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July 5, 2017 Credit: CC0 Public Domain

Pioneering research using the tropical zebrafish could provide new insights into the genetic basis of myopathy, a type of human muscle disease.

An international research team, led by Professor Philip Ingham FRS, inaugural Director of the University of Exeter's Living Systems Institutehas taken the first steps in determining the central role a specific gene mutation in a poorly characterised human myopathy.

Myopathies are diseases that prevent muscle fibres from functioning properly, causing muscular weakness. At present, there is no single treatment for the disease, as it can develop via a number of different pathways.

One particular type is nemaline myopathy, which primarily affects skeletal muscles and can lead to sufferers experiencing severe feeding and swallowing difficulties as well as limited locomotor activity.

Mutations in a specific gene, called MY018B, have recently been found to be present in people exhibiting symptoms of this disease, but the role these mutations play in muscle fibre integrity has until now been unclear.

In this new research, the Ingham team, based in Singapore and Exeter, has used high-resolution genetic analysis to create a zebrafish model of MYO18B malfunction; this research takes advantage of the remarkable similarity between the genomes of zebrafish and humans,which have more than 70 per cent of their genes in common.

The Singapore/Exeter team found that the MYO18B gene is active specifically in the 'fast-twitch' skeletal muscles of the zebrafish, typically used for powerful bursts of movement. Crucially, by studying fish in which the MYO18B gene is disrupted, they were able to show that it plays an essential role in the assembly of the bundles of actin and myosin filaments that give muscle fibres their contractile properties.

The team believe this new research offers a vital new step towards understanding the cause of myopathy in humans, which in turn could give rise to new, tailored treatments in the future.

The leading research is published in the scientific journal, Genetics.

Professor Ingham, said: "The identification of a MYO18B mutation in zebrafish provides the first direct evidence for its role in human myopathy and gives us a model in which to study the molecular basis of MYO18B function in muscle fibre integrity."

A pioneer in the genetic analysis of development using fruit flies and zebrafish as model systems, Prof Ingham is internationally renowned for his contributions to several influential discoveries in the field of developmental biology over the last century.

This is the latest research by Professor Ingham that has revealed important links between the processes that underpin normal embryonic development and disease.

His co-discovery of the 'Sonic Hedgehog' gene, recognised as one of 24 centennial milestones in the field of developmental biology by Nature, in 2004, led directly to the establishment of a biotechnology company that helped develop the first drug to target non-melanoma skin cancer.

The research comes at the University of Exeter holds the official opening of the Living Systems Institute with an Opening Symposium event, from July 5-6 2017.

Two Nobel Laureates, Sir Paul Nurse FRS and Christiane Nsslein-Volhard ForMemRS, who separately won the Nobel Prize for Physiology or Medicine, will deliver keynote speeches as part of the opening event.

The high-profile event, held at the University's Streatham Campus marks the official opening of the LSIa 52 million inter-disciplinary research facility designed to bring new, crucial insights into the causes and preventions of some of the most serious diseases facing humanity.

A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B is published in Genetics.

Explore further: Zebrafish help identify mutant gene in rare muscle disease

Journal reference: Genetics

Provided by: University of Exeter

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Research could give insight into genetic basis of of the human muscle disease, myopathy - Medical Xpress

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Chief medical officer calls for gene testing revolution - BBC News BBC News Cancer patients should be routinely offered DNA tests to help select the best treatments for them, according to England's chief medical officer. Prof Dame Sally ... UK medical chief vows to spread 'genetics dream'Financial Times All cancer patients should have their DNA tested to save lives, Chief Medical Officer saysTelegraph.co.uk Cancer breakthrough: Treatment could be personalised to YOU by using your genesExpress.co.uk Sky News -iNews -BT.com all 25 news articles »

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Chief medical officer calls for gene testing revolution - BBC News - BBC News

Cancer patients should have routine access to genetic testing to improve diagnosis and treatment, according to Englands chief medical officer.

Despite the UK being a world leader in genomic medicine its full potential is still not being realised, Professor Dame Sally Davies said in a new report.

This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS. - Sir Harpal Kumar, Cancer Research UK

Davies urged clinicians and the Government to work together and make wider use of new genetic techniques in an attempt to improve cancer survival rates.

Genetic testing can pinpoint the faults in DNA that have led to a cancer forming. Different cancers have different faults, and these determine which treatments may or may not work.

Such testing could lead to patients being diagnosed faster and receiving more targeted or precise treatments.

Davies said that the age of precision medicine is now and that the NHS must act quickly to remain world class.

This technology has the potential to change medicine forever but we need all NHS staff, patients and the public to recognise and embrace its huge potential. said Davies.

Sir Harpal Kumar, Cancer Research UKs chief executive, agreed, saying that it would be a disservice to patients if the UK were slow to respond to innovations in this area.

The report recommends that within 5 years training should be available to current and future clinicians and that all patients should be being offered genomic tests just as readily as theyre given MRI scans today.

Davies also called for research and international collaboration to be prioritised, along with investment in research and services so that patients across the country have equal access.

However the report recognises potential challenges such as data protection issues and attitudes of clinicians and the public.

This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS, added Sir Kumar.

Cancer Research UK is determined to streamline research, to find the right clinical trial for cancer patients and to ensure laboratory discoveries benefit patients.

And the design of clinical trials are starting to change. A number of trials are underway, like Cancer Research UKs National Lung Matrix Trial with AstraZeneca and Pfizer, where patients with a certain type of lung cancer are assigned a specific treatment based on the genetic makeup of their cancer.

However, Sir Harpal Kumar stressed that to bring the reports vision to life the Government, the NHS, regulators and research funders need to act together.

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Greater access to genetic testing needed for cancer diagnosis and treatment - Cancer Research UK

Two new studies suggest that one in five seemingly healthy people hasDNA mutations that puts him or herat increased risk for genetic disease.

BlackJack3D/iStockPhoto

By Ryan CrossJun. 26, 2017 , 6:15 PM

Some doctors dream of diagnosing diseasesor at least predicting disease riskwith a simple DNA scan. But others have said the practice, which could soon be the foundation of preventative medicine, isnt worth the economic or emotional cost. Now, a new pair of studies puts numbers to the debate, and one is the first ever randomized clinical trial evaluating whole genome sequencing in healthy people. Together, they suggest that sequencing the genomes of otherwise healthy adults can for about one in five people turn up risk markers for rare diseases or genetic mutations associated with cancers.

What that means for those people and any health care system considering genome screening remains uncertain, but some watching for these studies welcomed the results nonetheless. It's terrific that we are studying implementation of this new technology rather than ringing our hands and fretting about it without evidence, says Barbara Biesecker, a social and behavioral researcher at the National Human Genome Research Institute in Bethesda, Maryland.

The first genome screening study looked at 100 healthy adults who initially reported their family history to their own primary care physician. Then half were randomly assigned to undergo an additional full genomic workup, which cost about $5000 each and examined some 5 million subtle DNA sequence changes, known as single-nucleotide variants, across 4600 genessuch genome screening goes far beyond that currently recommended by the American College of Medical Genetics and Genomics (ACMG), which suggests informing people of results forjust 59 genes known or strongly expected to cause disease.

Of the 50 participants whose genomes were sequenced, 11 had alterations in at least one letter of DNA suspected to causeusually rarediseases, researchers report today in The Annals of Internal Medicine. But only two exhibited clear symptoms. One was a patient with extreme sensitivity to the sun. Their DNA revealed a skin condition called variegate porphyria. Now that patient knows they will be much less likely to get bad sunburns or rashes if they avoid the sun and certain medications, says Jason Vassy, a primary care clinician-investigator at Veteran Affairs Boston Healthcare System and lead author of the study.

The team also found that every sequenced patient carried at least one recessive mutation linked to a diseasea single copy of a mutant gene that could cause an illness if two copies are present. That knowledge can be used to make reproductive decisionsa partner may get tested to see if they have a matching mutationand prompt family members to test themselves for carrier status. And in what Vassy calls a slightly more controversial result, the team examined participants chances of developing eight polygenic diseases, conditions that are rarely attributed to a single genetic mutation. Here, they compiled the collective effects of multiple genesup to 70 for type II diabetes and 60 for coronary heart diseaseto predict a patients relative risk of developing the disease.

Just 16% of study volunteers who only reported their family history were referred to genetic counselors or got follow-up laboratory tests. In the genome sequencing group, the number was 34%.

Some researchers have expressed concern that such whole genome screening will skyrocket medical costs or cause undue psychological harm. Aside from the initial cost of sequencing (which was covered by the study), patients who underwent the genomic screen paid an average of $350 additional in healthcare costs over the next 6 months, Vassy and colleagues reported. But contrary to fears of emotional trauma, neither the sequencing group nor the control group showed any changes in anxiety or depression 6 months after the study.

Vassy stresses that their study was small and needs follow-up, but it still impressed Christa Martin, a geneticist at Geisinger Health System, in Danville, Pennsylvania, who worked on the ACMGs recommendations for genome sequencing. I almost feel like the authors undersold themselves, she says. Many of their patients are making health behavioral changes, so they are using the information in a positive way.

The study was extremely well designed and very appropriately run, adds Barbara Koenig, a medical anthropologist who directs the University of CaliforniaSan Francisco Bioethics Program. But she still questions the assumption by many physicians, ethicists, and patient advocates that more information is always beneficial. It is just hard to know how all this information is going to be brought together in our pretty dysfunctional healthcare system.

Another paper published last week on the preprint server bioRxiv, which has not yet undergone peer review, yields similar results. Using whole-exome sequencing, which looks only at the protein-coding regions of the genome, Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine in Palo Alto, California, and colleagues found that 12 out of 70 healthy adults, or 17%, unknowingly had one or more DNA mutations that increased the risk for genetic diseases for which there are treatment or preventative options.

Both studies suggest that physicians should look at genes beyond the ACMGs 59 top priorities, Snyder says. He argues that whole-genome sequencing should be automatically incorporated into primary care. You may have some super-worriers, but I would argue that the information is still useful for a physician to have. Vassy, however, says that there isnt yet enough evidence to ask insurance companies to reimburse whole genome sequencing of healthy patients.

We like a quick fix and the gene is an important cultural icon right now, so we probably give it more power than it really has, Koenig says. But these are still really early days for these technologies to be useful in the clinic.

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One in five 'healthy' adults may carry disease-related genetic mutations - Science Magazine

June 30, 2017

Uncovering rare susceptibility variants that contribute to the causes of complex diseases requires large sample sizes and massively parallel sequencing technologies. These sample sizes, often made up of exome and genome data from tens to hundreds of thousands of individuals, are often too large for current analytical tools to process. A team at Baylor College of Medicine, led by Dr. Suzanne Leal, professor of molecular and human genetics, has developed new software called SEQSpark to overcome this processing obstacle. A study on the new technology appears in The American Journal of Human Genetics.

"To handle these large data sets, we built the SEQSpark tool based on the commonly used Spark program, which allows SEQSpark to utilize multiple processing platforms to increase the speed and efficiency of performing data quality control, annotation and rare variant association analysis," Leal said.

To test and validate the versatility and speed of SEQSpark, Leal and her team analyzed benchmarks from the whole genome sequence data from the UK10K, testing specifically for waist-to-hip ratios.

"The analysis and related tasks took about one and a half hours to complete, in total. This includes loading the data, annotation, principal components analysis and single and rare variant aggregate association analysis for the more than 9 million variants present in this sample set," explained Di Zhang, a postdoctoral associate in the Leal lab at Baylor and first author on the paper.

To evaluate SEQSpark's performance in a larger data set, Leal and the research team generated 50,000 simulated exomes. The SEQSprak program ran the analysis for a quantitative trait using several variant aggregate association methods in an hour and forty-five minutes.

When compared to other variant association tools, SEQSpark was consistently faster, reducing computation to a hundredth of the time in some cases.

"What is unique about SEQSpark is that it is scalable, and smaller labs can run it without super specific hardware, and it can also be run in a multi-server environment to increase its speed and capacity for large genetic data sets," Zhang said. "It is ideal for large-scale genetic epidemiological studies and is highly efficient from a computational standpoint."

"We see this software as being very useful as the demand for the analysis of massively parallel sequence data grows. SEQSpark is highly versatile, and as we analyze increasingly large sets of rare variant data, it has the potential to play a key role in furthering personalized medicine," Leal said.

In the future, Leal and her team will continue to test and increase SEQSpark's capabilities and will be analyzing soon data sets that have 500,000 samples or more.

Explore further: Genetic test for familial data improves detection genes causing complex diseases such as Alzheimer's

More information: Di Zhang et al. SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant Association Studies using Whole-Genome and Exome Sequence Data, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.05.017

A team of researchers at Baylor College of Medicine has developed a family-based association test that improves the detection in families of rare disease-causing variants of genes involved in complex conditions such as Alzheimer's. ...

Precision medicine, which utilizes genetic and molecular techniques to individually tailor treatments and preventative measures for chronic diseases, has become a major national project, with President Obama launching the ...

