrosis, cancer, and ADA deficiency (an immune deficiency), sickle cell disease, hemophilia, and thalassemia. However, severe complications have occurred in some patients receiving gene therapy, so current research with gene therapy is very carefully controlled.

Although genetic treatments for some conditions may be a long way off, there is still great hope that many more genetic cures will be found. The Human Genome Project, which was completed in 2003, identified and mapped out all of the genes (about 25,000) carried in our human chromosomes. The map is just the start, but it's a very hopeful beginning.

Date reviewed: April 2014

More:
An Introduction to Genetics and Genetic Testing - KidsHealth

for 1st YEAR STUDENTS INTRODUCTION

he applications of Mendelian genetics, chromosomal abnormalities, and multifactorial inheritance to medical practice are quite evident. Physicians work mostly with patients and families. However, as important as they may be, genes affect populations, and in the long run their effects in populations have a far more important impact on medicine than the relatively few families each physician may serve. It is important that certain polymorphisms are maintained so that the species may survive, even at the expense of individuals. Genetic polymorphisms often are detrimental to the homozygote, but they allow others of the species to survive. Before medical intervention was possible, populations that lacked the sickle cell anemia allele could not survive in the malaria regions of West Africa. Those that had the sickle cell anemia allele survived, and the gene remains in the population at high frequency today, even though the homozygous recessive phenotype was at a severe disadvantage in the past. The high rate of thalassemia in people of Mediterranean origin, the high rate of sickle cell anemia in people of West African descent, the high rate of cystic fibrosis in people from Western Europe, and the high rate of Tay-Sachs disease in ethnic groups from Eastern Europe may all owe their origin to environmental factors that cause changes in gene frequencies in large populations by giving some advantage to heterozygotes who carry a deleterious allele. Although one may never use the calculations of population genetics in medical practice, the underlying principles should be understood.

Population genetics is also the most widely misused area of human genetics, sometimes bordering on "vigilante genetics," a term coined by Newton Morton. Persons have mistakenly applied population genetics to "prove" race superiority for intelligence and aptitudes, and have misused it in eugenics. As an educated and, I hope, a respected member of your community you must be alert to "vigilante genetics."

Population genetics is concerned with gene and genotype frequencies, the factors that tend to keep them constant, and the factors that tend to change them in populations. It is largely concerned with the study of polymorphisms. It directly impacts counseling, forensic medicine, and genetic screening.

Consider a population of 1000 individuals all typed for the simplest test at the MN blood group locus. At its most simplistic form this locus can be reduced to a codominant system with two alleles M and N. (In reality it is considerably more complex than this but this simple form will suffice for our examples.) Every individual in the population will be either M (having two M alleles), MN (heterozygous), or N (having two N alleles). Suppose the blood typing results were as follows: 300 M individuals, 600MN individuals, and 100 N individuals. You probably want to ask, "What is the gene frequency of the M allele in the above population of 1000 individuals?" I'm glad you're interested!

1000 individuals each have two alleles at the MN locus = 2000 genes

Each M individual has 2 M alleles 300 x 2 = 600 M alleles

Each MN individual has 1 M allele 600 x 1 = 600 M alleles

There is a total of 1200 M genes in a population of 2000 genes. The gene frequency of the M allele is 1200/2000 = 0.6

I'll bet you want to know, "What is the gene frequency of the N allele?" Well, I'll show you how to find out.

Each MN individual has 1 N allele 600 x 1 = 600 N genes

Each N individual has 2 N genes 100 x 2 = 200 N genes

Again, there is a total of 2000 genes in the population for the MN locus. The gene frequency of the N allele is 800/2000 = 0.4

Notice that when there are only two alleles in the population, their gene frequencies must add to 1. If they don't, you've done something wrong. This counting method of calculating the gene frequency must be used whenever the heterozygote can be detected.

Gene frequency = (2 x homozygote + heterozygote) / 2 x population

Gene frequency for one allele = 1 - gene frequency of the other allele

These two general formulas assume nothing of the population, only that it is a single interbreeding group. All other methods make some assumptions of the population in order to simplify calculations.

For many human autosomal recessive traits the heterozygote cannot be distinguished from the normal homozygote. When this occurs the Hardy-Weinberg equilibrium is assumed to apply. These authors, Hardy in England and Weinberg in Germany, used different approaches but came to the same conclusions in 1908. They made several assumptions of the population:

Under these assumptions, Hardy and Weinberg found that the gene frequency and the genotype frequency in the population do not change from generation to generation. Furthermore, if the frequency of the dominant allele A in the founding population was p , and the frequency of the recessive allele a in the founding population was q, then after one generation of random mating the genotype frequencies would remain fixed and would be in the ratio:

If you want to see evidence that this is true, see Figure 20. If, on the other hand, you believe everything you read, and only want to study what will be covered on the examination, continue on.

Hopefully, someone will ask the question, "Is there any evidence that the human population meets the requirements of Hardy-Weinberg equilibrium, or is this just a mental exercise?" Of course there is evidence! Consider the following:

In my experience, one may use several criteria for selecting a person to mate with, but one usually doesn't select a mate based on blood types at the MN blood group locus. Therefore, we might assume that this locus would be a good test of random mating. All of the other Hardy-Weinberg criteria also seem to be met. Mutations at this autosomal locus are rare. We know of no selective advantage or disadvantage in the present environment. And migration wouldn't be much of a factor if we took the sample at one short interval of time. This locus should provide a good test.

We have already seen that gene frequencies and genotype frequencies for this locus can be determined without using assumptions of Hardy-Weinberg equilibrium. Let's see if a real population sample is distributed as p2 (M), 2pq (MN), q2 (N).

In 1975, Race and Sanger reported the typing results from 1279 individuals in London. They were not collecting these data for the purpose of testing for Hardy-Weinberg equilibrium, so they could not be accused of typing individuals until a certain distribution was achieved, a question that has always remained about Mendel's original studies. Race and Sanger found 363 persons were M, 634 were MN, and 282 were N. Using our original method of calculating gene frequencies, the frequency of the M allele (p) would be:

p = (2 x 363) + 634 / (2 x 1279) = 0.53167

The frequency of the N allele (q) would be:

q = (2 x 282) + 634 / (2 x 1279) = 0.46833

If the population were in Hardy-Weinberg equilibrium, then the number of M individuals should be p2 x 1279, the number of MN individuals should be 2pq x 1279, and the number of N individuals should be q2 x 1279, or

For the MN blood group locus there can be little doubt that the conditions for Hardy-Weinberg equilibrium are met in the human population, at least the population in London where the sample was taken. The observed frequencies closely approximate what would be expected if the population were in Hardy-Weinberg equilibrium.

This gives us the assurance that we can use Hardy-Weinberg as a method when the heterozygote cannot be detected. An example of the use of the Hardy-Weinberg principle in medical genetics is given below.

Suppose there is an autosomal recessive disease where the frequency of affected in the population is 1/10,000. If the population is in Hardy-Weinberg equilibrium, this frequency would equal q2. The gene frequency of the recessive allele (q) would then be the square root of q2, or the square root of 1/10,000 which equals 1/100. The carrier (heterozygote) frequency (2pq) is usually approximated as 2q since p (0.99) is so close to 1. The carrier frequency is then 1/50.

For an autosomal recessive disease with a population frequency of 1/10,000, the carrier frequency is 1/50. Put another way, on average, as many as 3 or 4 first year medical students at UIC are carriers of such a disease.

From time to time, certain groups have suggested that the way to eliminate a deleterious disease from the population is to not allow affected individuals to mate. The above example should provide some evidence that this will have little effect on gene frequencies in the population. Although the frequency of the disease is only 1/10,000, (we should have one affected first year medical student at UIC every 50 years) the carrier frequency is 1/50 (we should have 3 or 4 carriers at UIC in every incoming class). These phenotypically normal carriers will keep the gene in the population.

If, by chance, a student in the first year class has a sibling with an autosomal recessive disease that is present at birth, the student would have a 2/3 chance of being a carrier. If that student were to have a child with an unrelated partner selected at random from the general population, and the disease frequency in the general population is 1/10,000, the probability of their child being affected is:

Compare that to the probability that two unrelated individuals, with no history of the disease in their families would have an affected child, when the carrier frequency is 1/50:

Since it is a stated goal of medicine to do what is best for the patient, what happens to genes in populations when exceptions to Hardy-Weinberg occur?

Although mutation rates are usually very low, geneticists have long been concerned about environmental factors that will lead to even slight increases. There are two general types of mutation, a mutation that changes a gene that makes a functional product into a gene that makes a nonfunctional product (forward mutation) and a mutation that changes a gene that makes a nonfunctional product into a gene that makes a functional product (reverse mutation). Several events can lead to a forward mutation, base change, base insertion, base deletion, etc., but a reverse mutation must correct the specific change that produced the original forward mutation. For example if a single base deletion caused the original forward mutation, then that base must be re-inserted in exactly the same place for a reverse mutation to occur. In general, forward mutations occur at a frequency that is at least 10 times that of reverse mutations. A method of estimating forward mutation rates is given in Gelehrter, Collins, and Ginsburg, 2nd ed., Chapter 4. Students will be well advised to read this chapter carefully.

