April 12, 2017 at 8:24 PM

More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called "human knockouts," are described in the first major study to be published in Nature this week by an international collaboration led by the Perelman School of Medicine at the University of Pennsylvania and colleagues. The program, which has so far sequenced the protein-coding regions of over 10,500 adults living in Pakistan, is illuminating the basic biology and possible therapeutics for several different disorders.

The team has identified more than 1,300 genes completely knocked out in at least one individual. They first turned their attention for deeper analysis to genes involved in cardiovascular and metabolic diseases. One gene in particular, APOC3, which regulates the metabolism of triglyceride-rich lipoproteins in the blood, was missing in several dozen individuals in a small fishing village on the coast of Pakistan where first-cousin marriages are culturally prevalent. These APOC3-knockout individuals had very low triglyceride levels. The researchers challenged their system with a high-fat meal. Compared with family members who were not APOC3 knockouts, the APOC3 knockout family members did not have the usual post-meal rise in plasma triglycerides.

"These are the world's first APOC3 human knockouts that have been identified," said co-first author and the principal investigator of the study, Danish Saleheen, MD, PhD, an assistant professor of Epidemiology and Biostatistics at Penn. "Their genetic makeup has provided unique insights about the biology of APOC3, which may further help in validating APOC3 inhibition as a therapeutic target for cardiometabolic diseases - the leading cause of death globally.

In addition to Penn, the team includes scientists from the Center for Non-Communicable Diseases (CNCD) in Karachi, Pakistan, the Broad Institute of MIT and Harvard, and the University of Cambridge, UK.

Saleheen has been working for over a decade in Pakistan, in collaboration with the CNCD to collect blood samples from all over his country. This Pakistan-based study already includes more than 70,000 participants and the recruitment is rapidly being expanded to include 200,000 people. "We are continuing protein-coding region sequencing studies in the Pakistani population. If we are able to sequence 200,000 participants, we will be able to identify human knockouts for more than 8,000 unique genes." Saleheen said. "These observations provide us with a roadmap, a systematic way to understand the physiological consequences of complete disruption of genes in humans," Saleheen said.

"The Human Genome Project gave us a 'parts' list of 18,000 genes. We are now trying to understand gene function by studying people who naturally lack a 'part,'" said co-senior author Sekar Kathiresan, Director of the Center for Genomic Medicine at Massachusetts General Hospital. "We think that over the next ten to twenty years, with a concerted, systematic effort, it's possible to find humans who naturally lack any one of several thousand genes in the genome and understand what the phenotypic consequences are."

"The project highlights the value of looking at diverse populations, particularly for genetic analyses--you'll find variants in one ethnicity and not another," said co-first author Pradeep Natarajan, an associate scientist at Broad Institute and a postdoctoral research fellow in Kathiresan's lab.

Co-senior author Daniel J. Rader, MD, chair of Genetics at Penn, hopes that future dives into this rich dataset will bring even more novel insights into human biology and point toward new therapeutic targets for treating and preventing disease. "Linking DNA sequencing with deep phenotyping at scale in this population will be an incredible source of new knowledge about how gene alterations influence human health and disease," Rader said. In addition to a continued focus on the biology of heart attacks, type 2 diabetes, and stroke, the team will also be looking for clues for early-onset Parkinson's disease, autism, congenital blindness, and mental retardation, among many other conditions.

Penn scientists are now collaborating with CNCD researchers to conduct deep phenotyping studies in all human knockouts the project identifies. These studies will include detailed physiological and mechanistic studies to understand the biological and pharmacological consequences of both partial and complete disruption of genes in humans.

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'Human knockouts': Genetics in families reveals basic biology and ... - News-Medical.net

MARWAYNE, Alta. Art Wheat says it feels like Christmas when the bull catalogues start arriving at his farm in eastern Alberta.

I look for cattle that bend the curve, he said, referring to cattle with low birth weights and high weaning rates.

I want lots of weight in the fall because I get paid on pounds.

He, with his partner and kindergarten teacher Kathy Kent, combine forces to operate T-Bone Cattle Co., renting and owning eight quarters of land and calving 300 cows in their commercial herd.