A multi-institutional team of researchers has sequenced the DNA of 6,700 exomes, the portion of the genome that contains protein-coding genes, as part of the National Heart, Lung and Blood Institute (NHLBI)-funded Exome Sequencing ...

(Medical Xpress)Via genetic analysis, a large international team of researchers has found rare, damaging gene variants that they believe contribute to the risk of a person developing schizophrenia. In their paper published ...

Human genome sequencing costs have dropped precipitously over the last few years, however the analytical ability to meet the growing demand for making sense of large data sets remains as a bottleneck. With the introduction ...

Researchers at EMBL-EBI have developed a new approach to studying the effect of multiple genetic variations on different traits. The new algorithm, published in Nature Methods, makes it possible to perform genetic analysis ...

Following up on findings from a an earlier genome-wide association study (GWAS) of type 2 diabetes (T2D) in Latinos, researchers from the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH) traced ...

Although the basic outlines of human hearing have been known for years - sensory cells in the inner ear turn sound waves into the electrical signals that the brain understands as sound - the molecular details have remained ...

Using a new skin cell model, researchers have overcome a barrier that previously prevented the study of living tissue from people at risk for early heart disease and stroke. This research could lead to a new understanding ...

The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating ...

Whole genome sequencing involves the analysis of all three billion pairs of letters in an individual's DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease. However, the ...

Researchers have found that genes for coronary heart disease (CAD) also influence reproduction, so in order to reproduce successfully, the genes for heart disease will also be inherited.

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Researchers build SEQSpark to analyze massive genetic data sets - Medical Xpress

Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted. Sam Edwards/Caiaimage/Getty Images hide caption

Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted.

Two years ago, Cheasanee Huette, a 20-year-old college student in Northern California, decided to find out if she was a carrier of the genetic mutation that gave rise to a disease that killed her mother. She took comfort in knowing that whatever the result, she'd be protected by the Affordable Care Act's guarantees of insurance coverage for pre-existing conditions.

Her results came back positive. Like her mother, she's a carrier of one of the mutations known as Lynch syndrome. The term refers to a cluster of mutations that can boost the risk of a wide range of cancers, particularly colon and rectal.

As Republican lawmakers advance proposals to overhaul the ACA's consumer protections, Huette frets that her future health coverage and employment options will be defined by that test.

She even wonders if documentation of the mutation in her medical records and related screenings could rule out individual insurance plans. She's currently covered under her father's policy. "Once I move to my own health care plan, I'm concerned about who is going to be willing to cover me, and how much will that cost," she says.

In recent years, doctors have urged patients to be screened for a variety of diseases and predisposition to illness, confident it would not affect their future insurability. Being predisposed to an illness such as carrying the BRCA gene mutations associated with breast and ovarian cancer does not mean a patient will come down with the illness. But knowing they could be at risk may allow patients to take steps to prevent its development.

Under the current health law, many screening tests for widespread conditions such as prediabetes are covered in full by insurance. The Centers for Disease Control and Prevention and the American Medical Association have urged primary care doctors to test patients at risk for prediabetes. But doctors, genetic counselors and patient advocacy groups now worry that people will shy away from testing as the ACA's future becomes more uncertain.

Dr. Kenneth Lin, a family physician at Georgetown University School of Medicine in Washington, D.C., says if the changes proposed by the GOP become law, "you can bet that I'll be even more reluctant to test patients or record the diagnosis of prediabetes in their charts." He thinks such a notation could mean hundreds of dollars a month more in premiums for individuals in some states under the new bill.

Huette says she's sharing her story publicly since her genetic mutation is already on her medical record.

But elsewhere, there have been "panicked expressions of concern," says Lisa Schlager of the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE). "Somebody who had cancer even saying, 'I don't want my daughter to test now.' Or 'I'm going to be dropped from my insurance because I have the BRCA mutation.' There's a lot of fear."

Those fears, which come in an era of accelerating genetics-driven medicine, rest upon whether a gap that was closed by the ACA will be reopened. That remains unclear.

A law passed in 2008, the Genetic Information Nondiscrimination Act, bans health insurance discrimination if someone tests positive for a mutation. But that protection stops once the mutation causes "manifest disease" essentially, a diagnosable health condition.

That means "when you become symptomatic," although it's not clear how severe the symptoms must be to constitute having the disease, says Mark Rothstein, an attorney and bioethicist at the University of Louisville School of Medicine in Kentucky, who has written extensively about GINA.

The ACA, passed two years after GINA, closed that gap by barring health insurance discrimination based on pre-existing conditions, Rothstein says.

On paper, the legislation unveiled by Senate Majority Leader Mitch McConnell last week wouldn't let insurers set higher rates for people with pre-existing conditions, but it could effectively exclude such patients from coverage by allowing states to offer insurance plans that don't cover certain maladies, health analysts say. Meanwhile, the bill that passed the House last month does have a provision that allows states to waive protections for people with pre-existing conditions, if they have a gap in coverage of 63 days or longer in the prior year.

When members of a Lynch Syndrome social media group were asked for their views on genetic testing amid the current health care debate, about two dozen men and women responded. Nearly all said they were delaying action for themselves or suggesting that family members, particularly children, hold off.

Huette was the only one who agreed to speak for attribution. She says before the ACA was enacted, she witnessed the impact that fears about insurance coverage had on patients. Her mother, a veterinarian, had wanted to run her own practice but instead took a federal government job for the guarantee of health insurance. She died at the age of 57 of pancreatic cancer, one of six malignancies she had been diagnosed with over the years.

Huette says she doesn't regret getting tested. Without the result, Huette points out, how would she have persuaded a doctor to give her a colonoscopy in her 20s?

"Ultimately, my health is more important than my bank account," she says.

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

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Patients Who Tested Positive For Genetic Mutations Fear Bias ... - NPR - NPR

Born in August, Charlie Gard has a rare genetic disorder known as mitochondrial DNA depletion syndrome. Caused by a genetic mutation, it leads to weakened muscles and organ dysfunction, among other symptoms, with a poor prognosis for most patients.

Charlie is on life support and has been in the intensive care unit at the Great Ormond Street Hospital for Children in London since October. His doctors wish to take him off life support, but his parents disagree.

"The domestic courts concluded that it would be lawful for the hospital to withdraw life sustaining treatment because it was likely that Charlie would suffer significant harm if his present suffering was prolonged without any realistic prospect of improvement, and the experimental therapy would be of no effective benefit," a press release from the court announcing the decision said.

Charlie's parents appealed to the UK Supreme Court to decide the best interests of their child. After they lost that appeal, the 10-month-old was due to have his life support switched off at the end of the day June 13.

Gard and Yates then filed a request with the European Court of Human Rights, an international court based in Strasbourg, France, to consider the case.

The original ruling to provide life support until June 13 was extended by European Court of Human Rights initially for one week, until June 19. Rather than making a decision then, the court granted a three week-extension, until July 10, to allow for a more informed decision by the court. That extension ended Tuesday with the courts decision.

However, parental rights are not absolute, and in cases in which doctors and parents disagree, the courts may exercise objective judgment in a child's best interest.

In April, a judge tasked with ruling on the impasse between doctors and parents decided in favor of the Great Ormond Street Hospital doctors. In his decision, Justice Francis said life support treatment should end so Charlie could die with dignity.

The boy's parents challenged this ruling in May, yet it was upheld by a Court of Appeal. Three Supreme Court justices later dismissed another challenge from the couple.

Since Charlie's birth, "his condition has deteriorated seriously," the UK Supreme Court stated in a decision June 8; his brain is severely affected, and "he cannot move his arms or legs or breathe unaided."

On this basis, the court ruled that the child's life support should be switched off June 13, but the family appealed to the European court.

Charlie's parents argued that the UK courts gave insufficient weight to their own human rights, and some of Charlie's human rights, in their decision-making, Wilson said.

After the European court's ruling to extend the deadline while judges considered the case further, the Supreme Court told doctors it "would not be unlawful" to continue to provide life support.

After the extension, a Supreme Court hearing was requested by the government and the Great Ormond Street Hospital for Children, which did not know whether the Strasbourg court order was legally binding in the UK, Wilson explained.

"There was also a secondary issue, which was that (Great Ormond Street Hospital's) legal representatives were concerned that at present, doctors did not have sufficient legal clarity about what they can and can't do if Charlie's condition deteriorates," Wilson said. "So this court was also invited to consider whether any UK court, and if so which court, should handle that matter."

In fact, it has never been used to treat this form of mitochondrial DNA depletion syndrome, according to the British ruling, though it has proved beneficial to patients with a different form of the disease.

"He literally has nothing to lose but potentially a healthier, happier life to gain," they said.

Parents are rightly at the "heart" of decisions made about life-sustaining treatment for critically ill children, noted Dominic Wilkinson, director of medical ethics at the Oxford Uehiro Centre.

"Sadly, reluctantly, doctors and judges do sometimes conclude -- and are justified in concluding -- that slim chances of life are not always better than dying." Sometimes, the "best that medicine can do" -- and the most ethical decision -- is to provide comfort and to avoid painful and unhelpful medical treatments, he wrote.

The court said the decision was meticulous, noting that they spoke with Charlie's health care providers, independent experts, experts recommended by the family, and Charlie's parents to inform the ruling. In the end, the press released said they determined, "it was most likely Charlie was being exposed to continued pain, suffering and distress and that undergoing experimental treatment with no prospects of success would offer no benefit, and continue to cause him significant harm."

CNN's Stephanie Halasz, Debra Goldschmidt and Judith Vonberg contributed to this report.

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Court rules hospital can withdraw life support for sick baby Charlie Gard - CNN International

June 29, 2017 Micrograph showing prostatic acinar adenocarcinoma (the most common form of prostate cancer) Credit: Wikipedia

Scientists have had limited success at identifying specific inherited genes associated with prostate cancer, despite the fact that it is one of the most common non-skin cancers among men. Researchers at University of Utah Health studied prostate cancer patients with multiple cancer diagnoses, many who would not be recommended for genetic tests following current guidelines, to identify genetic mutations that may influence cancer treatment and cancer risk assessment for family members. Their findings are reported in the June issue of the journal Cancer.

"We commonly use a combination of a patient's personal and family cancer histories to identify those individuals who may have a mutation in a gene that predisposes that individual to developing cancers," said Patrick Pili, M.D., medical oncology fellow at the University of Texas MD Anderson Cancer Center. "Testing for hereditary cancers impacts not only the patient with cancer but also potentially the cancer screening and health outcomes of their entire family, but many prostate cancer patients do not meet the current guidelines to test for genetic cancer heritability."

Pili was part of a research team led by Kathleen Cooney, M.D., chair of the Department of Internal Medicine at U of U Health and a Huntsman Cancer Institute investigator, who proposed a strategy to identify germline mutations in men selected for the study based on their clinical history not their family history.

The study was highly selective, including 102 patients who had been diagnosed with prostate cancer and at least one additional primary cancer, like melanoma, pancreatic cancer, testicular cancer, or Hodgkin lymphoma.

The researchers examined the frequency of harmful germline mutations in this group of men. These mutations originate on either the egg or sperm and become incorporated into the DNA of every cell in the body of the resulting offspring.

Using next generation sequencing, the researchers found that 11 percent of the patients had a disease-causing mutation in at least one cancer-predisposing gene, which suggests these genetic variations contributed to their prostate cancer. Cooney found no difference in cancer aggressiveness or age of diagnosis compared to patients without these mutations.

In addition, a certified genetic counselor and co-investigator Elena Stoffel, M.D., University of Michigan Comprehensive Cancer Center, reviewed personal and family histories from each patient to determine whether they would meet clinical genetic testing guidelines. The majority of the men in the study, 64 percent, did not meet current criteria to test for hereditary cancer based on personal and/or family history.

The findings suggest that there are men with heritable prostate cancer-predisposing mutations that are not eligible for genetic screening under current guidelines.

"This is the first paper in which we can show the potential of using a clinical history of multiple cancers, including prostate cancer, in a single individual to identify inherited germline mutations," Cooney said.

The majority of harmful mutations identified were in genes involved in DNA repair.

"These mutations prevent the DNA from healing itself, which can lead to a predisposition for cancer," Cooney said.

This result is also beneficial because drugs like PARP [poly ADP ribose polymerase] inhibitors have a better success rate in treating cancers with the underlying gene mutation associated with DNA repair.

Cooney cautions that this is a small pilot study rather than a broader epidemiological survey, and it consists of a highly specific subset of patients.

"We cannot generalize these findings to the broader population, because we used highly selective criteria to tip us off to patients that may have mutations outside typical hereditary genetic patterns," she said.

The 102 patients included in the study were identified from the University of Michigan's Prostate Cancer Genetics Project, which registers patients who are diagnosed with prostate cancer before age 55 or who have a first- or second-degree relative with prostate cancer. In addition, the research team identified patients from the University of Michigan's Cancer Genetics Registry, which includes individuals with personal or family history suggestive of a hereditary risk of cancer.

"Our findings are in line with those of other studies, suggesting that approximately 1 in 10 men with advanced prostate cancer harbors a genetic variant associated with increased cancer risk," said Stoffel. "While family history is an important tool, there may be better ways to identify patients with genetic risk."