If is the forward mutation rate from a functional to a nonfunctional allele, and is v the reverse mutation rate from a nonfunctional allele to a functional allele at the same locus, an equilibrium will be established between these two mutation rates that determines q, the gene frequency of the nonfunctional allele.

At equilibrium, q = /(+v)

If v is truly one tenth the frequency of , then we can assign the value 1 for v and 10 as the value for . The above equation reduces to

qequil = 10/(10+1) or 10/11 =0.90909090909

Gene frequencies for nonfunctional alleles tend to increase in the population because of recurrent mutation. They will not entirely eliminate functional alleles but they tend to replace them, and can, if no other factors are involved, reach very high frequencies.

As a possible human example of the effects of recurrent mutation consider the following. In the ABO blood group system, there are two functional alleles, A and B. Alleles A and B control transferase enzymes that connect the proper sugar molecule (glucosamine or n-acetyl glucosamine) to a common precursor substance. Most likely, B was the result of arare mutation of the A allele. O is a nonfunctional allele that recognizes no substrate, and no sugar molecule is transferred, leaving the precursor unchanged. In the ABO system, O is now the most frequent allele. If there is no selective advantage, O should continue to increase at the expense of A and B.

The derivations of the equations used to calculate the effects of recurrent mutation are shown in Figure 21. Again, if you are interested only in studying for possible test questions, this material is not required.

Assume a population of N individuals with two alleles at a locus, D with a frequency of p and d with a frequency of q. At generation 0 there will be 2Np D alleles , or 2N(1-q) D alleles, and 2Nq d alleles. Assume D mutates to d at a frequency of and that d mutates to D at a frequency of v. Assume that is 10 times as frequent as v. Then at generation 1 the number of d alleles (2Nq1) would be:

2Nq1 = 2Nq (from gen. 0) + 2N (1-q) (mutations from D to d) - 2Nqv (mutations from d to D)

This reduces to:

q1 = q + (1-q) - qv Or the change in q = q1 - q or the change in q = q + (1-q) - qv - q

At equilibrium the change in q = 0, so at equilibrium 0 = q +(1-q) -qv -q, or, qv = (1-q), or, qv = - q

This reduces to q (at equilibrium) = /(+v)

One factor assumed in the discussion of recurrent mutation was that the nonfunctional allele and the functional allele have the same selective advantage. This may be true of the ABO blood group system, but it is not usually true of autosomal recessive diseases. The disease state, by definition, is always a deleterious phenotype. In autosomal recessive diseases the phenotype is almost always the result of nonfunctional alleles in the homozygous state. If left untreated the recessive phenotype for a disease would be less fit than the heterozygote or normal homozygote. How does selection against the homozygous recessive individual affect gene frequencies in the population?

Fitness, to a geneticist, is not the same as fitness to a movie director or a sports columnist. Fitness is not measured by physical attributes, it is measured by the number of offspring produced in the next generation that survive and reproduce. In a hunting-gathering society, the most fit person may have been the near sighted male who could not go on the hunt because he would stumble and make too much noise. If he were left behind to gather fruit and berries with the women, he may have become the most fit person in the tribe. Grandchildren, great-grandchildren, etc., are the best measures of the fitness of an individual. This has alway been my favorite explanation of why so many of us are near sighted, and why society changed from hunting-gathering to agriculture. It's all population genetics!

The most fit phenotype in the population is assigned a fitness of 1. If there are two equally fit phenotypes, each is assigned a fitness of 1. Those less fit must be assigned a fitness of less than 1. The difference between 1 and the fitness value is called the selection coefficient. The relationship between fitness, w, and the selection coefficient, s, is given by the equation, w = 1-s. The textbook uses f as the symbol for fitness, although historically most geneticists reserve f as the symbol for the inbreeding coefficient and use w as the symbol for fitness.

The effect of selection against the recessive phenotype is that, no matter how little the selection coefficient, as long as s is not 0, recessive alleles will be lost at each generation until no more remain in the population. Selection tends to reduce nonfunctional recessive alleles from the population; recurrent mutation tends to create nonfunctional recessive alleles in the population. The derivations of the effects of selection against the recessive phenotype are shown if Figure 22. Again, the material in Figure 22 will not be examined in this course.

The frequency of q in generation 1, q1, = (2 x homozygote + heterozygote)/ 2 x total

q1 = [2(1-s)q2 + 2pq]/ 2(1-sq2) , and q, the change in q, = q1 - q

q = [(1-s)q2 + (1-q)q]/ (1-sq2) , which reduces to q = [-spq2]/ (1-sq2)

q = 0 only when q = 0. There will be no equilibrium until the recessive allele is eliminated.

Since mutation tends to increase nonfunctional alleles in the population, and selection against the recessive phenotype tends to remove them, is there a point where these two will reach an equilibrium where gene frequencies remain stable from generation to generation? Again, if is the mutation rate, and s is the selection coefficient, an equilibrium will be reached when

= sq2

If the fitness of the homozygous recessive individual is 0, that is, the individual with that phenotype cannot reproduce, then s equals 1 and the above equation reduces to

= q2

The disease frequency cannot go lower than the recurrent mutation rate, even if affected individuals cannot reproduce.

The derivations of these equations are shown in Figure 23.

For mutation, the change in q = - q -qv. For selection, the change in q = [-spq2]/ [1-sq2]. If they balance at an equilibrium, the net effect is that they should sum to 0.

- q - qv + ([-spq2]/[1-sq2]) = 0

To simplify calculations, we will get rid of second order variables (qv) is only 1/10 of (q) and can be eliminated. Similarly, sq2 is very small in the denominator when compared to 1, and can be eliminated. This reduces the equation to

-q - spq2 = 0 to first order magnitude.

This reduces to - q = s(1-q) q2 or (1 - q) = (1-q)sq2

At equilibrium, = sq2 to first order magnitude.

Some genes exist at a rather high frequency in the population because the heterozygote is more fit than either homozygote. The only documented example of this is sickle cell anemia in Western Africa. There are three major genotypes for the sickle cell locus, each producing a different phenotype, in West Africans, AA, or normal individuals, AS or heterozygote individuals (often called carriers), and SS individuals who will have sickle cell anemia. Without medical intervention, SS individuals will have a fitness less than 1. In the falciparum malarial environment of West Africa, AA and AS individuals get malaria, but AS individuals usually have much milder cases of the disease and usually survive while AA individuals are less likely to do so. The heterozygote is the most fit phenotype of the three. If the selection coefficient against the homozygous normal AA individual is t, and the selection coefficient against the homozygous SS individual is s, and if p is the frequency of the A allele and q the frequency of the S allele then an equilibrium will be reached in which

p = s/(s + t) and q = t/(s + t). The gene frequencies at equilibrium are determined only by the relative sizes of the selection coefficients, not by their absolute magnitudes.

The derivations of these formulas are shown in Figure 24. Again, you are not responsible for knowing how to derive these formulas.

The gene frequency of the q allele at generation 1, q1 = [2pq + 2q2(1-s)]/2[1- tp2 - sq2]

Again the change in q, q, = q1 - q and at equilibrium, q = 0

0 = [pq + (1-s)q2/ [1-tp2-sq2] Substituting (1- q) for p, this equation will reduce to:

0 = -spq + tp2 or sq = tp

When (1-q) is substituted for p or (1-p) is substituted for q, this reduces to:

q = t/(s + t) and p = q/(s + t).

Assortive mating in humans may occur to a limited degree for traits such as intelligence. In some studies, married couples have higher correlation coefficients for intelligence than do siblings. In modern western culture, we tend to marry someone who is about our own intelligence, although this is probably an over simplification. If intelligence were controlled by a single genetic locus with two alleles, S for smart and D for dumb, then three phenotypes would be possible, SS for smart persons, SD for persons with average intelligence, and DD for persons who are mentally challenged. Of course, we know that intelligence is a multifactorial trait and not a single gene trait, but it is interesting to see what happens if it were a single gene trait with assortive mating where smart persons were only allowed to mate with smart persons, average persons with average persons, and mentally challenged only with mentally challenged. Strangely enough the gene frequencies do not change, only the genotype frequencies. The results are shown in Figure 25.

Two different populations result, one smart, the other mentally challenged. Average gets lost. Assortive mating eventually results in two species being formed from one.

Gene frequencies in small isolate populations do not reflect those of the larger founding population from which they were derived because of two factors, founder effect and random genetic drift. Founder effect occurs when the population grew from a few founding individuals. A few individuals cannot represent all of the genomes of the founding population. As we discussed before, each of us is carrying from 1 to 8 mutant genes in the heterozygous state, even though we are normal. When the founding population is small, intermarriage must result even though steps are taken to avoid it. The mutations carried by the founders are in higher frequency than they would be in the general population from which the founders came. Island populations founded by pirates or shipwreck, that were isolated for several generations tend to have different gene and genotype frequencies because of founder effect. Similarly, religious isolates, where marriage outside the religion is forbidden, also have founder effects.