They retain some heifer calves for breeding and steers, selling some of each in fall. As well, they favour low maintenance cows and avoid larger framed animals.

Art is very selective, Kathy said.

We dont want to touch anything if we dont have to.

An easy-care herd begins with good genetics.

This day, son-in-law Justin Hozack is preparing hair samples from his bulls for DNA testing. He and Arts daughter, Dr. Joan Wheat Hozack, have launched their own operation by buying land with Art and acquiring cattle.

Were trying to figure out traits on the bulls, good and bad. Then well know what well use on our calves, said Justin, who has worked on a sheep farm in New Zealand and a cattle farm near Calgary and has taken courses in artificial insemination.

Its early days in the Wheat farm succession plan, but the couple currently resides on an acreage closer to Marwayne and keeps their animals at the family farm.

Arts three daughters pursue careers off the farm. Kate is helping on the farm while doing an instrumentation apprenticeship, while Joan is an orthopedic surgeon in Lloydminster and Jill is a lawyer in Edmonton.

Kathy has two adult children who are not involved in the farm.

Over the years, family and friends have gathered to help with branding and cattle drives.

I like to move my cows slowly, said Art, who uses horses almost exclusively for cattle chores.

These days, Art trails cattle partway to distant pastures and trucks them the rest of the way because of increased traffic and lack of labour.

He shows off a double alley Bud Box handling area that allows for a good flow of cattle into the squeeze chutes and back out to the pens.

Art has his oats and corn custom seeded, harvested and silaged.

I dont have time, said Art, whose cattle graze standing corn in the fall and winter.

Kathy assists with farm chores, which can include checking cows, making ear tags, preparing medications and overseeing meals when large groups gather to help out on the farm or enjoy a barn dance and gymkhana.

The farms origins date back to Arts mothers uncle, who came here from Ireland in 1903. Without children of his own, he passed the farm on to Arts parents, Margaret and Frank, who operated a mixed farm here and raised six children.

When Art started farming, he chose the T-Bone Cattle name because its memorable.

When you hear it, you associate it with cattle and ranching, he said.

Keen to farm from an early age, he prepared by studying farm and ranch production at Olds College and briefly did artificial insemination work on hockey legend Bobby Hulls cattle farm near Winnipeg.

T-Bone maintains a website, http://www.tbonecattleco.com, selling cattle online and young steer calves to a small family feedlot. He previously exported semen from a commercial bull to Ireland.

The family is active in ranch rodeos and cow horse events such as reining, calf (chalk) branding, trailer loading of heifers and penning.

Art said its a way to hone their skills and promote the horses they raise, train and sell. They have 25 brood mares, colts and yearlings, of which eight are used in their operation.

Its all done with horses, we like to keep it that way, said Art, who grew up riding horses.

His daughters were also involved in 4-H light horse and cattle programs.

They knew more about horses than I did, said Art.

Kathy praised 4-H for instilling in participants a strong work ethic and sense of responsibility in caring for stock.

The last two years have been decent for cattle, said Art, who cited BSE, poor cattle prices and drought among the farms many past challenges.

He managed BSE simply by cutting spending.

It set you back, said Art, citing deteriorating vehicles, equipment and corrals as a result of such austerity. No new genetics were introduced, and animals were also kept longer than they should have.

Were still working our way out of it, he said.

Off-farm activities for Art have included sitting on Albertas Livestock Identification Services board, serving as president of a local community pasture and belonging to a grazing group.

Kathy said Art has much knowledge to impart to the next generation.

Its a time in Arts life when hes ready to pass that knowledge on, said Kathy.

That includes a good eye for cattle.

He knows how to read them, work them properly, she said.

The couple plan to be involved with the farm in some way for another five to 10 years, maybe with fewer cattle.

They took a warm weather holiday this winter and think more of that may be in their future.

We may holiday more because Justin is here and we are able to get away, said Kathy.

Its hard to leave this property. Old ranchers are all the same, said Art.

Read this article:
Good genetics help make easy-care herd - Western Producer (subscription)

April 12, 2017 A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called "human knockouts," are described in the first major study to be published in Nature this week by an international collaboration led by the Perelman School of Medicine at the University of Pennsylvania and colleagues. The program, which has so far sequenced the protein-coding regions of over 10,500 adults living in Pakistan, is illuminating the basic biology and possible therapeutics for several different disorders.