Future studies with larger sample sizes will include sequencing of tumors that will allow investigators to more carefully explore the different features associated with tumors that arise in individuals with germline mutations.

"This approach will help us identify patients at greater risk for aggressive prostate cancer so they can seek earlier screening while pre-symptomatic," Cooney said.

Explore further: Are men with a family history of prostate cancer eligible for active surveillance?

More information: Patrick G. Pili et al. Germline genetic variants in men with prostate cancer and one or more additional cancers, Cancer (2017). DOI: 10.1002/cncr.30817

Journal reference: Cancer

Provided by: University of Utah

Active surveillancecareful monitoring to determine if or when a cancer warrants treatmentis an increasingly prevalent choice for prostate cancer, but it's unclear if the strategy is appropriate for men with a family ...

Inherited mutations in genes that function to repair DNA may contribute to metastatic prostate cancer more than previously recognized, according to a study out today in the New England Journal of Medicine. Though infrequent ...

African-American men develop prostate cancer more often than other men, and it tends to be more deadly for this population. Some of the differences seem to be due to socioeconomic factors, but scientists wondered whether ...

(HealthDay)A man's risk of aggressive and fatal prostate cancer may be heavily influenced by gene mutations previously linked to breast and ovarian cancer in women, a trio of new studies suggests. Findings from the studies ...

Scientists are reporting a test which can predict which patients are most at risk from aggressive prostate cancer, and whether they suffer an increased chance of treatment failure. This test, reported at the European Association ...

A form of genetic variation, called differential RNA splicing, may have a role in tumor aggressiveness and drug resistance in African American men with prostate cancer. Researchers at the George Washington University (GW) ...

While mutations in protein-coding genes have held the limelight in cancer genomics, those in the noncoding genome (home to the regulatory elements that control gene activity) may also have powerful roles in driving tumor ...

A molecular test can pinpoint which patients will have a very low risk of death from breast cancer even 20 years after diagnosis and tumor removal, according to a new clinical study led by UC San Francisco in collaboration ...

Scientists have had limited success at identifying specific inherited genes associated with prostate cancer, despite the fact that it is one of the most common non-skin cancers among men. Researchers at University of Utah ...

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Leukemia researchers led by Dr. John Dick have traced the origins of relapse in acute myeloid leukemia (AML) to rare therapy-resistant leukemia stem cells that are already present at diagnosis and before chemotherapy begins.

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June 26, 2017 Credit: CC0 Public Domain

Between 15 and 20 percent of black people carry a genetic mutation that puts them at risk for certain chronic kidney disease, but only about half of them develop the illness - a variance that long has puzzled researchers. Now a study has found that the gene mutation's toxic effects require higher than normal levels of a protein called suPAR to trigger the onset and progression of the disease.

The results of the study, published in a research article in the journal Nature Medicine today, could lead soon to new treatments for chronic kidney disease that target these risk factors, according to Dr. Jochen Reiser, the senior author of the paper. Reiser is the chairperson of the Department of Internal Medicine and Ralph C. Brown MD Professor of Medicine at Rush University Medical Center, Chicago.

Chronic kidney disease - or CKD for short - is a progressive failure of function that prevents kidneys from fulfilling their role filtering waste from the blood stream. Nearly 17 percent of people in the U.S. have chronic kidney disease, and approximately 4 percent require dialysis and/or a kidney transplant due to kidney failure. Currently, there are no drugs that can treat CKD in an effective way.

Study analyzed samples from more than 1,000 people with genetic risk for CKD

For the study recounted in the Nature Medicine paper, Reiser worked with a team that included researchers at Emory University, Harvard University, Johns Hopkins University, the National Institute of Health, Ruprecht Karls University of Heidelberg, the Israel Institute of Technology and others. Together, they looked at two well-known genetic risk factors for CKD in black people, the mutated G1 or G2 variations in the gene known as apolipoprotein L1 (APOL1). To be at risk for developing CKD, an individual must have inherited two of these gene variants, one from each parent.

The study analyzed blood samples for suPAR levels, screened for APOL1 gene mutations and measured kidney function from two separate cohorts of black patients - 487 people from the Emory Cardiovascular Biobank, 15 percent of whom had a high-risk APOL1 genotype; and 607 from the multi-center African American Study of Kidney Disease and Hypertension, including 24 percent with the high-risk mutation.

Using these two large, unrelated cohorts, the researchers found that plasma suPAR levelsindependently predict renal function decline in individuals with two copies of APOL1 risk variants. APOL1-related risk is reduced by lower levels of plasma suPAR and strengthened by higher levels.

The team then went on and used purified proteins to study if suPAR and APOL1 bind to each other. They found that the mutated G1 and G2 variant did so particularly well on what's known as a receptor on the surface of kidney cells, in this case the suPAR activated receptor alphavbeta3 integrin. "This binding appears to be a key step in the disease onset" adds Dr. Kwi Hye Ko, a scientist at Rush and the study's co-first author.

This binding causes kidney cells to change their structure and function, permitting disease onset. Using cell models and genetically engineered mice, the authors then could reproduce kidney disease changes upon expression of APOL1 gene variants, but the disease required the presence suPAR.

Without elevated suPAR levels, genetic mutation much less likely to trigger disease

Everybody has suPAR, which is produced by bone marrow cells, in their blood, with normal levels around 2400 picogram per milliliter (pg/ml). As levels of suPAR rise, risk for kidney disease rises in turn.

Patients with levels above 3000 picogram per milliliter carry a much higher risk for kidney disease in the general population. Black people are particularly at risk, given the study's finding that suPAR activates its receptor on kidney cells that then attract the APOL1 risk proteins. Over time, these assaults can damage and eventually destroy the kidney.

On the other hand, without high levels of suPAR, the ability of the genetic mutation of APOL1 to exert its damaging effects is impaired, which helps identify patients in most need of suPAR lowering or future anti-suPAR therapy.

"Patients with APOL1 mutations who don't get kidney disease have more commonly low suPAR levels," said Dr. Salim Hayek, co-first author of the paper and a cardiologist at Emory University School of Medicine. "The suPAR level needs to be high to activate the mechanism in the kidney that enables APOL1 proteins" and set off the chain of events the genetic mutation can trigger.

suPAR 'is to the kidneys as cholesterol is to the heart'

Like some other pathological gene mutations, the APOL1 variations may have persisted in the population, in this case in Africa, because they could protect people from infection with the parasites known as trypanosome. explained Sanja Sever, PhD, co-correspondent author of the paper and associate professor of medicine at Harvard Medical School. In the United States, however, fighting parasitic trypanosomes isn't a significant concern, while lifestyle and environmental pressures such as obesity promote the rise in suPAR levels. This scenario sets up people for high risk of kidney disease.

Reiser has spent his career studying a scarring type of chronic kidney disease, focal segmental glomerulosclerosis. In past studies, he discovered that suPAR not only is a marker for kidney disease, but also a likely cause.

"What we are learning today is that suPAR in a general way is to kidneys what cholesterol is to the heart, a substance that can cause damage if levels rise too high, or a substance that can likely make many forms of kidney disease worse," Reiser says. "Based on these fundamental insights, suPAR level testing may become a routine test at many institutions around the world."

Like cholesterol, suPAR levels vary from person to person. Some environmental factors can contribute significantly to elevated suPAR levels. "Lifestyle is a big factor, bigger than we thought," Reiser says.

Smoking, weight gain and even frequent infections can add up and send suPAR to dangerous heights. Weight loss and smoking cessation can help bring levels down, but once elevated, suPAR may not recede to a healthy level again, said Dr. Melissa Tracy, co-author of the study and an associate professor of cardiology at Rush. People at genetic risk for kidney disease should aim to live a healthy life to keep suPAR levels low.

Explore further: Circulating blood factor linked with a leading cause of kidney failure

More information: A tripartite complex of suPAR, APOL1 risk variants and v3 integrin on podocytes mediates chronic kidney disease, Nature Medicine (2017). DOI: 10.1038/nm.4362

Patients with a disease that is a leading cause of kidney failure tend to have high levels of a particular factor circulating in their blood, according to a study appearing in an upcoming issue of the Journal of the American ...

A protein known as suPAR has been identified in recent years as both a reliable marker for chronic kidney disease and a pathogen of the often deadly condition. Its place of origin in the human body, however, has been a mysteryuntil ...

Make room, cholesterol. A new disease marker is entering the medical lexicon: suPAR, or soluble urokinase-type plasminogen activator receptor. A study in the New England Journal of Medicine shows that suPAR, a circulating ...

African Americans have a heightened risk of developing chronic and end-stage kidney disease. This association has been attributed to two common genetic variants - named G1 and G2in APOL1, a gene that codes for a human-specific ...

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Catalyst for genetic kidney disease in black people identified - Medical Xpress

Picture a time in the not-too-distant future when whole genome sequencing is routine. A time when, before babies even learn to talk, their parents will have the ability to learn what the future may have in store for their offspring: Is their little girl predisposed to getting breast cancer? Will their happy-go-lucky son one day develop Alzheimer's?

"There is no doubt in my mind that, in addition to going in and having blood chemistry done, you're gonna have DNA sequencing done, too. It will be there at some point," says Nicholas Schork, a quantitative geneticist at the J. Craig Venter Institute in La Jolla, California, who has studied genomic medicine for more than three decades. "We can debate about the timeline, but it'll become routine."

The hope is that genetic testing will make health care more effective by allowing doctors and patients to focus on areas that need attention the patient's genetic "vulnerabilities." At the same time, patients may learn of areas where they won't need to be quite as vigilant. And treatments could, in turn, be perfectly tailored to a patient's specific needs.

But as with any significant and broadly applicable medical advance, there are questions. For example, should patients learn that they carry markers for currently incurable genetic diseases, or that they are at high risk for developing a condition like Alzheimer's, which has no effective treatment? And just who owns all that genetic data? Who will have access to it?

Even with important questions left unanswered, health educators are moving forward to take advantage of the promises genetic testing offers. Washington State University's new Elson S. Floyd College of Medicine has announced it is partnering with Arivale, a Seattle-based company that conducts whole genome sequencing, to help complete a portrait of a person a "portrait" that can be used to promote wellness over that individual's entire lifespan. Every member of the school's inaugural class will have the opportunity to undergo testing, which will also include blood tests and a lifestyle evaluation. Then, over the next year, Arivale's team of nurses and dietitians will provide individually tailored follow-up, based on each individual's risks and goals. It's a unique partnership, made possible in large part because the medical school is new, with its first class of students starting in 2017.

Allowing the medical students to experience genetic testing firsthand is just part of the goal. "We need physicians that understand it well enough that they can make it better going forward," says John Tomkowiak, founding dean of WSU's College of Medicine. "That's where our students are going to be uniquely positioned."

WHAT GENES TELL US

Genetic testing already provides important information about a person's health or their heritage. Hospitals screen newborn babies for certain genetic disorders, and in some cases, tests can detect disorders before birth. And diagnostic testing can confirm, or rule out, many disorders in adults.

Testing doesn't have to be ordered by a physician. For $200, you can provide a saliva sample, mail it back to 23andMe.com and find out not only your ancestry, but also your risks for a number of diseases, including Alzheimer's and Parkinson's. Ancestry.com offers a glimpse into your heritage for $99. Color.com claims to reveal your risk for the most common hereditary cancers, and even offers "complimentary genetic counseling" for a $249 fee.

But if genetic testing is to revolutionize the health care industry, as many have promised, there's still a ways to go. "The technology is at the beginning stages," says Thomas May, a faculty researcher for the HudsonAlpha Institute for Biotechnology.

Companies like 23andMe offer genetic tests that may provide information about some genetic disorders from currently known genetic variants. But whole genome sequencing is different; it will reveal all your individual genetic variants.

How valuable is that information? There are a relatively small number of conditions that researchers are confident result from a specific genetic variant, May says. For example, there is one variant that researchers have found is associated with an increased risk of developing breast or ovarian cancer. A genetic test that shows an increased risk for breast cancer is considered an "actionable" outcome, meaning there are things you can do to prevent the outcome, like beginning mammograms earlier. Though there are more than 50 actionable outcomes like that, it's still a relatively small number.

Adding to the confusion is the fact that not everyone who develops breast cancer actually has the genetic variant in fact, May says only about 10 percent do. So even if testing shows that you don't have the "breast cancer gene," that doesn't mean it's OK to stop getting mammograms.

"Most variants and correlations are of that type: We can't say for certain if you're gonna get a disease," May says.

Doctors are mixed about whether genetic testing is currently having a real impact on patients. In a May survey conducted by the Medscape Physician Oncology Report on Genomics Testing, 71 percent of oncologists surveyed felt that genetic testing was either "very" or "extremely" important to the oncology field. At the same time, 61 percent said that, currently, fewer than a quarter of their patients would actually benefit from genetic testing.

The number of diseases with "actionable" outcomes will inevitably grow, as more people are tested and more data becomes available. But this leaves deeper questions, says Schork, the quantitative geneticist. A company or health care provider would likely give patients information about diseases that can be prevented or cured. If someone is predisposed to obesity, for instance, then he or she can elect to receive targeted care to reduce that risk.