Even if the founders of small isolate populations had exactly the same genotypes and gene frequencies of the original parent population, gene and genotype frequencies would change because of random genetic drift. Random genetic drift occurs because a small population cannot maintain randomness. Consider a population with 10 individuals with only two alleles at a locus, D with a frequency of 0.5 and d with a frequency of 0.5. By chance alone one would expect to find 10D and 10 d gametes being passed to the next generation. But one may find 11 D and only 9 d gametes. The next generation, one could find 10 and 10 again, or could find 12 and 8. But suppose after drifting to 12 D and 8 d, by chance a really skewed sampling occurred and one got 15 D and 5 d. It would be difficult, if not impossible to get back to the original 10D and 10 d. Sampling errors in small populations are always going to occur if given enough opportunities. These errors assure that random genetic drift will always occur. Isolate populations never have the same gene and genotype frequencies as their founding populations.

It is obvious that the major difference between autosomal loci and X-linked loci in populations is that the males (usually half the population) have only one X. Males cannot have the distribution, p2, 2pq, and q2 because they have only one X, they have either the normal allele p, or the recessive allele, q. In males, gene and genotype frequencies are the same. Thus, the genotype frequencies in the male and female can never be the same. In addition, there can be no heterozygote x heterozygote mating class since there are no male heterozygotes, and as of this date females cannot mate and produce a child. X-linked traits can reach stable gene frequencies in males and females, but cannot reach Hardy-Weinberg equilibrium.

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Historical Examples

Eugenics is the science of reproducing better humans by applying the established laws of genetics or heredity.

It sprang from genetics and bears the mark of an implicit Darwinian mechanism.

They also opened new horizons for hypotheses in astronomy, genetics, anthropology.

If, then, progress was to be made in genetics, work of a different kind was required.

But a better definition, based on the results of genetics, looks at it as a mechanism, not as an external appearance.

British Dictionary definitions for genetics Expand

(functioning as sing) the branch of biology concerned with the study of heredity and variation in organisms

the genetic features and constitution of a single organism, species, or group

Word Origin and History for genetics Expand

1872, "laws of origination;" see genetic + -ics. A coinage of English biologist William Bateson (1861-1926). Meaning "study of heredity" is from 1891.

genetics in Medicine Expand

genetics genetics (j-nt'ks) n. The branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the variation of inherited traits among similar or related organisms.

genetics in Science Expand

genetics in Culture Expand

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Genetics | Define Genetics at Dictionary.com

Population genetics is the study of the distribution and change in frequency of alleles within populations, and as such it sits firmly within the field of evolutionary biology. The main processes of evolution are natural selection, genetic drift, gene flow, mutation, and genetic recombination and they form an integral part of the theory that underpins population genetics. Studies in this branch of biology examine such phenomena as adaptation, speciation, population subdivision, and population structure.

Population genetics was a vital ingredient in the emergence of the modern evolutionary synthesis. Its primary founders were Sewall Wright, J. B. S. Haldane and Ronald Fisher, who also laid the foundations for the related discipline of quantitative genetics.

Traditionally a highly mathematical discipline, modern population genetics encompasses theoretical, lab and field work. Computational approaches, often utilising coalescent theory, have played a central role since the 1980s.

Population genetics began as a reconciliation of Mendelian inheritance and biostatistics models. A key step was the work of the British biologist and statistician Ronald Fisher. In a series of papers starting in 1918 and culminating in his 1930 book The Genetical Theory of Natural Selection, Fisher showed that the continuous variation measured by the biometricians could be produced by the combined action of many discrete genes, and that natural selection could change allele frequencies in a population, resulting in evolution. In a series of papers beginning in 1924, another British geneticist, J.B.S. Haldane worked out the mathematics of allele frequency change at a single gene locus under a broad range of conditions. Haldane also applied statistical analysis to real-world examples of natural selection, such as the Peppered moth evolution and industrial melanism, and showed that selection coefficients could be larger than Fisher assumed, leading to more rapid adaptive evolution.[1][2]

The American biologist Sewall Wright, who had a background in animal breeding experiments, focused on combinations of interacting genes, and the effects of inbreeding on small, relatively isolated populations that exhibited genetic drift. In 1932, Wright introduced the concept of an adaptive landscape and argued that genetic drift and inbreeding could drive a small, isolated sub-population away from an adaptive peak, allowing natural selection to drive it towards different adaptive peaks.

The work of Fisher, Haldane and Wright founded the discipline of population genetics. This integrated natural selection with Mendelian genetics, which was the critical first step in developing a unified theory of how evolution worked.[1][2]John Maynard Smith was Haldane's pupil, whilst W.D. Hamilton was heavily influenced by the writings of Fisher. The American George R. Price worked with both Hamilton and Maynard Smith. American Richard Lewontin and Japanese Motoo Kimura were heavily influenced by Wright.

The mathematics of population genetics were originally developed as the beginning of the modern evolutionary synthesis. According to Beatty (1986), population genetics defines the core of the modern synthesis. In the first few decades of the 20th century, most field naturalists continued to believe that Lamarckian and orthogenic mechanisms of evolution provided the best explanation for the complexity they observed in the living world. However, as the field of genetics continued to develop, those views became less tenable.[3] During the modern evolutionary synthesis, these ideas were purged, and only evolutionary causes that could be expressed in the mathematical framework of population genetics were retained.[4] Consensus was reached as to which evolutionary factors might influence evolution, but not as to the relative importance of the various factors.[4]

Theodosius Dobzhansky, a postdoctoral worker in T. H. Morgan's lab, had been influenced by the work on genetic diversity by Russian geneticists such as Sergei Chetverikov. He helped to bridge the divide between the foundations of microevolution developed by the population geneticists and the patterns of macroevolution observed by field biologists, with his 1937 book Genetics and the Origin of Species. Dobzhansky examined the genetic diversity of wild populations and showed that, contrary to the assumptions of the population geneticists, these populations had large amounts of genetic diversity, with marked differences between sub-populations. The book also took the highly mathematical work of the population geneticists and put it into a more accessible form. Many more biologists were influenced by population genetics via Dobzhansky than were able to read the highly mathematical works in the original.[5]

Fisher and Wright had some fundamental disagreements about the relative roles of selection and drift.[6]

In Great Britain E.B. Ford, the pioneer of ecological genetics, continued throughout the 1930s and 1940s to demonstrate the power of selection due to ecological factors including the ability to maintain genetic diversity through genetic polymorphisms such as human blood types. Ford's work, in collaboration with Fisher, contributed to a shift in emphasis during the course of the modern synthesis towards natural selection over genetic drift.[1][2][7][8]

Recent studies of eukaryotic transposable elements, and of their impact on speciation, point again to a major role of nonadaptive processes such as mutation and genetic drift.[9] Mutation and genetic drift are also viewed as major factors in the evolution of genome complexity.[10]

Biston betularia f. carbonaria is the black-bodied form of the peppered moth.

Population genetics is the study of the frequency and interaction of alleles and genes in populations.[11] A sexual population is a set of organisms in which any pair of members can breed freely together. This implies that all members belong to the same species and are located near each other.[12]

For example, all of the moths of the same species living in an isolated forest are a population. A gene in this population may have several alternate forms, which account for variations between the phenotypes of the organisms. An example might be a gene for coloration in moths that has two alleles: black and white. A gene pool is the complete set of alleles for a gene in a single population; the allele frequency for an allele is the fraction of the genes in the pool that is composed of that allele (for example, what fraction of moth coloration genes are the black allele). Evolution occurs when there are changes in the frequencies of alleles within a population; for example, the allele for black color in a population of moths becoming more common.

Natural selection, which includes sexual selection, is the fact that some traits make it more likely for an organism to survive and reproduce. Population genetics describes natural selection by defining fitness as a propensity or probability of survival and reproduction in a particular environment. The fitness is normally given by the symbol w=1-s where s is the selection coefficient. Natural selection acts on phenotypes, or the observable characteristics of organisms, but the genetically heritable basis of any phenotype which gives a reproductive advantage will become more common in a population (see allele frequency). In this way, natural selection converts differences in fitness into changes in allele frequency in a population over successive generations.

Before the advent of population genetics, many biologists doubted that small differences in fitness were sufficient to make a large difference to evolution.[5] Population geneticists addressed this concern in part by comparing selection to genetic drift. Selection can overcome genetic drift when s is greater than 1 divided by the effective population size. When this criterion is met, the probability that a new advantageous mutant becomes fixed is approximately equal to 2s.[13][14] The time until fixation of such an allele depends little on genetic drift, and is approximately proportional to log(sN)/s.[15]

Natural selection will only cause evolution if there is enough genetic variation in a population. Before the discovery of Mendelian genetics, one common hypothesis was blending inheritance. But with blending inheritance, genetic variance would be rapidly lost, making evolution by natural or sexual selection implausible. The HardyWeinberg principle provides the solution to how variation is maintained in a population with Mendelian inheritance. According to this principle, the frequencies of alleles (variations in a gene) will remain constant in the absence of selection, mutation, migration and genetic drift.[16] The HardyWeinberg "equilibrium" refers to this stability of allele frequencies over time.

A second component of the HardyWeinberg principle concerns the effects of a single generation of random mating. In this case, the genotype frequencies can be predicted from the allele frequencies. For example, in the simplest case of a single locus with two alleles: the dominant allele is denoted A and the recessive a and their frequencies are denoted by p and q; freq(A)=p; freq(a)=q; p+q=1. If the genotype frequencies are in HardyWeinberg proportions resulting from random mating, then we will have freq(AA)=p2 for the AA homozygotes in the population, freq(aa)=q2 for the aa homozygotes, and freq(Aa)=2pq for the heterozygotes.