The team has identified more than 1,300 genes completely knocked out in at least one individual. They first turned their attention for deeper analysis to genes involved in cardiovascular and metabolic diseases. One gene in particular, APOC3, which regulates the metabolism of triglyceride-rich lipoproteins in the blood, was missing in several dozen individuals in a small fishing village on the coast of Pakistan where first-cousin marriages are culturally prevalent. These APOC3-knockout individuals had very low triglyceride levels. The researchers challenged their system with a high-fat meal. Compared with family members who were not APOC3 knockouts, the APOC3 knockout family members did not have the usual post-meal rise in plasma triglycerides.

"These are the world's first APOC3 human knockouts that have been identified," said co-first author and the principal investigator of the study, Danish Saleheen, MD, PhD, an assistant professor of Epidemiology and Biostatistics at Penn. "Their genetic makeup has provided unique insights about the biology of APOC3, which may further help in validating APOC3 inhibition as a therapeutic target for cardiometabolic diseases - the leading cause of death globally.

In addition to Penn, the team includes scientists from the Center for Non-Communicable Diseases (CNCD) in Karachi, Pakistan, the Broad Institute of MIT and Harvard, and the University of Cambridge, UK.

Saleheen has been working for over a decade in Pakistan, in collaboration with the CNCD to collect blood samples from all over his country. This Pakistan-based study already includes more than 70,000 participants and the recruitment is rapidly being expanded to include 200,000 people. "We are continuing protein-coding region sequencing studies in the Pakistani population. If we are able to sequence 200,000 participants, we will be able to identify human knockouts for more than 8,000 unique genes." Saleheen said. "These observations provide us with a roadmap, a systematic way to understand the physiological consequences of complete disruption of genes in humans," Saleheen said.

"The Human Genome Project gave us a 'parts' list of 18,000 genes. We are now trying to understand gene function by studying people who naturally lack a 'part,'" said co-senior author Sekar Kathiresan, Director of the Center for Genomic Medicine at Massachusetts General Hospital. "We think that over the next ten to twenty years, with a concerted, systematic effort, it's possible to find humans who naturally lack any one of several thousand genes in the genome and understand what the phenotypic consequences are."

"The project highlights the value of looking at diverse populations, particularly for genetic analysesyou'll find variants in one ethnicity and not another," said co-first author Pradeep Natarajan, an associate scientist at Broad Institute and a postdoctoral research fellow in Kathiresan's lab.

Co-senior author Daniel J. Rader, MD, chair of Genetics at Penn, hopes that future dives into this rich dataset will bring even more novel insights into human biology and point toward new therapeutic targets for treating and preventing disease. "Linking DNA sequencing with deep phenotyping at scale in this population will be an incredible source of new knowledge about how gene alterations influence human health and disease," Rader said. In addition to a continued focus on the biology of heart attacks, type 2 diabetes, and stroke, the team will also be looking for clues for early-onset Parkinson's disease, autism, congenital blindness, and mental retardation, among many other conditions.

Penn scientists are now collaborating with CNCD researchers to conduct deep phenotyping studies in all human knockouts the project identifies. These studies will include detailed physiological and mechanistic studies to understand the biological and pharmacological consequences of both partial and complete disruption of genes in humans.

Explore further: Study reveals the effect of genetic 'knockouts' on human health

More information: Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity, Nature (2017). nature.com/articles/doi:10.1038/nature22034

The study, published in Science, found that individuals with certain inactive genes, or 'knockouts', did not have any related adverse health effects.

By scouring the DNA of thousands of patients, researchers at the Broad Institute, Massachusetts General Hospital, and their colleagues have discovered four rare gene mutations that not only lower the levels of triglycerides, ...

The value of intersecting the sequencing of individuals' exomes (all expressed genes) or full genomes to find rare genetic variantson a large scalewith their detailed electronic health record (EHR) information has "myriad ...

Screening methods for cardiovascular diseases such as heart attacks and strokes could be improved by measuring different biological signposts to those currently being tested, a new study led by researchers from King's College ...