But what about diseases that, right now, are incurable?

Take Huntington's disease, a genetic disorder that breaks down nerve cells in the brain. It's rare, but it's a "hideous way to die," Schork says. A person can be screened at the age of 25 and be found to carry the Huntington's gene, but there's debate about whether or not that information should be shared with a client or not. The same goes for genetic variants related to Alzheimer's disease.

"If there's nothing they can do about it, then there's a concern about whether or not that information should be imparted," Schork says.

When the Food and Drug Administration ordered 23andMe to stop telling customers their odds of contracting diseases in 2013, Harvard Medical School genetics professor Robert Green and Laura Beskow, a professor at Duke University's Institute for Genome Sciences and Policy, argued against the FDA. They cited a number of studies showing that direct-to-consumer genetic testing does not cause a large percentage of customers despair. In an interview with the New York Times in April, Green said the potential for distress based on results of a genetic test for Alzheimer's was "much smaller than anticipated."

Another question: Who really owns the DNA data that is being collected from willing users of genetic testing? Consider Myriad, a company that offers genetic testing both to help determine cancer risk and design better treatment plans for patients who already have cancer. The company has something that "others do not," Schork says: insight into which genetic variants predispose women to breast cancer.

What Myriad is really selling, then, is not the genetic test itself, but access to insights it has gained through mining its database, insights that can be leveraged into whatever level of payment the company decides to charge.

It's potentially critical information that could help save a life, and some argue that the data should be in the public domain not held by a private company.

"There have been huge debates about whether the community should challenge the monopoly that Myriad has," Schork says. "There are many groups out there that would like to counteract the monopoly Myriad has, by building public domain data sets."

JUST ONE TOOL

"Genetic testing is not a blueprint. It's really not," says Jennifer Lovejoy, chief translational science officer for Arivale. "Genes are really just one factor the environment, diet, exercise, pollutants and even emotional state have a big impact on genes."

That's why Arivale not only collects genetic information on each client, but also evaluates various blood tests and lifestyle factors to create a "dense data cloud" of information about a patient.

"That is the grand vision: that everybody would have these dense, dynamic data clouds, and understand the choices that will be optimal to optimize wellness and avoid disease," says Lovejoy.

Arivale touts the success stories among its nearly 2,000 clients. One client found out he had a gene associated with high sensitivity to saturated fat, giving him a better indication of an appropriate diet that helped him lose weight. Another client discovered that his genes may have an impact on his cholesterol. Another learned he was at risk of developing diabetes.

Ideally, this type of preventive care will soon be covered by insurance, Lovejoy says. The thinking is that preventing disease will bring down the cost of health care overall, making insurers likely to cover more preventive care, "but we have to prove it," Lovejoy says. Researchers are conducting studies and trials to do just that, and if they can prove it, then genetic testing could soon be routine in health care.

"If you think about what health care should mean, it should mean, one, the ability to deal with disease and that's what everyone does today," Arivale co-founder Leroy Hood said at a press conference in April announcing the company's partnership with WSU. "But two, it should mean the ability to optimize wellness for each individual. That is, improving their health and/or letting them avoid disease." That's a concept Hood calls "scientific wellness, and he thinks it could lead to "a whole new health care industry in the future."

Tomkowiak, of WSU's College of Medicine, agrees: "The concept of scientific wellness has the potential to disrupt the entire industry by shifting the cost curve, by keeping people healthier and reducing the cost of health care overall."

Regardless of whether or not Arivale becomes an industry leader, Tomkowiak believes that the practice of medicine will be fundamentally altered in the near future.

"We absolutely believe that seven years from now, the practice of scientific medicine and scientific wellness will be common," he says. "Instead of being behind the curve, we want... to be leading this effort."

For about $3,500, clients can sign up for Arivale's program. The fee includes whole genome sequencing, which is also available from other sources. So how do Arivale clients achieve "scientific wellness"? Here are the elements of their program:

Welcome package: Clients get a welcome package with a Fitbit to track sleep, activity and heart rate. The package asks for information to help understand a client's bacteria in their gut, and asks for a sample of saliva to measure a person's stress level.

Online test: Clients take a series of online assessments about their goals, health history, lifestyle, stress, personality and happiness.

Call from coach: You'll talk to a coach who will get to know what you want to accomplish and give you a personalized action plan.

Labs: You'll take blood tests so your coach can understand your current health. While you're there, they'll take your vital signs.

A picture emerges: The various test create a picture of you, which an Arivale coach will use to provide a step-by-step plan to "optimize your wellness," according to the company.

Follow-up: You're not done yet. You'll be contacted by your coach regularly to review your action plan, and Arivale will provide reports on how you're progressing. Every six months, you'll complete another set of clinical labs.

Source: arivale.com/your-journey

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What's In Your Genes? - Pacific Northwest Inlander

Pacific Standard

The Future of Medicine Depends on Protections for Pre-Existing Conditions Pacific Standard Biomedical researchers can see a future where genetic tests are used to treat and prevent many diseases before major symptoms even present themselves. But that future won't be possible without strong insurance protections for pre-existing conditions.

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The Future of Medicine Depends on Protections for Pre-Existing Conditions - Pacific Standard

This file photo shows doctors at Memorial Sloan Kettering Cancer Center in New York City.

An experimental cancer medicine called larotrectinib has shown promise treating a diverse range of cancers in people young and old, researchers said at a major cancer conference in the United States.

The treatment targets a genetic abnormality which is often found in rare cancers - including salivary gland cancer, juvenile breast cancer, and a soft tissue cancer known as infantile fibrosarcoma - which are particularly difficult to treat.

This abnormality also occurs in about 0.5 percent to one percent of many common cancers.

In the study released at the American Society of Clinical Oncology conference, 76 percent of cancer patients - both children and adults with 17 different kinds of cancer - responded well to the medicine.

A total of 79 percent were alive after one year. The study is ongoing.

Twelve percent went into complete remission from their cancer.

The clinical trial included 55 patients - 43 adults and 12 children. All had advanced cancers in various organs, including the colon, pancreas and lung, as well as melanoma.

"These findings embody the original promise of precision oncology: treating a patient based on the type of mutation, regardless of where the cancer originated," said lead study author David Hyman, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York.

"We believe that the dramatic response of tumors with TRK fusions to larotrectinib supports widespread genetic testing in patients with advanced cancer to see if they have this abnormality."

Made by Loxo Oncology Inc., larotrectinib is a selective inhibitor of tropomyosin receptor kinase (TRK) fusion proteins.

TRK proteins are a product of a genetic abnormality when a TRK gene in a cancer cell fuses with one of many other genes, researchers said.

The US Food and Drug Administration has not yet approved the treatment for widespread use.

The treatment was well tolerated by patients, and the most common side effects were fatigue and mild dizziness.

"If approved, larotrectinib could become the first therapy of any kind to be developed and approved simultaneously in adults and children, and the first targeted therapy to be indicated for a molecular definition of cancer that spans all traditionally-defined types of tumors," said Hyman.

(Source:AFP)

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New cancer medicine targets rare genetic flaw - Press TV

SUNDAY, June 4, 2017 (HealthDay News) -- A twice-daily pill could help some advanced breast cancer patients avoid or delay follow-up sessions of chemotherapy, a new clinical trial reports.

The drug olaparib (Lynparza) reduced the chances of cancer progression by about 42 percent in women with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study.

Olaparib delayed cancer progression by about three months. The drug also caused tumors to shrink in three out of five patients who received the medication, the researchers reported.

"Clearly the drug was more effective than traditional chemotherapy," said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society.

"This is a group where a response is more difficult to obtain -- a young group with a more aggressive form of cancer -- and nonetheless we saw a close to 60 percent objective response rate," he said.

The study was funded by AstraZeneca, the maker of Lynparza.

Olaparib works by cutting off the avenues that malignant cancer cells use to stay alive, said lead researcher Dr. Mark Robson. He's a medical oncologist and clinic director of Clinical Genetics Service at Memorial Sloan Kettering Cancer Center in New York City.

The drug inhibits PARP, an enzyme that helps cells repair damaged DNA, Robson said.

Normal cells denied access to PARP will turn to the BRCA genes for help, since they also support the repair of damaged DNA, Robson said.

But that "backup capability" is not available to breast cancer cells in women with BRCA gene mutations, Robson said.

"When you inhibit PARP, the cell can't rescue itself," Robson said. "In theory, you should have a very targeted approach, one specifically directed at the cancers in people who have this particular inherited predisposition."

Olaparib already has been approved by the U.S. Food and Drug Administration for use in women with BRCA-related ovarian cancer. Robson and his colleagues figured that it also should be helpful in treating women with breast cancer linked to this genetic mutation.

The study included 302 patients who had breast cancer that had spread to other areas of their body (metastatic breast cancer). All of the women had an inherited BRCA mutation.

They were randomly assigned to either take olaparib twice a day or receive standard chemotherapy. All of the patients had received as many as two prior rounds of chemotherapy for their breast cancer. Women who had hormone receptor-positive cancer also had been given hormone therapy.

After 14 months of treatment, on average, people taking olaparib had a 42 percent lower risk of having their cancer progress compared with those who received another round of chemotherapy, Robson said.

The average time of cancer progression was about seven months with olaparib compared with 4.2 months with chemotherapy.

Tumors also shrank in about 60 percent of patients given olaparib. That compared with a 29 percent reduction for those on chemotherapy, the researchers said.

Severe side effects also were less common with olaparib. The drug's side effects bothered 37 percent of patients compared with half of those on chemo. The drug's most common side effects were nausea and anemia.

"There were fewer patients who discontinued treatment because of toxicity compared to those who received chemotherapy," Robson said. "Generally it was pretty well tolerated."

Only about 3 percent of breast cancers occur in people with BRCA1 and BRCA2 mutations, the researchers said in background notes.

Despite this, the results are "quite exciting," said Dr. Julie Fasano, an assistant professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City.

Olaparib could wind up being used early in the treatment of metastatic breast cancer as an alternative to chemotherapy, and future studies might find that the drug is effective against other forms of breast cancer, Fasano said.

"It may be a practice-changing study, in terms of being able to postpone IV chemotherapy and its associated side effects" like hair loss and low white blood cell counts, Fasano said.

Lichtenfeld noted that olaparib also places less burden on patients.

"It may be easier for women to take two pills a day rather than go in for regular chemotherapy," Lichtenfeld said. "Clearly, this is a treatment that will garner considerable interest.

The findings were scheduled to be presented Sunday at the American Society of Clinical Oncology's annual meeting, in Chicago. The study was also published June 4 in the New England Journal of Medicine.

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Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' - Sioux City Journal

A genetic predisposition is a genetic characteristic which influences the possible phenotypic development of an individual organism within a species or population under the influence of environmental conditions. In medicine, genetic susceptibility to a disease refers to a genetic predisposition to a health problem,[1] which may eventually be triggered by particular environmental or lifestyle factors, such as tobacco smoking or diet. Genetic testing is able to identify individuals who are genetically predisposed to certain diseases.

Predisposition is the capacity we are born with to learn things such as language and concept of self. Negative environmental influences may block the predisposition (ability) we have to do some things. Behaviors displayed by animals can be influenced by genetic predispositions. Genetic predisposition towards certain human behaviors is scientifically investigated by attempts to identify patterns of human behavior that seem to be invariant over long periods of time and in very different cultures.

For example, philosopher Daniel Dennett has proposed that humans are genetically predisposed to have a theory of mind because there has been evolutionary selection for the human ability to adopt the intentional stance.[1] The intentional stance is a useful behavioral strategy by which humans assume that others have minds like their own. This assumption allows you to predict the behavior of others based on personal knowledge of what you would do.

E. O. Wilson's book on sociobiology and his book Consilience discuss the idea of genetic predisposition to behaviors

The field of evolutionary psychology explores the idea that certain behaviors have been selected for during the course of evolution.

The Genetic Information Nondiscrimination Act, which was signed into law by President Bush on May 21, 2008,[2] prohibits discrimination in employment and health insurance based on genetic information.

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Genetic predisposition - Wikipedia

To aid our variant interpretation process, we created an openly-available online tool to efficiently classify variants based on the evidence categories outlined in the article: Richards, et al. Standards and guidelines for the interpretation of sequence variants. 2015. This site displays the evidence categories and descriptions from Table 3 and Table 4 with simple checkboxes for selecting appropriate criteria. The site then incorporates the algorithm in Table 5 to automatically assign the pathogenicity or benign impact based on the selected evidence categories. Since our process often requires analyzing multiple variants per patient, we have also allowed the option of aggregating each variant into an exportable table at the foot of the website for easy documentation of the variant review process for our records. Although this tool is based on the ACMG/AMP Standards and Guidelines, it is not affiliated with ACMG, AMP, or any of the authors of the publication.