Genetic drift is a change in allele frequencies caused by random sampling.[17] That is, the alleles in the offspring are a random sample of those in the parents.[18] Genetic drift may cause gene variants to disappear completely, and thereby reduce genetic variability. In contrast to natural selection, which makes gene variants more common or less common depending on their reproductive success,[19] the changes due to genetic drift are not driven by environmental or adaptive pressures, and may be beneficial, neutral, or detrimental to reproductive success.

The effect of genetic drift is larger for alleles present in few copies than when an allele is present in many copies. Scientists wage vigorous debates over the relative importance of genetic drift compared with natural selection. Ronald Fisher held the view that genetic drift plays at the most a minor role in evolution, and this remained the dominant view for several decades. In 1968 Motoo Kimura rekindled the debate with his neutral theory of molecular evolution which claims that most of the changes in the genetic material are caused by neutral mutations and genetic drift.[20] The role of genetic drift by means of sampling error in evolution has been criticized by John H Gillespie[21] and Will Provine,[22] who argue that selection on linked sites is a more important stochastic force.

The population genetics of genetic drift are described using either branching processes or a diffusion equation describing changes in allele frequency.[23] These approaches are usually applied to the Wright-Fisher and John Moran models of population genetics. Assuming genetic drift is the only evolutionary force acting on an allele, after t generations in many replicated populations, starting with allele frequencies of p and q, the variance in allele frequency across those populations is

Mutation is the ultimate source of genetic variation in the form of new alleles. Mutation can result in several different types of change in DNA sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning. Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.[25]

Mutations can involve large sections of DNA becoming duplicated, usually through genetic recombination.[26] These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years.[27] Most genes belong to larger families of homologous shared ancestry.[28] Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.[29][30] Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties.[31] For example, the human eye uses four genes to make structures that sense light: three for the cone cell which produce color vision and one for the rod cell which produces night vision; all four arose from a single ancestral gene.[32] Another advantage of duplicating a gene (or even an entire genome) is that this increases redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function.[33][34] Other types of mutation occasionally create new genes from previously noncoding DNA.[35][36]

In addition to being a major source of variation, mutation may also function as a mechanism of evolution when there are different probabilities at the molecular level for different mutations to occur, a process known as mutation bias.[37] If two genotypes, for example one with the nucleotide G and another with the nucleotide A in the same position, have the same fitness, but mutation from G to A happens more often than mutation from A to G, then genotypes with A will tend to evolve.[38] Different insertion vs. deletion mutation biases in different taxa can lead to the evolution of different genome sizes.[39][40] Developmental or mutational biases have also been observed in morphological evolution.[41][42] For example, according to the phenotype-first theory of evolution, mutations can eventually cause the genetic assimilation of traits that were previously induced by the environment.[43][44]

Mutation bias effects are superimposed on other processes. If selection would favor either one out of two mutations, but there is no extra advantage to having both, then the mutation that occurs the most frequently is the one that is most likely to become fixed in a population.[45][46] Mutations leading to the loss of function of a gene are much more common than mutations that produce a new, fully functional gene. Most loss of function mutations are selected against. But when selection is weak, mutation bias towards loss of function can affect evolution.[47] For example, pigments are no longer useful when animals live in the darkness of caves, and tend to be lost.[48] This kind of loss of function can occur because of mutation bias, and/or because the function had a cost, and once the benefit of the function disappeared, natural selection leads to the loss. Loss of sporulation ability in a bacterium during laboratory evolution appears to have been caused by mutation bias, rather than natural selection against the cost of maintaining sporulation ability.[49] When there is no selection for loss of function, the speed at which loss evolves depends more on the mutation rate than it does on the effective population size,[50] indicating that it is driven more by mutation bias than by genetic drift.

Due to the damaging effects that mutations can have on cells, organisms have evolved mechanisms such as DNA repair to remove mutations.[51] Therefore, the optimal mutation rate for a species may be trade-off between costs of a high mutation rate, such as deleterious mutations, and the metabolic costs of maintaining systems to reduce the mutation rate, such as DNA repair enzymes.[52] Viruses that use RNA as their genetic material have rapid mutation rates,[53] which can be an advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.[54]

Gene flow is the exchange of genes between populations, which are usually of the same species.[55] Examples of gene flow within a species include the migration and then breeding of organisms, or the exchange of pollen. Gene transfer between species includes the formation of hybrid organisms and horizontal gene transfer.

Migration into or out of a population can change allele frequencies, as well as introducing genetic variation into a population. Immigration may add new genetic material to the established gene pool of a population. Conversely, emigration may remove genetic material. Population genetic models can be used to reconstruct the history of gene flow between populations.[56]

As barriers to reproduction between two diverging populations are required for the populations to become new species, gene flow may slow this process by spreading genetic differences between the populations. Gene flow is hindered by mountain ranges, oceans and deserts or even man-made structures such as the Great Wall of China, which has hindered the flow of plant genes.[57]

Depending on how far two species have diverged since their most recent common ancestor, it may still be possible for them to produce offspring, as with horses and donkeys mating to produce mules.[58] Such hybrids are generally infertile, due to the two different sets of chromosomes being unable to pair up during meiosis. In this case, closely related species may regularly interbreed, but hybrids will be selected against and the species will remain distinct. However, viable hybrids are occasionally formed and these new species can either have properties intermediate between their parent species, or possess a totally new phenotype.[59] The importance of hybridization in creating new species of animals is unclear, although cases have been seen in many types of animals,[60] with the gray tree frog being a particularly well-studied example.[61]

Hybridization is, however, an important means of speciation in plants, since polyploidy (having more than two copies of each chromosome) is tolerated in plants more readily than in animals.[62][63] Polyploidy is important in hybrids as it allows reproduction, with the two different sets of chromosomes each being able to pair with an identical partner during meiosis.[64] Polyploids also have more genetic diversity, which allows them to avoid inbreeding depression in small populations.[65]

Because of physical barriers to migration, along with limited tendency for individuals to move or spread (vagility), and tendency to remain or come back to natal place (philopatry), natural populations rarely all interbreed as convenient in theoretical random models (panmixy) (Buston et al., 2007). There is usually a geographic range within which individuals are more closely related to one another than those randomly selected from the general population. This is described as the extent to which a population is genetically structured (Repaci et al., 2007). Genetic structuring can be caused by migration due to historical climate change, species range expansion or current availability of habitat.

Horizontal gene transfer is the transfer of genetic material from one organism to another organism that is not its offspring; this is most common among bacteria.[66] In medicine, this contributes to the spread of antibiotic resistance, as when one bacteria acquires resistance genes it can rapidly transfer them to other species.[67] Horizontal transfer of genes from bacteria to eukaryotes such as the yeast Saccharomyces cerevisiae and the adzuki bean beetle Callosobruchus chinensis may also have occurred.[68][69] An example of larger-scale transfers are the eukaryotic bdelloid rotifers, which appear to have received a range of genes from bacteria, fungi, and plants.[70]Viruses can also carry DNA between organisms, allowing transfer of genes even across biological domains.[71] Large-scale gene transfer has also occurred between the ancestors of eukaryotic cells and prokaryotes, during the acquisition of chloroplasts and mitochondria.[72]

Basic models of population genetics consider only one gene locus at a time. In practice, epistatic and linkage relationships between loci may also be important.

Because of epistasis, the phenotypic effect of an allele at one locus may depend on which alleles are present at many other loci. Selection does not act on a single locus, but on a phenotype that arises through development from a complete genotype.

According to Lewontin (1974), the theoretical task for population genetics is a process in two spaces: a "genotypic space" and a "phenotypic space". The challenge of a complete theory of population genetics is to provide a set of laws that predictably map a population of genotypes (G1) to a phenotype space (P1), where selection takes place, and another set of laws that map the resulting population (P2) back to genotype space (G2) where Mendelian genetics can predict the next generation of genotypes, thus completing the cycle. Even leaving aside for the moment the non-Mendelian aspects of molecular genetics, this is clearly a gargantuan task. Visualizing this transformation schematically:

(adapted from Lewontin 1974, p.12). XD

T1 represents the genetic and epigenetic laws, the aspects of functional biology, or development, that transform a genotype into phenotype. We will refer to this as the "genotype-phenotype map". T2 is the transformation due to natural selection, T3 are epigenetic relations that predict genotypes based on the selected phenotypes and finally T4 the rules of Mendelian genetics.

In practice, there are two bodies of evolutionary theory that exist in parallel, traditional population genetics operating in the genotype space and the biometric theory used in plant and animal breeding, operating in phenotype space. The missing part is the mapping between the genotype and phenotype space. This leads to a "sleight of hand" (as Lewontin terms it) whereby variables in the equations of one domain, are considered parameters or constants, where, in a full-treatment they would be transformed themselves by the evolutionary process and are in reality functions of the state variables in the other domain. The "sleight of hand" is assuming that we know this mapping. Proceeding as if we do understand it is enough to analyze many cases of interest. For example, if the phenotype is almost one-to-one with genotype (sickle-cell disease) or the time-scale is sufficiently short, the "constants" can be treated as such; however, there are many situations where it is inaccurate.