A team of investigators from the Broad Institute, Massachusetts General Hospital and other leading biomedical research institutions has pinpointed rare mutations in a gene called APOA5 that increase a person's risk of having ...

An international team of researchers from institutions around the world, including Baylor College of Medicine, has discovered that mutations of the OTUD6B gene result in a spectrum of physical and intellectual deficits. This ...

More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called "human knockouts," are described in the first major study to be published in Nature this week by an international collaboration ...

Patients with colon and rectal cancer have somatic insertions of mitochondrial DNA into the nuclear genomes of the cancer cells, University of Alabama at Birmingham researchers report in the journal Genome Medicine.

A new 'deep learning' method, DeepCpG, has been designed by researchers at the Wellcome Trust Sanger Institute, the European Bioinformatics Institute and the Babraham Institute to help scientists better understand the epigenome ...

Researchers discovered three novel genetic mutations associated with Fuchs endothelial corneal dystrophy, the most common corneal disorder requiring transplantation.

A big data study of hepatitis C and more than 500 patients with the virus has opened the way for a better understanding of how the virus interacts with its human hosts.

Scientists at The Wistar Institute have unveiled part of the protein complex that protects telomeresthe ends of our chromosomes. The study, published online in Nature Communications, explains how a group of genetic mutations ...

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Originally posted here:
Genetics of first-cousin marriage families show how some are protected from heart disease - Medical Xpress

Browse > Home / In Focus / On the genetics trail

Posted on Tuesday, April 11, 2017

Dr. Donald Vinh (left), a researcher at the RI-MUHC and Steven Francis. Finally knowing makes me super happy and excited. Cant wait to see what will come next, says Steven Francis.

By solving one patients case, doctors develop a molecular therapy that could help many

By MUHC Communications

Researchers have identified the genetic mutation responsible for one patients serious health problems, finally solving a medical mystery that has endured for over 30 years. Thanks to this discovery, the researcher developed a therapy that could also help a lot of people who have problems related to the immune system, whether they are genetic or due to a transplant or an illness.

In the laboratory, we demonstrated that a molecule called Morpholino Antisense Oligonucleotide could correct this kind of genetic anomaly and allow the patients immune system to function properly, explains Dr. Donald Vinh, a researcher at the Research Institute of the McGill University Health Centre (RI-MUHC) and the principal author of the study published in the Journal of Allergy and Clinical Immunology.

As a child, I often had to miss school and it was difficult to make friends. I was often mad. It is hard not knowing why you are sick, says Steven Francis

Steven Francis, the MUHC patient at the centre of this discovery, has dealt with significant health issues his whole life. Followed at the MUHC since childhood, he has faced sinus infections, fungal infections, inflammations of the colon, shingles, respiratory problems, renal issues, and impeded growth, throughout all of which doctors were unable to discover an underlying cause; they suspected that it was genetic, but were unable to prove it. His family went so far as to consult specialists in the United States without success.

The tide finally turned in his favour when Dr. Vinh examined his case in 2012. When this patient was referred to me, I went over his entire file in detail, covering some 30 years and literally filling two large cardboard boxes. I also looked at his family history. Since the 1980s, many new immune deficiencies have been identified, and I was able to apply the knowledge from these advances to solve the case, he explains.

Dr. Vinh discovered that Francis had a mutation on a gene that is critical for the proper function of the immune system, called ZAP70. It serves to synthesize a protein of the same name that helps activate our T cells. Without the ZAP70 protein, the body cant defend itself effectively against most infections.

A mutation on this gene is known to be fatal, and the only treatment available up until now has been a bone marrow transplant that must take place before the age of five. With this new discovery, we have found out that genetic mutations of this kind are also found in adults, which could lead to tremendous advances in research. Solving this mystery has opened a new door into the way that the scientific community will look at immune system deficiencies, says Dr. Vinh. The discovery is all the more remarkable considering this gene cannot be studied in mice.

Francis is now 35 years old. In his case, Dr. Vinh and his team now understand exactly where to find the mutation and how it behaves. His specific mutation subtly affects the slicing of the gene and doesnt affect the amino acid sequence that synthesizes the ZAP70 protein. Inspired by a little known treatment used in cases of hypercholesterolemia, Dr. Vinh successfully developed a molecule that exclusively blocks the mutation while allowing the protein to be synthesized.