_ PVS1 null variant (nonsense, frameshift, canonical 1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease

_ PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change _ PS2 De novo (both maternity and paternity confirmed) in a patient with the disease and no family history _ PS3 Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product _ PS4 The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls _ PP1 (Strong evidence) Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease

_ PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation _ PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium _ PM3 For recessive disorders, detected in trans with a pathogenic variant _ PM4 Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants _ PM5 Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before _ PM6 Assumed de novo, but without confirmation of paternity and maternity _ PP1 (Moderate evidence) Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease

_ PP1 Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease _ PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease _ PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) _ PP4 Patients phenotype or family history is highly specific for a disease with a single genetic etiology _ PP5 Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation

_ BP1 Missense variant in a gene for which primarily truncating variants are known to cause disease _ BP2 Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern _ BP3 In-frame deletions/insertions in a repetitive region without a known function _ BP4 Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) _ BP5 Variant found in a case with an alternate molecular basis for disease _ BP6 Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation _ BP7 A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved

_ BS1 Allele frequency is greater than expected for disorder _ BS2 Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age _ BS3 Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing _ BS4 Lack of segregation in affected members of a family

_ BA1 Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

_ Sequencing artifact as determined by depth, quality, or other previously reviewed data

Download Table as CSV

Please note that the text of the variant evidence has been pulled directly from Richards, et al. Genet Med. 2015 May;17(5). This site does not claim authorship of any of the variant evidence descriptions.

This tool is based on the published ACMG/AMP Standards and Guidelines [Genet Med (2015)]. Anyone using this tool should be familiar with that publication. Individuals or institutions choosing to use this tool for clinical variant classification purposes assume legal responsibility for the consequences of its use. The authors make no warranty, express or implied, nor assume any legal liability or responsibility for any purpose for which the tool is used.

Please cite the following when using this tool in publications: Kleinberger J, Maloney KA, Pollin TI, Jeng LJ. An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants. Genet Med. 2016 Mar 17. doi: 10.1038/gim.2016.13. [Epub ahead of print] PubMed PMID: 26986878.

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Genetic Variant Interpretation Tool | University of ...

Imagine a world where an ambulance arrives to pick you up, not after a heart attack but before it happens, based on a signal sent from a device on your arm via your mobile phone. This sounds like the stuff of science fiction but could become a reality. It is all part of focusing healthcare more on prevention and less on cure. You dont wait for your car to break down before getting it repaired; you have it serviced and act on warning signs. Similarly, with healthcare, prevention is cheaper, more effective and less traumatic.

Another major change is a shift from a one size fits all approach to one tailored to individuals. Most medical treatments are designed for the average patient, and are successful for some but not others. Advances in what is called precision medicine will allow treatments to be tailored to characteristics, such as a persons genetic makeup or the genetic profile of a tumour.

The science that makes possible this combination of prevention and tailoring is genomics. The Human Genome Project mapped the human genome sequence in 2001, which is freely available in public databases. Less well known are the Precision Medicine Initiative in the US (which is creating a health database of a million Americans) and the 100,000 Genomes Project in the UK. These have only become viable because of huge advances in technology and data analytics.

Sequencing the first human genome cost $2.7bn and took 15 years. By 2008, the cost of sequencing had fallen to about $10m. Now sequencing can be done in a few days, with analysis in a few weeks, at cost of $1,000-$2,000.

Your genome is all the genetic information in your bodys instruction manual, encoded as DNA within the 23 chromosome pairs in cell nuclei. We are all very similar genetically: 99.9% of peoples genes are identical and it is the final tenth of a percent that determines differences like hair colour, build and predisposition to disease. Sequencing therefore has the ability to highlight a greater likelihood (or not) of developing conditions such as heart disease, lung cancer or Alzheimers.

The main aim of the 100,000 Genomes Project is to transform the use of genetics in the NHS. The project is run by Genomics England, a company owned by the Department of Health. It will sequence 100,000 whole genomes, half in people with rare genetic diseases (and close relatives who do not exhibit the disease) and half in patients with cancer. The results will be linked with patients medical records and stored securely and confidentially. By combining this information and allowing authorised researchers to access it, the project aims to provide a diagnosis for some patients with rare diseases and adapt cancer treatments. It will help to develop genomic medicine services for the NHS and support researchers to develop new medicines, therapies and diagnostic tests.

The 100,000 Genomes Project and similar ones around the world are unlikely to help the participants directly as the science of genomics is still in its infancy and there is a yawning gap between what sequencing technology enables us to discover and what doctors can do about it. However, it could provide invaluable data to help their children and grandchildren, as well as saving the NHS billions.

John Thornton is the director of e-ssential Resources and an independent adviser on business transformation, financial management and innovation.

John.Thornton@e-ssentialresources.co.uk

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Future medicine is all in the genes - Public Finance

New research published today in Genome Medicine uses large-scale DNA sequencing to identify genetic variants that cause developmental delay, a condition that currently goes undiagnosed in a large number of cases. Here to tell us more is author of the research, Dr. Greg Cooper.

Dr. Greg Cooper 30 May 2017

Developmental delay is associated with impaired cognition and failure to meet developmental milestones.

Developmental delay affects 1-2% of children worldwide. Symptoms often associated with developmental delay include impaired cognition, failure to meet developmental milestones, craniofacial and skeletal abnormalities, autism, and seizures. These disabilities can pose major medical, financial and psychological challenges.

Specific diagnoses for children with developmental delay are in many cases elusive, and the lack of a diagnosis is a major hardship for patients and their families. Inaccurate or unavailable diagnoses can result in years of expensive, invasive, and futile testing that complicates treatment decisions and may also lead to anxiety and emotional distress. Moreover, not knowing the reason for specific developmental delays slows research into improving therapeutic or educational options.

Anna Brooke Ainsworth, diagnosed with Cornelia de Lange syndrome (CDL), a rare genetic developmental disorder

In an effort to end the diagnostic odyssey for children with developmental delay, we have employed large-scale DNA sequencing to identify specific genetic variants that are causally relevant to developmental disabilities. As part of the NHGRI-funded Clinical Sequencing Exploratory Research Consortium, we began enrolling affected children into our study in 2013. Thus far, we have sequenced 371 children who present with developmental delay, and we have found the genetic cause and thus contributed to more precise and definitive clinical diagnoses in 27%.

We also enrolled biological parents when available to facilitate the identification of de novo i.e., present in a child but absent from his/her parents genetic variants, as these are known to be enriched among variants that cause developmental disabilities.

By sequencing the affected child and their parents, we were able in many cases to more efficiently identify the pathogenic variant relevant to their symptoms. In addition, by efficiently revealing relatively short lists of candidate de novo variants, trio sequencing also can greatly improve discovery of novel disease contributions.

That said, through retrospective analysis of proband genetic variants in the absence of parental sequence information, we were able to show that completing sequencing for only the child will often still yield a diagnosis, but will on average require more time and analytical effort when compared to the analysis of a trio.

Reanalysis success is driven by, and dependent upon, data sharing by clinicians and scientists who are also sequencing developmentally delayed patients.

Through our study, we observed that finding a pathogenic variant in an affected child is more challenging when close relatives have a neurological condition. This finding suggests that the underlying genetics in such multiplex families are more complex and harder to interpret than in simplex families, and that this distinction influences the success rate in terms of pathogenic variant discovery.

We also demonstrate that reanalysis over time of data from affected children with no initially identified causal genetic finding will often lead to new findings that considerably improve overall yield. Reanalysis success is driven by, and dependent upon, data sharing by clinicians and scientists who are also sequencing developmentally delayed patients.

Our data underscore the value of whole genome sequencing as an effective first-choice diagnostic tool in patients with developmental disabilities. Further, such sequencing, especially as proband-parent trios, will advance clinical and research progress and reduce the number and length of diagnostic odysseys that continue to impact numerous children and their families.

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Finding the genetic causes of developmental delay - BMC Blogs Network (blog)

Sessions/Tracks

On behalf of Conference Series LLC we are pleased to welcome you all to Chicago, Illinois, USA to attend the 10th Global Summit on Toxicology and Applied Pharmacology during July 20-22, 2017

Toxicology 2017 is one of the most significant conferences in the world where it contains many disciplines related to the research work and which are prominent in the field it is a leading platform to debate and acquire about the present and developing research works of Toxicology and Pharmacology. Toxicology 2017 which is scheduled at Chicago, USA influences main and important advances in the field. The conference may lead to long-lasting scientific collaborations.

Track 1: Toxicology and Pharmacology

The connected discipline of toxicology includes the study of the nature and mechanisms of deleterious effects of chemicals on living beings. The study of toxicology as a distinct, yet related, discipline to pharmacology highlights the emphasis of toxicologists in formulating measures aimed at protective public health against exposures associated with toxic materials in food, air and water, as well as hazards that may be related with drugs. The word pharmacology itself comes from the Greek word. Pharmacology not only includes the sighting of drugs, but also the study of their biochemical properties, mechanisms of action, uses and biological effects.

Toxicology Conferences | Pharmacology Conferences | Toxicology and Pharmacology Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; Society of Toxicology; Academy of Toxicological Sciences; American Board of Toxicology; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; EUROTOX; German Society of Toxicology

Track 2: Mechanisms of Toxicity

Mechanisms of toxicity are important in both practical and theory wise. It provides a rational basis for understanding descriptive toxicity data, approximating the possibility that a substance will cause risky effects, establishing measures to avoid or antagonize the toxic effects, designing drugs and industrialized chemicals that are fewer hazardous, and evolving pesticides that are more selectively poisonous for their target organisms.

Toxicity Conferences | Immunotoxicity Conferences | Drug Toxicity Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 5th Immunogenicity & Immunotoxicity Conference on February 6-7, 2017 in San Diego, CA; 2nd International Conference on Pollutant Toxic Ions and Molecules, 6 - 9 November 2017, Lisbon, Portugal; Stem Cells in Drug Discovery & Toxicity Screening, July 10-11, 2017, Boston, USA; 19th International Conference on Predictive Human Toxicity, February 16 - 17, 2017, London, United Kingdom; Predicting Drug Toxicity, June 13-14, 2017, Boston, USA; Academy of Toxicological Sciences; EUROTOX; American Board of Toxicology; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association;

Track 3: Molecular Toxicology

Molecular toxicology, the use of sub-atomic science standards and advancements to preclinical wellbeing appraisal, speaks to a key apparatus for comprehension systems of danger and surveying the dangers connected with toxicities. The utilization of quality expression markers to early stage preclinical security evaluation can possibly affect pipelines in two fundamental zones: lead improvement and issue administration.

Toxicology Conferences | Molecular Conferences | Molecular Toxicology Conferences

International Conference on Molecular Evolution July 18-19, 2016 Bangkok, Thailand; 2nd World Congress on Molecular Genetics and Gene Therapy July 3-5, 2017 Bangkok, Thailand; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; Computational Aspects: Biomolecular NMR (GRS) June 10 - 11, 2017, USA; Association for Molecular Pathology (AMP) April 3-5, 2017, Berlin, Germany; International Conference on Biochemistry and Molecular Biology April 3-5 2017, Munich, Germany; 60th Annual Conference of the Canadian Society for Molecular Biosciences May 16-20, 2017, Ottawa, Canada; Canadian Anatomic and Molecular Pathology, February 2-4, 2017, Whistler, Canada; 2nd International Conference on Pollutant Toxic Ions and Molecules, 6 - 9 November 2017, Lisbon, Portugal; Academy of Toxicological Sciences; American Board of Toxicology; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association;

Track 4: Applied Toxicology

Applied Toxicology deals with the fundamentals in toxicology and risk assessment, including the most important databases. The topics related to Applied Toxicology are Medicinal Chemistry, Biochemistry, Environmental Chemistry, Pharmacology, Pharmacodynamics, Pharmacokinetics and Instrumental Chemistry. Toxicology is the study of the toxic substances which are poisons and their risky effects on biological systems. Drugs are medicines for diseases but can also have unsafe effects prominent to toxicity and deadly injuries

Occupational Toxicology Conferences | Toxicology Conferences | Pharmaceutical Conferences

11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; EUROTOX; Academy of Toxicological Sciences; American Board of Toxicology; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology

Track 5: Regulatory Toxicology

Regulatory Toxicology includes the gathering, handling and evaluation of epidemiological as well as experimental toxicology data to license toxicologically grounded results absorbed to the safety of health against injurious effects of biochemical materials. Furthermore, Regulatory Toxicology supports the growth of regular procedures and new challenging approaches in order to constantly progress the technical basis for decision-making developments.

Regulatory Toxicology Conferences | Toxicology Conferences | Pharmacovigilance Conference

12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Academy of Toxicological Sciences; Argentine Toxicological Association; American Board of Toxicology; EUROTOX; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Austrian Society of Toxicology; Colombia Society of Toxicology;

Track 6: Clinical Toxicology

Clinical toxicology is absorbed on the diseases related with short-term and long-term disclosure to numerous toxic substances. It typically overlaps with other disciplines such as biochemistry, pharmacology, and pathology. Persons who specify in clinical toxicology are referred to as clinical toxicologists. Their work emphases around the identification, analysis, and treatment of conditions resulting from disclosure to harmful agents. They regularly study the toxic effects of numerous drugs in the body, and are also apprehensive with the treatment and prevention of drug toxicity in the population.