If all genes are in linkage equilibrium, the effect of an allele at one locus can be averaged across the gene pool at other loci. In reality, one allele is frequently found in linkage disequilibrium with genes at other loci, especially with genes located nearby on the same chromosome. Recombination breaks up this linkage disequilibrium too slowly to avoid genetic hitchhiking, where an allele at one locus rises to high frequency because it is linked to an allele under selection at a nearby locus. This is a problem for population genetic models that treat one gene locus at a time. It can, however, be exploited as a method for detecting the action of natural selection via selective sweeps.

In the extreme case of primarily asexual populations, linkage is complete, and different population genetic equations can be derived and solved, which behave quite differently from the sexual case.[73] Most microbes, such as bacteria, are asexual. The population genetics of microorganisms lays the foundations for tracking the origin and evolution of antibiotic resistance and deadly infectious pathogens. Population genetics of microorganisms is also an essential factor for devising strategies for the conservation and better utilization of beneficial microbes (Xu, 2010).

Read more:
Population genetics - Wikipedia, the free encyclopedia

The History of the Highland Breed

Highland cattle are unique among British breeds of cattle in that they have remained virtually unchanged since records began. The western Highlands and Islands of Scotland have always been regarded as their true home where they formed a vital part of the economy. It was this hardy Highland breed that first brought commerce to the Highlands of Scotland. Arguably it could be said that cattle brought about the beginning of end of clan system and the traditional Scottish Highland way of life.

There are accounts of the droving trade in Highland cattle as early as 1359 and it was to continue well into the nineteenth century. This highly lucrative trade was at its height from 1760 to 1820. At that time, tens of thousands of 2-3 year old cattle left the Highlands and Islands throughout the summer and autumn and made their long and treacherous journey south to the great cattle fayres in Muir of Ord in the northeast Highlands and then they went on to, gathering in numbers, to the major fayres in the towns of Crieff, Falkirk and Dumbarton in the southern Highlands and then travelled a further three hundred miles south, across the border to be fattened on the lush pastures of England. Eventually, these cattle were sold as prime beef in the ever-expanding cities such as Manchester and London.

To quote the well known writer Daniel Defoe in 1724 referring to the cattle of the Highlands of Scotland These Scots runts as they call them, coming out of the cold barren mountains of the Highlands of Scotland, feed so eagerly on the rich pastures of its marshes that they thus in an unusual manner grow monstrously fat and the beef is so delicious for taste that the inhabitants prefer them to the English cattle. Another well known writer of the same period, Thomas Hurtley in 1786, when referring to the cattle of the West Highlands was quoted as saying To say the truth, when fattened on these rich old pastures there is no beef equal to them in fineness either of grain or flavour.

In order to reach their destination good feet and legs were essential. The cattle were expected to travel between ten and fifteen miles in one day over the roughest terrain and even on occasion, swim rivers that had swollen after days of torrential rain.

The drovers were every bit as hardy as the cattle under their care. They slept with their droves at night just in case they should stray or be stolen in the dead of night by the likes of Rob Roy MacGregor or by those other renowned cattle thieves the Loch Earnhead Stewarts of Ardvorlich to name but a few. These hardy drovers would also drive the hardest of bargains when selling their cattle to the English dealers at the annual fayres. It was the descendants of those tough Highland drovers that helped to establish the great cattle trails of the western United States and Australia, through the long journeys to the rail heads during the nineteenth century, at a time when only the very toughest men and cattle would survive. One of the earliest pioneers in America to develop commercial cattle droving was called John Chisholm whose forefathers once droved cattle from Skye to the Lowlands. And Australian readers may recognize the line from 1889 For the drovers life has pleasures that the townsfolk never know which was written by the son of Scottish immigrants.

What is it about this great Highland breed of cattle that has allowed them to endure over the centuries not only in their homeland but also throughout the world? They can be ideal where the terrain and climatic conditions demand a breed which can thrive on low quality vegetation whilst enduring long and hard winters and rearing calves every year well into the dams teens. If cared for correctly the quality of the beef has without question, as Thomas Hurtley put it there is no equal in fineness of grain or flavour. It is this fact about the Highland Breed that has attracted beef producers throughout the world today, that is to say those producers who listen to the customer. Todays consumer has a far greater awareness of how they want their beef to taste and a far greater interest in the manner in which it is reared. There can be few breeds of cattle which lend themselves better to a grass based system of production, whether in the breeding herd or finishing system. The Highlander is the master of utilising low quality roughage and turning it into the finest beef. This has been proven over the centuries.

There are many reasons why Highland genetics should be used to improve the efficiency in beef production throughout the world today:

*improvements in feed conversion

*long productive lives lowering replacement costs

*utilisation of land that was once considered unsuitable for livestock production

*improvement in the quality of the end product

. Which is to say, beef that is so delicious for taste

Why not let the Hardy Highlander help you whatever your system?

For more information, see the Gallery pages.

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The History of the Highland Breed | Scottish Genetics

Woman's genetic counselors can help you understand your genetic risks for certain diseases, such as cancer, or for passing an existing disease on to a child. Genetic counseling can lead to the earliest detection of diseases you or your baby may be at-risk of developing.

If you are concerned about diseases that run in your family, talk to you doctor about genetic counseling.

Genetics is the study of heredity, the process in which parents pass certaingenesonto their children. A person's physical appearance height, hair color, skin color and eye color are determined by genes. Other characteristics affected by heredity include:

Humans have an estimated 100,000 different genes that contain specific genetic information, and these genes are located on stick-like structures in the nucleus of cells called chromosomes.

When a gene is abnormal, or when entire chromosomes are left off or duplicated, defects in the structure or function of the body's organs or systems can occur. These mutations or abnormalities can result in disorders such as cystic fibrosis, a recessive genetic disease, or Down syndrome, an abnormality that occurs when a baby receives three No. 21 chromosomes.

Each person has more than 100,000 genes that direct the growth and development of every part of the body. These genes carry instructions for dominant or recessive traits that can be passed on to a child.

People who might be especially interested in genetic counseling for pregnancy include:

Women who might be especially interested in genetic testing regarding disease specific genes include:

Should it be necessary, Woman's genetics team,which includes geneticist,Dr. Duane Superneau,can work with your oncologists and breast surgeons in determining a need forgenetic testing and your course of treatment.

Visit link:
Genetic Counseling | Woman's Hospital | Baton Rouge, LA

The Department of Genetics provides a supportive and unique environment for students to understand the full spectrum of molecular, evolutionary, and population genetics. Our major prepares students for careers in biomedical-related fields, as well as teaching, academic research, and the pharmaceutical and biotechnology industry. And, our students are competitive for admission to the top medical and professional schools and graduate programs in the country.

After taking introductory courses in genetics and evolutionary biology, majors may choose from a variety of upper level Genetics courses. Depending on the interests and career goals of a particular student, our majors can also satisfy requirements for major electives by taking upper level courses in other departments. In addition to lecture courses, majors can choose from several different laboratory courses, which focus on molecular genetics, evolutionary genetics, or genomics. The Department strongly encourages undergraduates to pursue independent research with one of our faculty. In addition to the high value placed on research by medical and graduate school admissions committees, an undergraduate research experience serves to consolidate all your Genetics training into a single keystone experience.

All details of the Genetics major are available at http://www.genetics.uga.edu/undergrad.html, and information about the department, including a list of faculty research interests, is available at http://www.genetics.uga.edu.

Originally posted here:
Genetics - B.S. - University of Georgia

"Half of your DNA is determined by your mother's side, and half is by your father. So, if you seem to look exactly like your mother, perhaps some DNA that codes for your body and how your organs run was copied from your father's genes."

So close, yet so far. This quote, taken from a high school student's submission in a national essay contest, represents just one of countless misconceptions many people have about the basic nature of heredity and how our bodies read the instructions stored in our genetic material (Shaw et al. 2008). Although it is true that half of our genome is inherited from our mother and half from our father, it is certainly not the case that only some of our cells receive instructions from only some of our DNA. Rather, every diploid, nucleated cell in our body contains a full complement of chromosomes, and our specific cellular phenotypes are the result of complex patterns of gene expression and regulation.

In fact, it is through this dynamic regulation of gene expression that organismal complexity is determined. For example, when the first draft of the human genome was published in 2003, scientists were surprised to find that sequence analysis revealed only around 25,000 genes, instead of the 50,000 to 100,000 genes originally hypothesized. Clues from studies examining the genomic structure of a variety of organisms suggest that much of human uniqueness lies not in our number of genes, but instead in our regulatory control over when and where certain genes are expressed.

Additional examination of different organisms has revealed that all genomes are more complex and dynamic than previously thought. Thus, the central dogma proposed by Francis Crick as early as 1958 that DNA encodes RNA, which is translated into protein is now considered overly simplistic. Today, scientists know that beyond the three types of RNA that make the central dogma possible (mRNA, tRNA, and rRNA), there are many additional varieties of functional RNA within cells, many of which serve a number of known (and unknown) functions, including regulation of gene expression. Understanding how the structure of these and other nucleic acids belies their function at both the macroscopic and microscopic levels, and discovering how that understanding can be manipulated, is the essence of where genetics and molecular biology converge.

Detailed comparative analysis of different organisms' genomes has also shed light on the genetics of evolutionary history. Using molecular approaches, information about mutation rates, and other tools, scientists continue to add more detail to phylogenetic trees, which tell us about the relationships between the marvelous variety of organisms that have existed throughout the planet's history. Examining how different processes shape populations through the culling or maintenance of deleterious or beneficial alleles lies at the heart of the field of population genetics.