Toxicology Conferences | Clinical Toxicology Conferences | Pharmacology Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States;Academy of Toxicological Sciences; American Board of Toxicology; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology;

Track 7: Computational Toxicology

Computational toxicology is a discipline in the area of computational molecular sciences which is definitely swiftly emerging due to the overall public attention stimulated by many of us initiatives. Health care specialists beauty sector fragrance and flavour as well seeing that lawmakers and chemical substance protection regulators. It really is of particular concern in remedy discovery and progression and its own assessment is compulsory for the getting of new medicines for humans make use of it. The effect of toxicity and safety connected events in the progression of new biochemical elements is significant whether it pertains to medications or other chemical substances.

Computational Conferences | Toxicology Conferences | Computational Toxicology Conferences

3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology; EUROTOX; Academy of Toxicological Sciences; American Board of Toxicology;

Track 8: Organ Toxicity

The gathering of antimicrobial drugs and their metabolic by-products in organs can be poisonous, leading to organ injury. Toxicity is the degree to which a material can harm an organism. Toxicity can mention to the effect on an entire organism and the result on a substructure of the creature such as organ which may effect on any organ of the human being organ or tissue in the human body can be affected by antimicrobial toxicity

Organ Toxicology Conferences | Toxicity Conferences | Neurotoxicology Conferences

3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; Predicting Drug Toxicity, June 13-14, 2017, Boston, USA 5th Immunogenicity & Immunotoxicity Conference ImmunoTX Summit on February 6-7, 2017 in San Diego, CA; 2nd International Conference on Pollutant Toxic Ions and Molecules, 6 - 9 November 2017, Lisbon, Portugal; 19th International Conference on Predictive Human Toxicity, February 16 - 17, 2017, London, United Kingdom; Stem Cells in Drug Discovery & Toxicity Screening, July 10-11, 2017, Boston, USA; American Board of Toxicology; Society of Toxicology ; Society of Toxicology of Canada; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology; EUROTOX; Academy of Toxicological Sciences;

Track 9: Applied Pharmacology

Applied Pharmacology is the clinical utilizations of the medications and its use in genuine medicinal practice. Where in this it lets the doctors to extend his realities of the medication the approach it would really work in the medicinal science. It is the utilization of the medications and how the pharmacological activities or data could be connected to the therapeutics. Additionally to give clarification to various medications having associated with the pharmacological activity. It Provides elucidations about medication collaborations and to clear up the activity of different medications on the numerous organs in the body when they are sick state with symptoms disagreements

Pharmacology Conferences | Toxicology Conferences | Pharmaceutical Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 5th International Conference on Pharmacology and Ethnopharmacology Mar 23-25, 2017 Orlando, USA; 6th Global Experts Meeting on Cardiovascular Pharmacology and Cardiac Medications April 13-14, 2017 Dubai, UAE; 7th Global Experts Meeting on Neuropharmacology July 31-Aug 02, 2017 Milan, Italy; 10th International Conference on Neuropharmacology and Neuropharmaceuticals Oct 23-24, 2017 Dubai, UAE; 7th European Congress of Pharmacology 26-30 June 2016 stanbul, Turkey; Annual International Conference on Pharmacology and Pharmaceutical Sciences (PHARMA), 26 - 27 October 2015 Bangkok, Thailand; 18th International Conference on Pharmaceutical Sciences and Pharmacology January 21-22,2016 Paris, France; 117th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics March 8 - 12, 2016 San Diego, California, USA; World congress on pharma and Advanced Clinical Research November 6-8, 2017, Singapore; American Board of Toxicology; Society of Toxicology ; Society of Toxicology of Canada; EUROTOX; Academy of Toxicological Sciences; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology

Track 10: Genetic Toxicology

Genetic toxicology is of the toxic effects of harm to deoxyribonucleic acid (DNA). Genetic info, programmed chemically in DNA, is conserved, simulated and transmitted to consecutive generations with high reliability. Damage to DNA can happen through usual biological procedure or as the result of contact of DNA, directly or indirectly, with biochemical, physical or agents. Genetic toxicology over the years has been to examine mechanisms of inheritance by providing tools to study DNA and RNA structure, DNA repair and the role of mutation at both the individual and population levels

Genetic Conferences | Medical Toxicology Conferences | Genetic Toxicology Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Society of Toxicology; Society of Toxicology of Canada; EUROTOX; Academy of Toxicological Sciences; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology; American Board of Toxicology

Track 11: Risk assessment

Risk assessment is a methodical investigation of an assignment, job or procedure that we carry out at work for the persistence of classifying the important risks that are present. Risk assessments are very significant as they form an essential part of a virtuous occupational health and safety management strategy. They help to make consciousness of exposures and risks. Identify them who may be at risk. The identification, assessment, and valuation of the levels of risks complicated in a situation, their assessment against standards, and determination of an acceptable level of risk

Risk Assessment Conferences | Occupational Conferences | Toxicology Conferences

11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Society of Toxicology; Society of Toxicology of Canada; EUROTOX; Academy of Toxicological Sciences; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology; American Board of Toxicology

Track 12: Environmental and Occupational Toxicology

Environmental Toxicology is the investigation of effects of contaminations on the structure and capacity of biological communities. It does exclude the regular poisons, additionally the synthetic chemicals and their impact on the earth. It relies on upon the impacts of the toxicants on the organic chemistry and physiology. The principle motivation behind the natural toxicology is to recognize the mode/site of the activity of a xenobiotic. It additionally incorporate how the chemicals travel through biological systems and how they are consumed and metabolized by plants and creatures, the instruments by which they cause illness, result in inherent deformities, or toxin living beings

Environmental Toxicology Conferences | Ecologic Conferences | Occupational Conferences

12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Academy of Toxicological Sciences; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Colombia Society of Toxicology; American Board of Toxicology; Society of Toxicology; Society of Toxicology of Canada

Track 13: Experimental Toxicology

Protection of any live non-human vertebrate drifting animals of a tame species shall not be used in processes. The take care of animals used in processes, including management, shall have had suitable education and preparation. Experimental Toxicology widely covers all features of experimental and clinical studies of functional, biochemical and structural disorder. Validity announcements are also given in valuation procedures particularly if a skilled must choose which data of.

Experimental Conferences | Toxicology Conferences | Pharmaceutical Conferences

10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA;9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; American College of Medical Toxicology; Argentine Toxicological Association; American Board of Toxicology; Society of Toxicology; Society of Toxicology of Canada

Track 14: Immunotoxicology

Immunotoxicology offers a critical assessment of planned experimental animal models and methods, and discusses the influence that immunotoxicity can make to the overall valuation of chemical-induced adverse health effects on individuals and the ecosystem. Animal models of autoimmunity associated with chemical exposure, includes recommendations for the selection of sentinel species in ecotoxicology

Immunological Conferences | Immunotoxicology Conferences | Toxicity Conferences

12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; 53rd European Societies of Toxicology, September 10-13, 2017, Bratislava, Slovak; 19th International Conference on Toxicology and Applied Pharmacology, March 29 - 30, 2017 Singapore, SG; 15th International Conference on Toxicology and Clinical Pharmacology December 14-16, 2017 Dubai, UAE; 56th Annual Meeting of Society of Toxicology March 12-16, 2017 Baltimore USA; Society of Environmental Toxicology and Chemistry North America 38th Annual Meeting, November 1216, 2017, Minneapolis, Minnesota, United States; Academy of Toxicological Sciences; International Union of Toxicology; American College of Medical Toxicology; Argentine Toxicological Association; Colombia Society of Toxicology; American Board of Toxicology; Society of Toxicology

Track 15: Toxicity Testing

Toxicity is key to evaluate potential dangers to people through the intense, sub endless, and interminable presentation of creatures to pesticides. The more correct sorts of harmfulness that are resolved incorporate cancer-causing nature; developing incorporating teratogenicity in regenerative danger and neurotoxicity the degree of metabolite testing required relies on upon the level of conceivable poisonous quality and ecological steadiness of the metabolite. A toxicity test, by augmentation, is intended to create information in regards to the antagonistic impacts of a material on human or creature wellbeing, or the earth.

Toxicology Conferences | Toxicity Conferences | Pharmaceutical Conferences

9th Euro-Global Summit on Toxicology and Applied Pharmacology June 22-24, 2017 Paris, France; 11th Global Toxicology and Risk Management Meeting October 10-12, 2017 London, UK; 10th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, USA; 3rd Global Genomics and Toxicogenomics Meeting September 27-28, 2017 Chicago, USA; 12th International Conference on Environmental Toxicology and Ecological Risk Assessment October 19-20, 2017 Atlanta, USA; Stem Cells in Drug Discovery & Toxicity Screening, July 10-11, 2017, Boston, USA; 2nd International Conference on Pollutant Toxic Ions and Molecules, 6 - 9 November 2017, Lisbon, Portugal; Predicting Drug Toxicity, June 13-14, 2017, Boston, USA 5th Immunogenicity & Immunotoxicity Conference, one of three parallel tracks to the ImmunoTX Summit on February 6-7, 2017 in San Diego, CA; 19th International Conference on Predictive Human Toxicity, February 16 - 17, 2017, London, United Kingdom; American Board of Toxicology; Society of Toxicology; Society of Toxicology of Canada; EUROTOX; Academy of Toxicological Sciences International Union of Toxicology; Argentine Toxicological Association; Austrian Society of Toxicology; Colombia Society of Toxicology; American College of Medical Toxicology

Toxicology 2016

6th Global Summit on Toxicology and Applied Pharmacology was hosted by the Conference Series LLC in Houston, USA during October 17-19, 2016. The conference was focused on the theme "Bringing together leading researchers to share pragmatic insights" and facilitated by the Conference Series LLC. Liberal reaction and cooperation was received from the Editorial Board Members of Conference Series LLC Journals, Toxicology-2016 Organizing Committee Members, and from researchers, analysts and pioneers in Toxicology.

The conference was started by the Keynote Forum and we are chuffed to thank all our Keynote Speakers, Honorable Guests, Speakers and Conference Attendees for creating a successful meeting.

The conference has encrusted through the following sessions:

We would like to specially mention our Keynote Speakers who participated very enthusiastically and actively

The speakers gave their productive commitment as exceptionally enlightening presentations and made the meeting an extraordinary achievement.

We thank all the members who supported the conference by encouraging the healthy discussions. Conference Series LLC expresses gratitude to the Organizing Committee Members for their generous nearness, support and help towards Toxicology-2016. After the immense idealistic reaction from logical crew, prestigious identities and the Editorial Board individuals from Conference Series LLC, we are pleased to announce our forth coming conference 10th Global Summit on Toxicology and Applied Pharmacology" to be held in Chicago, USA during July 20-22, 2017.

We anticipate your precious presence at the Toxicology-2017 Conference.

Let us meet again @ Toxicology-2017

Toxicology 2015

Toxicology 2015 Past Conference Report

Conference Series LLC is the proud host of the4thGlobal Summit on Toxicologywhich took place inPhiladelphia, USAduringAugust 24-26, 2015with the theme,Exploring the Tailored Strategies and Lucid Technologies in Toxicology and Pharmacology.The Editorial Board Members of Conference Series LLC Journals and the Organizing Committee Members of the conference have extended their unsparing support and active participation towards Toxicology 2015. The participants included eminent speakers, scientists, industrialists, delegates, researchers and students who thoroughly relished the conference.

The core of the conference revolved around interactive sessions on the following scientific tracks:

This event is a collaborative effort and Conference Series LLC would like to thank the following people for making this conference a grand success:

Moderators

Keynote Speakers

We would sincerely thank the distinguished speakers who resplendently conducted workshops on Genotoxicity:

The conference marked its start by an opening ceremony which included introduction by the Honorable Guests and the Members of Keynote Forum. All the speakers have extended their contribution in the form of highly informative presentations to lead the conference to the ladder of success. Conference Series LLC extends its warm gratitude towards all the Participants, Eminent Speakers, Young Researchers, Delegates and Students.

All accepted abstracts have been indexed inConference Series LLCjournal, theJournal ofClinical Toxicologyas a special issue.

After the huge optimistic response from scientific fraternity, renowned personalities and the Editorial Board Members ofConference Series LLCfrom across the world,Conference Series LLCis pleased to announce the5thGlobal Summit on Toxicology and Applied Pharmacologyto be held duringOctober 17-19, 2016inHouston, Texas, USA.

We look forward to welcoming you to theToxicology 2016Conference and hope that the event will be both informative and enjoyable.

Toxicology-2014

Toxicology 2014 Past Conference Report

The3rdInternational Summit on Toxicology & Applied Pharmacologytook place inChicago, USAonOctober 20-22, 2014. The conference was titled: New Challenges and Innovations in Pharmacological and Toxicological Sciences and hosted by theConference Series LLC. Generous response and active participation was received from the Editorial Board Members ofConference Series LLCJournals, Toxicology-2014 Organizing Committee Members, as well as from scientists, researchers and leaders in Toxicology.

Students from various parts of the world took active participation in poster presentations. Students who presented well were awarded Best Poster Presentations for their outstanding contribution in the field of Toxicology.

The conference was carried out through various sessions and the discussions were held on the following scientific tracks:

The conference was opened by introductions from the honorable guests and members of the keynote forum. On the first day of opening the keynote speakers were,

Gerhard Eisenbrand,University of Kaiserslautern, Germany

Pavel Vodicka,Institute of Experimental Medicine, Czech Republic

Anne Marie Vinggaard,Technical University of Denmark, Denmark

Special session was conducted by Carter Cliff, Cellular Dynamics International, USA on the topic Pluripotent stem cell models-Application in toxicology and beyond, Heres-Pulido M E, Universidad Nacional Autnoma de Mxico, Mexico on the topic The Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster.

Symposium conducted by Cinzia Forni from University of Rome Tor Vergata, Italy and Hemant Misra from Prolong Pharmaceuticals, USA and the title of the Symposium is Stress response in living organisms exposed to pollutants.

All the speakers gave their fruitful contribution in the form of highly informative presentations and made the conference a great success.

All accepted abstracts have been indexed inConference Series LLCJournal of Clinical Toxicologyas a special issue.

Toxicology-2013

Toxicology 2013 Past Conference Report

The2ndInternational Summit on Toxicologytook place inLas Vegas, USAonOctober 07-09, 2013.The conference was titled: Insight into the Global Issues of Toxicology and hosted by theConference Series LLC. Generous response and active participation was received from the Editorial Board Members ofConference Series LLCJournals, Organizing Committee Members, scientists, researchers, clinical experts and leaders from the field of Toxicology.

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Toxicology Conferences 2017 | Pharmacology Conferences ...

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

In contrast, the study of typically non-medical phenotypes such as the genetics of eye color would be considered part of human genetics, but not necessarily relevant to medical genetics (except in situations such as albinism). Genetic medicine is a newer term for medical genetics and incorporates areas such as gene therapy, personalized medicine, and the rapidly emerging new medical specialty, predictive medicine.

Medical genetics encompasses many different areas, including clinical practice of physicians, genetic counselors, and nutritionists, clinical diagnostic laboratory activities, and research into the causes and inheritance of genetic disorders. Examples of conditions that fall within the scope of medical genetics include birth defects and dysmorphology, mental retardation, autism, and mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer genetics, teratogens, and prenatal diagnosis. Medical genetics is increasingly becoming relevant to many common diseases. Overlaps with other medical specialties are beginning to emerge, as recent advances in genetics are revealing etiologies for neurologic, endocrine, cardiovascular, pulmonary, ophthalmologic, renal, psychiatric, and dermatologic conditions.

In some ways, many of the individual fields within medical genetics are hybrids between clinical care and research. This is due in part to recent advances in science and technology (for example, see the Human genome project) that have enabled an unprecedented understanding of genetic disorders.

Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders. Referrals are made to genetics clinics for a variety of reasons, including birth defects, developmental delay, autism, epilepsy, short stature, and many others. Examples of genetic syndromes that are commonly seen in the genetics clinic include chromosomal rearrangements, Down syndrome, DiGeorge syndrome (22q11.2 Deletion Syndrome), Fragile X syndrome, Marfan syndrome, Neurofibromatosis, Turner syndrome, and Williams syndrome.

In the United States, physicians who practice clinical genetics are accredited by the American Board of Medical Genetics and Genomics (ABMGG).[1] In order to become a board-certified practitioner of Clinical Genetics, a physician must complete a minimum of 24 months of training in a program accredited by the ABMGG. Individuals seeking acceptance into clinical genetics training programs must hold an M.D. or D.O. degree (or their equivalent) and have completed a minimum of 24 months of training in an ACGME-accredited residency program in internal medicine, pediatrics, obstetrics and gynecology, or other medical specialty.[2]

Metabolic (or biochemical) genetics involves the diagnosis and management of inborn errors of metabolism in which patients have enzymatic deficiencies that perturb biochemical pathways involved in metabolism of carbohydrates, amino acids, and lipids. Examples of metabolic disorders include galactosemia, glycogen storage disease, lysosomal storage disorders, metabolic acidosis, peroxisomal disorders, phenylketonuria, and urea cycle disorders.

Cytogenetics is the study of chromosomes and chromosome abnormalities. While cytogenetics historically relied on microscopy to analyze chromosomes, new molecular technologies such as array comparative genomic hybridization are now becoming widely used. Examples of chromosome abnormalities include aneuploidy, chromosomal rearrangements, and genomic deletion/duplication disorders.

Molecular genetics involves the discovery of and laboratory testing for DNA mutations that underlie many single gene disorders. Examples of single gene disorders include achondroplasia, cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer (BRCA1/2), Huntington disease, Marfan syndrome, Noonan syndrome, and Rett syndrome. Molecular tests are also used in the diagnosis of syndromes involving epigenetic abnormalities, such as Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-willi syndrome, and uniparental disomy.

Mitochondrial genetics concerns the diagnosis and management of mitochondrial disorders, which have a molecular basis but often result in biochemical abnormalities due to deficient energy production.

There exists some overlap between medical genetic diagnostic laboratories and molecular pathology.

Genetic counseling is the process of providing information about genetic conditions, diagnostic testing, and risks in other family members, within the framework of nondirective counseling. Genetic counselors are non-physician members of the medical genetics team who specialize in family risk assessment and counseling of patients regarding genetic disorders. The precise role of the genetic counselor varies somewhat depending on the disorder.

Although genetics has its roots back in the 19th century with the work of the Bohemian monk Gregor Mendel and other pioneering scientists, human genetics emerged later. It started to develop, albeit slowly, during the first half of the 20th century. Mendelian (single-gene) inheritance was studied in a number of important disorders such as albinism, brachydactyly (short fingers and toes), and hemophilia. Mathematical approaches were also devised and applied to human genetics. Population genetics was created.

Medical genetics was a late developer, emerging largely after the close of World War II (1945) when the eugenics movement had fallen into disrepute. The Nazi misuse of eugenics sounded its death knell. Shorn of eugenics, a scientific approach could be used and was applied to human and medical genetics. Medical genetics saw an increasingly rapid rise in the second half of the 20th century and continues in the 21st century.

The clinical setting in which patients are evaluated determines the scope of practice, diagnostic, and therapeutic interventions. For the purposes of general discussion, the typical encounters between patients and genetic practitioners may involve:

Each patient will undergo a diagnostic evaluation tailored to their own particular presenting signs and symptoms. The geneticist will establish a differential diagnosis and recommend appropriate testing. Increasingly, clinicians use SimulConsult, paired with the National Library of Medicine Gene Review articles, to narrow the list of hypotheses (known as the differential diagnosis) and identify the tests that are relevant for a particular patient. These tests might evaluate for chromosomal disorders, inborn errors of metabolism, or single gene disorders.

Chromosome studies are used in the general genetics clinic to determine a cause for developmental delay/mental retardation, birth defects, dysmorphic features, and/or autism. Chromosome analysis is also performed in the prenatal setting to determine whether a fetus is affected with aneuploidy or other chromosome rearrangements. Finally, chromosome abnormalities are often detected in cancer samples. A large number of different methods have been developed for chromosome analysis:

Biochemical studies are performed to screen for imbalances of metabolites in the bodily fluid, usually the blood (plasma/serum) or urine, but also in cerebrospinal fluid (CSF). Specific tests of enzyme function (either in leukocytes, skin fibroblasts, liver, or muscle) are also employed under certain circumstances. In the US, the newborn screen incorporates biochemical tests to screen for treatable conditions such as galactosemia and phenylketonuria (PKU). Patients suspected to have a metabolic condition might undergo the following tests:

Each cell of the body contains the hereditary information (DNA) wrapped up in structures called chromosomes. Since genetic syndromes are typically the result of alterations of the chromosomes or genes, there is no treatment currently available that can correct the genetic alterations in every cell of the body. Therefore, there is currently no "cure" for genetic disorders. However, for many genetic syndromes there is treatment available to manage the symptoms. In some cases, particularly inborn errors of metabolism, the mechanism of disease is well understood and offers the potential for dietary and medical management to prevent or reduce the long-term complications. In other cases, infusion therapy is used to replace the missing enzyme. Current research is actively seeking to use gene therapy or other new medications to treat specific genetic disorders.

In general, metabolic disorders arise from enzyme deficiencies that disrupt normal metabolic pathways. For instance, in the hypothetical example:

Compound "A" is metabolized to "B" by enzyme "X", compound "B" is metabolized to "C" by enzyme "Y", and compound "C" is metabolized to "D" by enzyme "Z". If enzyme "Z" is missing, compound "D" will be missing, while compounds "A", "B", and "C" will build up. The pathogenesis of this particular condition could result from lack of compound "D", if it is critical for some cellular function, or from toxicity due to excess "A", "B", and/or "C". Treatment of the metabolic disorder could be achieved through dietary supplementation of compound "D" and dietary restriction of compounds "A", "B", and/or "C" or by treatment with a medication that promoted disposal of excess "A", "B", or "C". Another approach that can be taken is enzyme replacement therapy, in which a patient is given an infusion of the missing enzyme.

Dietary restriction and supplementation are key measures taken in several well-known metabolic disorders, including galactosemia, phenylketonuria (PKU), maple syrup urine disease, organic acidurias and urea cycle disorders. Such restrictive diets can be difficult for the patient and family to maintain, and require close consultation with a nutritionist who has special experience in metabolic disorders. The composition of the diet will change depending on the caloric needs of the growing child and special attention is needed during a pregnancy if a woman is affected with one of these disorders.

Medical approaches include enhancement of residual enzyme activity (in cases where the enzyme is made but is not functioning properly), inhibition of other enzymes in the biochemical pathway to prevent buildup of a toxic compound, or diversion of a toxic compound to another form that can be excreted. Examples include the use of high doses of pyridoxine (vitamin B6) in some patients with homocystinuria to boost the activity of the residual cystathione synthase enzyme, administration of biotin to restore activity of several enzymes affected by deficiency of biotinidase, treatment with NTBC in Tyrosinemia to inhibit the production of succinylacetone which causes liver toxicity, and the use of sodium benzoate to decrease ammonia build-up in urea cycle disorders.

Certain lysosomal storage diseases are treated with infusions of a recombinant enzyme (produced in a laboratory), which can reduce the accumulation of the compounds in various tissues. Examples include Gaucher disease, Fabry disease, Mucopolysaccharidoses and Glycogen storage disease type II. Such treatments are limited by the ability of the enzyme to reach the affected areas (the blood brain barrier prevents enzyme from reaching the brain, for example), and can sometimes be associated with allergic reactions. The long-term clinical effectiveness of enzyme replacement therapies vary widely among different disorders.

There are a variety of career paths within the field of medical genetics, and naturally the training required for each area differs considerably. It should be noted that the information included in this section applies to the typical pathways in the United States and there may be differences in other countries. US Practitioners in clinical, counseling, or diagnostic subspecialties generally obtain board certification through the American Board of Medical Genetics.

Genetic information provides a unique type of knowledge about an individual and his/her family, fundamentally different from a typically laboratory test that provides a "snapshot" of an individual's health status. The unique status of genetic information and inherited disease has a number of ramifications with regard to ethical, legal, and societal concerns.

On 19 March 2015, scientists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited.[3][4][5][6] In April 2015 and April 2016, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[7][8][9] In February 2016, British scientists were given permission by regulators to genetically modify human embryos by using CRISPR and related techniques on condition that the embryos were destroyed within seven days.[10] In June 2016 the Dutch government was reported to be planning to follow suit with similar regulations which would specify a 14-day limit.[11]

The more empirical approach to human and medical genetics was formalized by the founding in 1948 of the American Society of Human Genetics. The Society first began annual meetings that year (1948) and its international counterpart, the International Congress of Human Genetics, has met every 5 years since its inception in 1956. The Society publishes the American Journal of Human Genetics on a monthly basis.

Medical genetics is now recognized as a distinct medical specialty in the U.S. with its own approved board (the American Board of Medical Genetics) and clinical specialty college (the American College of Medical Genetics). The College holds an annual scientific meeting, publishes a monthly journal, Genetics in Medicine, and issues position papers and clinical practice guidelines on a variety of topics relevant to human genetics.

The broad range of research in medical genetics reflects the overall scope of this field, including basic research on genetic inheritance and the human genome, mechanisms of genetic and metabolic disorders, translational research on new treatment modalities, and the impact of genetic testing

Basic research geneticists usually undertake research in universities, biotechnology firms and research institutes.