Within a population, beneficial alleles are typically maintained through positive natural selection, while alleles that compromise fitness are often removed via negative selection. Some detrimental alleles may remain, however, and a number of these alleles are associated with disease. Many common human diseases, such as asthma, cardiovascular disease, and various forms of cancer, are complex-in other words, they arise from the interaction between multiple alleles at different genetic loci with cues from the environment. Other diseases, which are significantly less prevalent, are inherited. For instance, phenylketonuria (PKU) was the first disease shown to have a recessive pattern of inheritance. Other conditions, like Huntington's disease, are associated with dominant alleles, while still other disorders are sex-linked-a concept that was first identified through studies involving mutations in the common fruit fly. Still other diseases, like Down syndrome, are linked to chromosomal aberrations that can be identified through cytogenetic techniques that examine chromosome structure and number.

Our understanding in all these fields has blossomed in recent years. Thanks to the merger of molecular biology techniques with improved knowledge of genetics, scientists are now able to create transgenic organisms that have specific characters, test embryos for a variety of traits in vitro, and develop all manner of diagnostic tests capable of identifying individuals at risk for particular disorders. This interplay between genetics and society makes it crucial for all of us to grasp the science behind these techniques in order to better inform our decisions at the doctor, at the grocery store, and at home.

As we seek to cultivate this understanding of modern genetics, it is critical to remember that the misconceptions expressed in the aforementioned essay are the same ones that many individuals carry with them. Thus, when working together, faculty and students need to explore not only what we know about genetics, but also what data and evidence support these claims. Only when we are equipped with the ability to reach our own conclusions will our misconceptions be altered.

-Kenna Shaw, Ph.D

Image: Mehau Kulyk/Science Photo Library/Getty Images.

Shaw, K. (2008) Genetics. Nature Education 2(10):1

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Genetics | Learn Science at Scitable

The recent sequencing of the human genome has accelerated scientific discoveries in genetics related to medicine and animal and plant science. Research universities in Georgia, supported by government funding and collaborations with private industry, conduct leading-edge research that contributes to improved prevention, diagnosis, and treatment of genetically caused diseases. The Georgia Research Alliance, a university, business, and government partnership, has been a key supporter of genetics research through eminent scholars, research laboratories and equipment, and technology incubators. Newborn Genetics Screening The state of Georgia has paid for newborn genetics screening since 1978. The program, developed in collaboration with the Emory University School of Medicine's Department of Human Genetics and Genetics Laboratory, tests all Georgia newborns for thirteen inherited diseases, including metabolic diseases. Emory, located in Atlanta, is one of the nation's leading research and treatment centers for inherited diseases, including lysosomal enzyme diseases, fragile X syndrome, and Down syndrome. Emory scientists are leaders in developing new enzyme replacement therapies for children born with Gaucher disease and Fabry disease, screening and treatment for maple syrup urine disease, and FISH technology (fluorescence in situ hybridization, which allows physicians to look for chromosomal abnormalities under a microscope). Emory's large staff of genetics counselors works with parents and prospective parents at centers throughout the state. In addition, genetics counseling and screening to predict adult cancers has developed rapidly since scientists discovered altered genes that increase the risk of breast, ovarian, and colon cancers. University Genetics Research Several of Georgia's research universities have extensive research centers focused on genetics. The Department of Human Genetics at the Emory University School of Medicine includes both laboratory research and clinical treatment programs in one of the largest academic genetics departments in the nation. Emory has the world's largest research program on fragile X syndrome to be funded by the National Institutes of Health (NIH). The gene responsible for fragile X syndrome, the most common cause of inherited mental retardation, was discovered by Emory professor Steven T. Warren, who led an international team of scientists. Warren and his team also have developed screening techniques and are working on potential new therapies for fragile X syndrome, which affects 3,500 individuals in Georgia either directly or as carriers. Emory geneticist Stephanie Sherman's discovery of what is known as the "Sherman Paradox," in which genetic diseases caused by the triplet repeat of amino acids are not passed on to offspring with the usual probabilities common among most genetic disorders, has been invaluable in helping physicians predict risk for these genetic diseases. Through support from the NIH, scientists at Emory and the Centers for Disease Control and Prevention have conducted sixteen years of research on the causes and clinical consequences of Down syndrome through the Atlanta Down Syndrome Project. All Atlanta-area newborns with Down syndrome and their parents are eligible to participate in the project. In 2000 the NIH expanded the Atlanta project into the National Down Syndrome Project by adding five other research centers (in Arkansas, California, Iowa, New Jersey, and New York). The Department of Genetics at the University of Georgia (UGA) in Athens includes many faculty who teach genetics to undergraduate and graduate students. Graduate research and training includes molecular genetics, evolutionary biology, and genomics. Four genetics faculty members are also members of the prestigious National Academy of Sciences.

The UGA Center for Applied Genetic Technologies (CAGT) brings together diverse expertise in plant and animal genomics, DNA markers, and transformation (a process of genetic alteration) and provides state-of-the-art facilities and instrumentation. Within CAGT are research labs and the Georgia BioBusiness Center incubator, which supports start-up companies in the biosciences by providing them access to management expertise and sophisticated instrumentation.

Link:
Genetics in Georgia | New Georgia Encyclopedia

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocytic cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular cellular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer."[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim (see Figure 3) or can appear somewhat eczematous. They often ulcerate (see Figure 3). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI's website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

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Figure 2. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

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Figure 3. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

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Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

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Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer." With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a person's skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowlers solution and Bells asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenatetreated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

However, the effect of arsenic on skin cancer risk may be more complex than previously thought. Evidence from in vivo models indicate that arsenic, alone or in combination with itraconazole, can inhibit the hedgehog pathway in cells with wild-type or mutated Smoothened by binding to GLI2 proteins; in this way, these drugs demonstrated inhibition of BCC growth in these animal models.[26,27] Additionally, the effect of arsenic on skin cancer risk may be modified by certain variants in nucleotide excision repair genes (xeroderma pigmentosum [XP] types A and D).[28]

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[29] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[30]

Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[31-33] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[34,35] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[31,36] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[37] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[38-43] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[44-47] however, other studies have contradicted this finding.[48-51] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[52] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[53,54] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[55,56] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[57] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[58] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[59]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[60,61] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[62] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[60,63]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[64] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[59,65] The clinical features of BCNS differ more among families than within families.[66] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[67-69]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[64] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[70] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[71-75] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[76]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[77-80] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[80] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[81,82] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[74,78,83] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[84] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[85]

Other associated benign neoplasms include gastric hamartomatous polyps,[86] congenital pulmonary cysts,[87] cardiac fibromas,[88] meningiomas,[89-91] craniopharyngiomas,[92] fetal rhabdomyomas,[93] leiomyomas,[94] mesenchymomas,[95] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[96-98] Radiation therapy of medulloblastomas may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[73,74,94]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon-like lesions, while larger lesions demonstrate more classic cutaneous features.[99] Nonpigmented BCCs are more common than pigmented lesions.[100] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[78,83] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[100] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[64] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[78,101,102] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[102] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[78,94] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% confidence interval [CI], 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[103]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[74,78,83,104] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[105,106] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[107] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[74,89] Other reported malignancies include ovarian carcinoma,[108] ovarian fibrosarcoma,[109,110] astrocytoma,[111] melanoma,[112] Hodgkin disease,[113,114] rhabdomyosarcoma,[115] and undifferentiated sinonasal carcinoma.[116]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[117] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[70] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[76,118] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[117,119] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[117] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[120] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[78,121] with higher rates of occurrence in young females.[122]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[83] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[123]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[124,125] fused, splayed or bifid ribs;[126] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[82] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[127]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[128] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[68,69] These mutations were first identified in individuals with childhood medulloblastoma,[129] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[68] SUFU mutations may also be associated with an increased predisposition to meningioma.[91,130] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare genetic disorder associated with BCC, has been outlined in three case series in the literature.[131-133] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[131] Development of BCC occurs in the fourth decade.[131] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[131,133] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[131,132]

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[134-136] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[137] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[138]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[134] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[139] a twisted/flattened appearance of the hair shaft on electron microscopy,[140] and increased hair shaft diameter on polarizing light microscopy.[136] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[136] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[141,142]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[143] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[144] One report cites an incidence of BCC of 44% by age 55 years in this population.[145] Individuals who inherit two EBS mutations may present with a more severe phenotype.[146] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[143] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[147]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for nonmelanoma skin cancers recommends complete skin examinations every 6 to 12 months for life.[158]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer. For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[159] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[159] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[159-161] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with XP, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[162] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

Treatment of individual basal cell cancers in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[163,164] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[78] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[163,164]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[165] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy) : 4

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[166] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[167] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer, annual incidence estimates range from 1 million to 3.5 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer. (Refer to the Sun exposure section in the Basal Cell Carcinoma section of this summary for more information.) This section focuses on sun exposure and increased risk of cutaneous SCC.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation had an increased risk of SCC at the site of previous radiation (OR, 2.94) as compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of nonmelanoma skin cancers in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

The influence of arsenic on the risk of nonmelanoma skin cancer is discussed in detail in the Other environmental factors section in the Basal Cell Carcinoma section of this summary. Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[31,32] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[33] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[33,34] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[35] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[36]

Immunosuppression also contributes to the formation of nonmelanoma skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[37-40] Nonmelanoma skin cancers in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[41,42] Additionally, there is a high risk of second SCCs.[43,44] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[43] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[37,45,46] The risk appears to be highest in geographic areas with high UV exposure.[46] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[47] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[37] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[48]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[49] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the middle of the sixth decade of life.[26,50-54]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in first-degree relatives (FDRs). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[55,56] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[57] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

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Genetics of Skin Cancer - National Cancer Institute

Human beings have cells with 46 chromosomes -- 2 chromosomes that determine what sex they are (X and Y chromosomes), and 22 pairs of nonsex (autosomal) chromosomes. Males are "46,XY" and females are "46,XX." The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of DNA called genes, which carry the information needed by your body to make certain proteins.

Each pair of autosomal chromosomes contains one chromosome from the mother and one from the father. Each chromosome in a pair carries basically the same information; that is, each chromosome pair has the same genes. Sometimes there are slight variations of these genes. These variations occur in less than 1% of the DNA sequence. The genes that have these variations are called alleles.

Some of these variations can result in a gene that is abnormal. An abnormal gene may lead to an abnormal protein or an abnormal amount of a normal protein. In a pair of autosomal chromosomes, there are two copies of each gene, one from each parent. If one of these genes is abnormal, the other one may make enough protein so that no disease develops. When this happens, the abnormal gene is called recessive, and the other gene in the pair is called dominant. Recessive genes are said to be inherited in an autosomal recessive pattern.

However, if only one abnormal gene is needed to produce a disease, it leads to a dominant hereditary disorder. In the case of a dominant disorder, if one abnormal gene is inherited from mom or dad, the child will likely show the disease.

A person with one abnormal gene is called heterozygous for that gene. If a child receives an abnormal recessive disease gene from both parents, the child will show the disease and will be homozygous (or compound heterozygous) for that gene.

GENETIC DISORDERS

Almost all diseases have a genetic component. However, the importance of that component varies. Disorders in which genes play an important role (genetic diseases) can be classified as:

A single-gene disorder (also called Mendelian disorder) is caused by a defect in one particular gene. Single gene defects are rare. But since there are about 4,000 known single gene disorders, their combined impact is significant.

Single-gene disorders are characterized by how they are passed down in families. There are six basic patterns of single gene inheritance:

The observed effect of a gene (the appearance of a disorder) is called the phenotype.

In autosomal dominant inheritance, the abnormality or abnormalities usually appear in every generation. Each time an affected woman has a child, that child has a 50% chance of inheriting the disease.

People with one copy of a recessive disease gene are called carriers. Carriers usually don't have symptoms of the disease. But, the gene can often be found by sensitive laboratory tests.

In autosomal recessive inheritance, the parents of an affected individual may not show the disease (they are carriers). On average, the chance that carrier parents could have children who develop the disease is 25% with each pregnancy. Male and female children are equally likely to be affected. For a child to have symptoms of an autosomal recessive disorder, the child must receive the abnormal gene from both parents. Because most recessive disorders are rare, a child is at increased risk of a recessive disease if the parents are related. Related individuals are more likely to have inherited the same rare gene from a common ancestor.

In X-linked recessive inheritance, the chance of getting the disease is much higher in males than females. Since the abnormal gene is carried on the X (female) chromosome, males do not transmit it to their sons (who will receive the Y chromosome from their fathers). However, they do transmit it to their daughters. In females, the presence of one normal X chromosome masks the effects of the X chromosome with the abnormal gene. So, almost all of the daughters of an affected man appear normal, but they are all carriers of the abnormal gene. Each time these daughters bear a son, there is a 50% chance the son will receive the abnormal gene.

In X-linked dominant inheritance, the abnormal gene appears in females even if there is also a normal X chromosome present. Since males pass the Y chromosome to their sons, affected males will not have affected sons. All of their daughters will be affected, however. Sons or daughters of affected females will have a 50% chance of getting the disease.

EXAMPLES OF SINGLE GENE DISORDERS

Autosomal recessive:

X-linked recessive:

Autosomal dominant:

X-linked dominant:

Only a few, rare, disorders are X-linked dominant. One of these is hypophosphatemic rickets, also called vitamin D -resistant rickets.

CHROMOSOMAL DISORDERS

In chromosomal disorders, the defect is due to either an excess or lack of the genes contained in a whole chromosome or chromosome segment.

Chromosomal disorders include:

MULTIFACTORIAL DISORDERS

Many of the most common diseasesare caused byinteractions of several genes and factors in the the environment (for example, illnesses in the mother and medications). These include:

MITOCHONDRIAL DNA-LINKED DISORDERS

Mitochondria are small organisms found in most of the body's cells. They are responsible for energy production inside cells. Mitochondria contain their own private DNA.

In recent years, many disorders have been shown to result from changes (mutations) in mitochondrial DNA. Because mitochondria come only from the female egg, most mitochondrial DNA-related disorders are passed down from the mother.

Mitochondrial DNA-related disorders can appear at any age. They have a wide variety of symptoms and signs. These disorders may cause:

Some other disorders are also known as mitochondrial disorders, but they do not involve mutations in the mitochondrial DNA. These disorders are usually single gene defects and they follow the same pattern of inheritance as other single gene disorders.

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Genetics: MedlinePlus Medical Encyclopedia

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Photos: People: courtesy of Denis Finnin, AMNH; Illustrations: Louis Pappas, Steve Thurston, Eric Hamilton; People: Jim Steck Genetics illustrations: Stephen Blue

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Ology Genetics - AMNH

The information in genomes provides the instruction set for producing each living organism on the planet. While we have a growing understanding of the basic biochemical functions of many of the individual genes in genomes, understanding the complex processes by which this encoded information is read out to orchestrate production of incredibly diverse cell types and organ functions, and how different species use strikingly similar gene sets to nonetheless produce fantastically diverse organismal morphologies with distinct survival and reproductive strategies, comprise many of the deepest questions in all of science. Moreover, we recognize that inherited or acquired variation in DNA sequence and changes in epigenetic states contribute to the causation of virtually every disease that afflicts our species. Spectacular advances in genetic and genomic analysis now provide the tools to answer these fundamental questions.

Members of the Department of Genetics conduct basic research using genetics and genomics of model organisms (yeast, fruit fly, worm, zebrafish, mouse) and humans to understand fundamental mechanisms of biology and disease. Areas of active investigation include genetic and epigenetic regulation of development, molecular genetics, genomics and cell biology of stem cells, the biochemistry of micro RNA production and their regulation of gene expression, and genetic and genomic analysis of diseases in model systems and humans including cancer, cardiovascular and kidney disease, neurodegeneration and regeneration, and neuropsychiatric disease. Members of the Department have also been at the forefront of technology development in the use of new methods for genetic analysis, including new methods for engineering mutations as well as new methods for production and analysis of large genomic data sets.

The Department sponsors a graduate program leading to the PhD in the areas of molecular genetics and genomics, development, and stem cell biology. Admission to the Graduate Program is through the Combined Programs in Biological and Biomedical Sciences (BBS).

In addition to these basic science efforts, the Department is also responsible for providing clinical care in Medical Genetics in the Yale New Haven Health System. Clinical genetics services include inpatient consultation and care, general, subspecialty, cancer and prenatal genetics clinics, and clinical laboratories for cytogenetics, DNA diagnostics, and biochemical diagnostics. The Department sponsors a Medical Genetics Residency program leading to certification by the American Board of Medical Genetics. Admission to the Genetics Residency is directly through the Department.

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Home > Genetics | Yale School of Medicine

Genetics

Background:

Homunculus in Sperm One question that has always intrigued us humans is Where did we come from? Long ago, Hippocrates and Aristotle proposed the idea of what they called pangenes, which they thought were tiny pieces of body parts. They thought that pangenes came together to make up the homunculus, a tiny pre-formed human that people thought grew into a baby. In the 1600s, the development of the microscope brought the discovery of eggs and sperm. Antonie van Leeuwenhoek, using a primitive microscope, thought he saw the homunculus curled up in a sperm cell. His followers believed that the homunculus was in the sperm, the father planted his seed, and the mother just incubated and nourished the homunculus so it grew into a baby. On the other hand, Regnier de Graaf and his followers thought that they saw the homunculus in the egg, and the presence of semen just somehow stimulated its growth. In the 1800s, a very novel, radical idea arose: both parents contribute to the new baby, but people (even Darwin, as he proposed his theory) still believed that these contributions were in the form of pangenes.

Modern genetics traces its beginnings to Gregor Mendel, an Austrian monk, who grew peas in a monastery garden. Mendel was unique among biologists of his time because he sought quantifiable data, and actually counted the results of his crosses. He published his findings in 1865, but at that time, people didnt know about mitosis and meiosis, so his conclusions seemed unbelievable, and his work was ignored until it was rediscovered in 1900 by a couple of botanists who were doing research on something else. Peas are an ideal organism for this type of research because they are easy to grow and it is easy to control mating.