Sometimes the link between a disease and an unusual gene variant is more subtle. The genetic architecture of common diseases is an important factor in determining the extent to which patterns of genetic variation influence group differences in health outcomes.[12][13][14] According to the common disease/common variant hypothesis, common variants present in the ancestral population before the dispersal of modern humans from Africa play an important role in human diseases.[15] Genetic variants associated with Alzheimer disease, deep venous thrombosis, Crohn disease, and type 2 diabetes appear to adhere to this model.[16] However, the generality of the model has not yet been established and, in some cases, is in doubt.[13][17][18] Some diseases, such as many common cancers, appear not to be well described by the common disease/common variant model.[19]

Another possibility is that common diseases arise in part through the action of combinations of variants that are individually rare.[20][21] Most of the disease-associated alleles discovered to date have been rare, and rare variants are more likely than common variants to be differentially distributed among groups distinguished by ancestry.[19][22] However, groups could harbor different, though perhaps overlapping, sets of rare variants, which would reduce contrasts between groups in the incidence of the disease.

The number of variants contributing to a disease and the interactions among those variants also could influence the distribution of diseases among groups. The difficulty that has been encountered in finding contributory alleles for complex diseases and in replicating positive associations suggests that many complex diseases involve numerous variants rather than a moderate number of alleles, and the influence of any given variant may depend in critical ways on the genetic and environmental background.[17][23][24][25] If many alleles are required to increase susceptibility to a disease, the odds are low that the necessary combination of alleles would become concentrated in a particular group purely through drift.[26]

One area in which population categories can be important considerations in genetics research is in controlling for confounding between population substructure, environmental exposures, and health outcomes. Association studies can produce spurious results if cases and controls have differing allele frequencies for genes that are not related to the disease being studied,[27] although the magnitude of this problem in genetic association studies is subject to debate.[28][29] Various methods have been developed to detect and account for population substructure,[30][31] but these methods can be difficult to apply in practice.[32]

Population substructure also can be used to advantage in genetic association studies. For example, populations that represent recent mixtures of geographically separated ancestral groups can exhibit longer-range linkage disequilibrium between susceptibility alleles and genetic markers than is the case for other populations.[33][34][35][36] Genetic studies can use this admixture linkage disequilibrium to search for disease alleles with fewer markers than would be needed otherwise. Association studies also can take advantage of the contrasting experiences of racial or ethnic groups, including migrant groups, to search for interactions between particular alleles and environmental factors that might influence health.[37][38]

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Medical genetics - Wikipedia

The genetic code is the set of rules by which information encoded within genetic material (DNA or mRNA sequences) is translated into proteins by living cells. Translation is accomplished by the ribosome, which links amino acids in an order specified by mRNA, using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

The code defines how sequences of nucleotide triplets, called codons, specify which amino acid will be added next during protein synthesis. With some exceptions,[1] a three-nucleotide codon in a nucleic acid sequence specifies a single amino acid. Because the vast majority of genes are encoded with exactly the same code (see the RNA codon table), this particular code is often referred to as the canonical or standard genetic code, or simply the genetic code, though in fact some variant codes have evolved. For example, protein synthesis in human mitochondria relies on a genetic code that differs from the standard genetic code.

While the "genetic code" determines a protein's amino acid sequence, other genomic regions determine when and where these proteins are produced according to a multitude of more complex "gene regulatory codes".

Serious efforts to understand how proteins are encoded began after the structure of DNA was discovered in 1953. George Gamow postulated that sets of three bases must be employed to encode the 20 standard amino acids used by living cells to build proteins. With four different nucleotides, a code of 2 nucleotides would allow for only a maximum of 42 = 16 amino acids. A code of 3 nucleotides could code for a maximum of 43 = 64 amino acids.[2]

The Crick, Brenner et al. experiment first demonstrated that codons consist of three DNA bases; Marshall Nirenberg and Heinrich J. Matthaei were the first to elucidate the nature of a codon in 1961 at the National Institutes of Health. They used a cell-free system to translate a poly-uracil RNA sequence (i.e., UUUUU...) and discovered that the polypeptide that they had synthesized consisted of only the amino acid phenylalanine.[3] They thereby deduced that the codon UUU specified the amino acid phenylalanine. This was followed by experiments in Severo Ochoa's laboratory that demonstrated that the poly-adenine RNA sequence (AAAAA...) coded for the polypeptide poly-lysine[4] and that the poly-cytosine RNA sequence (CCCCC...) coded for the polypeptide poly-proline.[5] Therefore, the codon AAA specified the amino acid lysine, and the codon CCC specified the amino acid proline. Using different copolymers most of the remaining codons were then determined. Subsequent work by Har Gobind Khorana identified the rest of the genetic code. Shortly thereafter, Robert W. Holley determined the structure of transfer RNA (tRNA), the adapter molecule that facilitates the process of translating RNA into protein. This work was based upon earlier studies by Severo Ochoa, who received the Nobel Prize in Physiology or Medicine in 1959 for his work on the enzymology of RNA synthesis.[6]

Extending this work, Nirenberg and Philip Leder revealed the triplet nature of the genetic code and deciphered the codons of the standard genetic code. In these experiments, various combinations of mRNA were passed through a filter that contained ribosomes, the components of cells that translate RNA into protein. Unique triplets promoted the binding of specific tRNAs to the ribosome. Leder and Nirenberg were able to determine the sequences of 54 out of 64 codons in their experiments.[7] In 1968, Khorana, Holley and Nirenberg received the Nobel Prize in Physiology or Medicine for their work.[8]

A codon is defined by the initial nucleotide from which translation starts and sets the frame for a run of uninterrupted triplets, which is known as an "open reading frame" (ORF). For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA, and CCC; and, if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Every sequence can, thus, be read in its 5' 3' direction in three reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asn, or Glu-Thr, respectively). With double-stranded DNA, there are six possible reading frames, three in the forward orientation on one strand and three reverse on the opposite strand.[9]:330 The actual frame from which a protein sequence is translated is defined by a start codon, usually the first AUG codon in the mRNA sequence.

In eukaryotes, ORFs in exons are often interrupted by introns.

Translation starts with a chain initiation codon or start codon. Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences such as the Shine-Dalgarno sequence in E. coli and initiation factors are also required to start translation. The most common start codon is AUG, which is read as methionine or, in bacteria, as formylmethionine. Alternative start codons depending on the organism include "GUG" or "UUG"; these codons normally represent valine and leucine, respectively, but as start codons they are translated as methionine or formylmethionine.[10]

The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means "amber" in German.[11] The other two stop codons were named "ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called "termination" or "nonsense" codons. They signal release of the nascent polypeptide from the ribosome because there is no cognate tRNA that has anticodons complementary to these stop signals, and so a release factor binds to the ribosome instead.[12]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low1 error in every 10100million basesdue to the "proofreading" ability of DNA polymerases.[14][15]

Missense mutations and nonsense mutations are examples of point mutations, which can cause genetic diseases such as sickle-cell disease and thalassemia respectively.[16][17][18] Clinically important missense mutations generally change the properties of the coded amino acid residue between being basic, acidic, polar or non-polar, whereas nonsense mutations result in a stop codon.[9]:266

Mutations that disrupt the reading frame sequence by indels (insertions or deletions) of a non-multiple of 3 nucleotide bases are known as frameshift mutations. These mutations usually result in a completely different translation from the original, and are also very likely to cause a stop codon to be read, which truncates the creation of the protein.[19] These mutations may impair the function of the resulting protein, and are thus rare in in vivo protein-coding sequences. One reason inheritance of frameshift mutations is rare is that, if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause death before the organism is viable.[20] Frameshift mutations may result in severe genetic diseases such as Tay-Sachs disease.[21]

Although most mutations that change protein sequences are harmful or neutral, some mutations have a beneficial effect on an organism.[22] These mutations may enable the mutant organism to withstand particular environmental stresses better than wild type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection.[23]Viruses that use RNA as their genetic material have rapid mutation rates,[24] 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.[25] In large populations of asexually reproducing organisms, for example, E. coli, multiple beneficial mutations may co-occur. This phenomenon is called clonal interference and causes competition among the mutations.[26]

Degeneracy is the redundancy of the genetic code. This term was given by Bernfield and Nirenberg. The genetic code has redundancy but no ambiguity (see the codon tables below for the full correlation). For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example, the amino acid leucine is specified by YUR or CUN (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using IUPAC notation), while the amino acid serine is specified by UCN or AGY (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position).[27]:102117:521522 A practical consequence of redundancy is that errors in the third position of the triplet codon cause only a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathy; NAN encodes average size hydrophilic residues. The genetic code is so well-structured for hydropathy that a mathematical analysis (Singular Value Decomposition) of 12 variables (4 nucleotides x 3 positions) yields a remarkable correlation (C = 0.95) for predicting the hydropathy of the encoded amino acid directly from the triplet nucleotide sequence, without translation.[28][29] Note in the table, below, eight amino acids are not affected at all by mutations at the third position of the codon, whereas in the figure above, a mutation at the second position is likely to cause a radical change in the physicochemical properties of the encoded amino acid.

The frequency of codons, also known as codon usage bias, can vary from species to species with functional implications for the control of translation. The following codon usage table is for the human genome.[30]

While slight variations on the standard code had been predicted earlier,[31] none were discovered until 1979, when researchers studying human mitochondrial genes discovered they used an alternative code.[32] Many slight variants have been discovered since then,[33] including various alternative mitochondrial codes,[34] and small variants such as translation of the codon UGA as tryptophan in Mycoplasma species, and translation of CUG as a serine rather than a leucine in yeasts of the "CTG clade" (Candida albicans is member of this group).[35][36][37] Because viruses must use the same genetic code as their hosts, modifications to the standard genetic code could interfere with the synthesis or functioning of viral proteins.[38] However, some viruses (such as totiviruses) have adapted to the genetic code modification of the host.[39] In bacteria and archaea, GUG and UUG are common start codons, but in rare cases, certain proteins may use alternative start codons not normally used by that species.[33]

In certain proteins, non-standard amino acids are substituted for standard stop codons, depending on associated signal sequences in the messenger RNA. For example, UGA can code for selenocysteine and UAG can code for pyrrolysine. Selenocysteine is now viewed as the 21st amino acid, and pyrrolysine is viewed as the 22nd.[33] Unlike selenocysteine, pyrrolysine encoded UAG is translated with the participation of a dedicated aminoacyl-tRNA synthetase.[40] Both selenocysteine and pyrrolysine may be present in the same organism.[41] Although the genetic code is normally fixed in an organism, the achaeal prokaryote Acetohalobium arabaticum can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth.[42]

Despite these differences, all known naturally occurring codes are very similar to each other, and the coding mechanism is the same for all organisms: three-base codons, tRNA, ribosomes, reading the code in the same direction and translating the code three letters at a time into sequences of amino acids.

Variant genetic codes used by an organism can be inferred by identifying highly conserved genes encoded in that genome, and comparing its codon usage to the amino acids in homologous proteins of other organisms. For example, the program FACIL[43] infers a genetic code by searching which amino acids in homologous protein domains are most often aligned to every codon. The resulting amino acid probabilities for each codon are displayed in a genetic code logo, that also shows the support for a stop codon.

The DNA codon table is essentially identical to that for RNA, but with U replaced by T.

The origin of the genetic code is a part of the question of the origin of life. Under the main hypothesis for the origin of life, the RNA world hypothesis, any model for the emergence of genetic code is intimately related to a model of the transfer from ribozymes (RNA enzymes) to proteins as the principal enzymes in cells. In line with the RNA world hypothesis, transfer RNA molecules appear to have evolved before modern aminoacyl-tRNA synthetases, so the latter cannot be part of the explanation of its patterns.[45]

A consideration of a hypothetical random genetic code further motivates a biochemical or evolutionary model for the origin of the genetic code. If amino acids were randomly assigned to triplet codons, there would be 1.51084 possible genetic codes to choose from.[46]:163 This number is found by calculating how many ways there are to place 21 items (20 amino acids plus one stop) in 64 bins, wherein each item is used at least once. [2] In fact, the distribution of codon assignments in the genetic code is nonrandom.[47] In particular, the genetic code clusters certain amino acid assignments. For example, amino acids that share the same biosynthetic pathway tend to have the same first base in their codons. This could be an evolutionary relic of early simpler genetic code with fewer amino acids, that later diverged to code for a larger set of amino acids.[48] It could also reflect steric and chemical properties that had another effect on the codon during its evolution. Amino acids with similar physical properties also tend to have similar codons,[49][50] reducing the problems caused by point mutations and mistranslations.[47]

Given the non-random genetic triplet coding scheme, it has been suggested that a tenable hypothesis for the origin of genetic code should address multiple aspects of the codon table such as absence of codons for D-amino acids, secondary codon patterns for some amino acids, confinement of synonymous positions to third position, a limited set of only 20 amino acids instead of a number closer to 64, and the relation of stop codon patterns to amino acid coding patterns.[51]

There are three main ideas for the origin of the genetic code, and many models belong to either one of them or to a combination thereof:[52]

Hypotheses for the origin of the genetic code have addressed a variety of scenarios:[56]

Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a corresponding transfer-RNA:aminoacyl tRNA-synthetase pair to encode it with diverse physicochemical and biological properties in order to be used as a tool to exploring protein structure and function or to create novel or enhanced proteins.[71][72]

H. Murakami and M. Sisido have extended some codons to have four and five bases. Steven A. Benner constructed a functional 65th (in vivo) codon.[73]

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Genetic code - Wikipedia