We will be looking at the sorts of genetic crosses Mendel did, but first, it is necessary to introduce some terminology:

Monohybrid Cross and Probabilities:

A monohybrid cross is a genetic cross where only one gene/trait is being studied. P stands for the parental generation, while F1 and F2 stand for the first filial generation (the children) and second filial generation (the grandchildren). Each parent can give one chromosome of each pair, therefore one allele for each trait, to the offspring. Thus, when figuring out what kind(s) of gametes an individual can produce, it is necessary to choose one of the two alleles for each gene (which presents no problem if they are the same).

Purple Pea Flower White Pea Flower For example, a true-breeding purple-flowered plant (the dominant allele for this gene) would have the genotype PP, and be able to make gametes with either P or P alleles. A true-breeding white-flowered plant (the recessive allele for this gene) would have the genotype pp, and be able to make gametes with either p or p alleles. Note that both of these parent plants would be homozygous. If one gamete from each of these parents got together to form a new plant, that plant would receive a P allele from one parent and a p allele from the other parent, thus all of the F1 generation will be genotype Pp, they will be heterozygous, and since purple is dominant, they will look purple. What if two individuals from the F1 generation are crossed with each other (PpPp)? Since gametes contain one allele for each gene under consideration, each of these individuals could contribute either a P or a p in his/her gametes. Each of these gametes from each parent could pair with each from the other, thus yielding a number of possible combinations for the offspring. We need a way, then, to predict what the possible offspring might be. Actually, there are two ways of doing this. The first is to do a Punnett square (named after Reginald Crandall Punnett). The possible eggs from the female are listed down the left side, and there is one row for each possible egg. The possible sperm from the male are listed across the top, and there is one column for each possible sperm. The boxes at the intersections of these rows and columns show the possible offspring resulting from that sperm fertilizing that egg. The Punnett square from this cross would look like this:

Note that the chance of having a gamete with a P allele is and the chance of a gamete with a p allele is , so the chance of an egg with P and a sperm with P getting together to form an offspring that is PP is =, just like the probabilities involved tossing coins. Thus, the possible offspring include: PP, ( Pp + pP, which are the same (Pp), since P is dominant over p), so = Pp, and pp.

Another way to calculate this is to use a branching, tree diagram:

Note, again, that the chance of Pp is +=. A shorter way of telling how many PP, Pp, and pp could be expected, would be to say that there is a 1:2:1 genotype ratio (that comes from the , , and , above, and by the way, notice that they add up to , so we know we have accounted for everything). The chance of getting at least one dominant allele (either PP or Pp) necessary for purple color (this can be written as P) is +=, so we could say that theres a 3:1 phenotype ratio. These two ratios are classic genotype and phenotype ratios for a monohybrid cross between two heterozygotes.

Mendels Four-Part Theory:

Based on his data, Mendel came up with a four-part theory of how genetics works:

Some special cases:

(Rh factor, by the way, is a totally separate gene with Rh+ [R] and Rh [r] alleles [actually, that gene also has multiple alleles, but the vast majority of people are positive or negative for one particular allele called D]. In the U. S., about 85% of the population is Rh+ [RR and Rr] and 15% Rh [rr], thus the chances of someone being O [having both ii and rr] would be 45% 15% = 6.75%. The rarest blood type in the U. S. would be AB, about 0.45% of the population.]

This is a cross where two traits/genes are under consideration. For example, in peas if R = round, so r = wrinkled, and Y = yellow, so y = green, in a cross between RRYY rryy, the gametes must have ONE ALLELE FOR EACH GENE, so in this case, RRYY could produce gametes with one R AND one Y, or RY, and rryy could produce gametes with one r AND one y, or ry. The F1 would get RY from one parent and ry from the other, thus would all be RrYy. Note that it is necessary to keep the alleles for the same gene together and put the dominant allele (capital letter) first for EACH GENE. In calculating what the F2 generation would be, you must first figure out what gametes (eggs or sperm) each parent can make. It is very important to remember that gametes must have ONE ALLELE FOR EACH GENE, so figure out the possibilities this way:

Thus, each parent could make four kinds of gametes, so the Punnett square would be 44 cells.

This would give the following possible offspring:

Thus the genotype ratio is 1:2:1:2:4:2:1:2:1 and the phenotype ratio is 9:3:3:1. Notice the shorthand used to represent the phenotypes. Since both RR and Rr will look round, rather than writing round pea seeds, we can use R to say its got at least one R, so itll be round.

Try This:

On your own, try IAiRr IBiRr, a cross involving both the ABO blood group and Rh factor. Note, a little later, we will discuss what those blood groups actually are/do.

Genotype and Phenotype Are Not the Same:

It is important to understand the difference between genotype and phenotype. For example, for most of the genes we will be discussing, an organism with the genotype of, say, BB and an organism who is Bb both have at least one dominant allele for that gene, and thus, would both express/show/be the dominant phenotype. If, for example, this was a gene for human eye color, then B would represent the dominant allele which codes for make brown eyes, and b would represent the recessive allele which codes for blue eyes (technically, more like, we dont know how to make brown, so blue is the default). Thus, people whose genotypes are either BB or Bb both have instructions for make brown, so the phenotypes of both are brown eye color.

As another example where many people get confused, an individuals sex is a phenotype, not a genotype! We can talk of a person as having either two X chromosomes (XX) or one X and one Y chromosome (XY). Those are, essentially, genotypes, and there are also a few people who have genotypes such as X (also called XO), XXX, or XXY. Those X and Y chromosomes contain/consist of a number of genes, and factors such as what alleles a person has for each of those genes, how those alleles are expressed, and how that gene expression affects/influences various body processes will all come together to produce that phenotype which we call a persons sex. In humans, if all those alleles are expressed in what we like to think of as being normal, then, usually, X, XX, and XXX are expressed as a female phenotype (with X and XXX producing some other physical characteristics considered to be typical for those genotypes), while the result of how the XY combination is expressed usually results in what we refer to as a male phenotype.

However, while uncommon, it is entirely possible that due to a mutation in some gene, somewhere, that codes for some enzyme or hormone, a person with 2 X chromosomes (XX) can have a male phenotype; can, clearly and unambiguously, be male. Similarly, while also not very common, it is also possible, due to a mutation in some gene, somewhere, that codes for some hormone or enzyme, that a person with an X and a Y chromosome (XY) can have a female phenotype; can, clearly and unambiguously, be female. Interestingly, because of differences in how the genes/alleles are expressed, the XXY combination typically results in a male in humans but results in a female in fruit flies.

Our culture, our way of thinking, is so locked into having/needing to choose between male and female as the only two options, that while in the unambiguous cases just mentioned where a persons expressed phenotype obviously fits our preconception of maleness or femaleness even if their genotype/chromosomes are different from what we might think (and of which we would not even be aware unless we were that persons doctor and maybe not even then), on the other hand, people whose bodies dont exactly and neatly fit into one of those two categories are lumped together in a group and labeled as intersex. Typically, at birth, their parents are advised by medical personnel to choose whether they wish to bring this child up as a boy or a girl, and may even be pressured into having cosmetic surgery performed on the child to make the child look more like the chosen sex assignment, yet it frequently happens as the child grows up, due to the influence of internal factors such as hormones, etc., that he or she does not feel like the sex which the doctors assigned/labeled at birth. On the other hand, if parents try to be more neutral and let the child make that choice when and if the child decides to do so, that tends to expose the child to a lot of ridicule from classmates and even other adults.

Pedigrees:

Sample Pedigree In pedigrees, a circle represents a female and a square represents a male. Filled-in vs. open symbols are used to distinguish between two phenotypes for the gene in question, and a half-filled symbol may be used to designate a carrier (a heterozygous individual who has a recessive allele for some gene, but is not showing that phenotype). Here is a sample pedigree for eye color. If the people with filled-in (dark) symbols have brown eyes and those with open (light) symbols have blue eyes, can you figure out the genotypes of the people marked with *?

Genetic Basis of Behavior, Polyploids:

Some further notes on genetics: We tend to think of genes that control what an organism looks like, etc., but genes can also control behavior of animals. For example, bird songs and other courtship rituals are under genetic control. The most successful competitors live and mate and pass on their genes. On a different subject, many of our horticultural plant varieties are polyploid plants. Typically, like us, plants are diploid. Horticulturists have figured out ways to manipulate plants and make triploid or tetraploid plants. Typically these plants are larger and/or have bigger or more ruffled flowers and/or larger seeds. While triploid plants are usually sterile (with three sets of chromosomes they have trouble doing meiosis), tetraploid plants are usually fertile and can reproduce. I believe I read somewhere that the wheat we eat is actually a hexaploid, resulting in seeds that are quite a bit larger than its grass-like ancestor.

References:

Borror, Donald J. 1960. Dictionary of Root Words and Combining Forms. Mayfield Publ. Co.

Campbell, Neil A., Lawrence G. Mitchell, Jane B. Reece. 1999. Biology, 5th Ed. Benjamin/Cummings Publ. Co., Inc. Menlo Park, CA. (plus earlier editions)

Campbell, Neil A., Lawrence G. Mitchell, Jane B. Reece. 1999. Biology: Concepts and Connections, 3rd Ed. Benjamin/Cummings Publ. Co., Inc. Menlo Park, CA. (plus earlier editions)

Marchuk, William N. 1992. A Life Science Lexicon. Wm. C. Brown Publishers, Dubuque, IA.

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Genetics - Biology