In the process of helping Francis, the researchers have shown in their laboratory that it is possible to create a molecular therapy that might improve the human immune system.

For Dr. Vinh, the battle is still only half won: while all the pieces of the puzzle might be found, they havent yet been fully put together. There are definitely more steps to take before we can test this treatment. For one thing, we have to convince the industry to support us. When Steven can finally get the benefit of the treatment, Ill be able to count this as a victory.

Dr. Vinh: on the genetics trail

Dr. Vinh studies genetic defects of the immune system. He seeks to understand why the genetic make-up of certain individuals leaves them more vulnerable to rare, severe or recurrent infections.

In his clinic and in his laboratory, he receives patients with complicated health problems that seem to be linked to their immune system. He treats what are called rare and orphan diseases affecting less than 1 person in 2000.

Dr. Vinh knows that there are people like Francis all across Canada they are getting sick but nobody knows why. His team is specialized in finding answers for complicated cases and more importantly, finding new solutions. It doesnt matter if you are in Montreal, Halifax or northern Qubec he wants people to know they are here for them. Patients are referred to him from all of Eastern Canada.

Dr. Vinh is sometimes compared to Dr. Gregory House of the popular television series. Like House, Dr. Vinh has a reputation across the country for his interest in the most atypical medical conditions within his field of practice. I may have a few things in common with him, but Id like to think people find me a nicer person than he is! he jokes.

Category: In Focus

Tag: Donald Vinh, genetics, molecular therapy

Continue reading here:
On the genetics trail - McGill Reporter

D

r. Maximilian Muenke has a superpower: He can diagnose disease just by looking at a persons face.

Specifically, he can spot certain genetic disorders that make telltale impressions on facial features.

Once youve done it for a certain amount of years, you walk into a room and its like, oh, that child has Williams syndrome, he said, referring to a genetic disorder that canaffecta persons cognitive abilities and heart.

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And thats an incredibly useful skill, even as genetic sequencing becomes more widespread. For one thing, it can be the factor that sends someone to get a genetic test in the first place. For another, people in many parts of the world dont have access to genetic tests at all.

Thats inspired years of effort to train a computer to do the same thing. Software that analyzes a patients face for signs of disease could help clinicians better diagnose and treat people withgenetic syndromes.

Some older attempts at facial analysis relied on large, clunky scanners a tool better suited to a lab, not the field. Now, in the era of smartphones, such efforts have a whole new promise. Face2Gene, a program developed by Boston-based startup FDNA, has a mobile app that clinicians can use to snap photos of their patients and get a list of syndromes they might have.

FDA approves sale of genetic tests for risk of Alzheimers and other diseases

Meanwhile, Muenke and his colleagues at the NIH last month published an important advance: the ability to diagnose disease in a non-Caucasian face.

Its a promising preliminary sign. But if facial recognition software is to be widely useful for diagnoses, software developers and geneticists will need to work together to overcome genetics systemic blind spots.

Thealgorithms in general work on the same principles: measuring the size of facial features and their placement to detect patterns. Theyre both trained on databases of photographs doctors take of their patients. The NIH works with partners around the world to collect their photos; FDNA accepts photos uploaded to Face2Gene.

But they differ in a key way: Whereas the algorithm the NIH uses can predict if someone has a given genetic disorder, the Face2Gene algorithm spits out not diagnoses, but probabilities. The app describes photos as being a certain percent similar to photos of people with one of the 2,000 disorders for which Face2Gene has image data, based on the overall look of the face as well as the presence of certain features. However, the app wont give clinicians a yes or no answer to the question of, Does my patient have a genetic disorder?

Thats intentional. Face2Gene is meant to be more like a search engine for diseases a means to an end.

We are not a diagnostic tool, and we will never be a diagnostic tool, said FDNA CEODekel Gelbman.

Drawing that bright line between Face2Gene and a diagnostic tool allows FDNA to stay compliant with FDA regulations governing mobile medical apps while avoiding some of the regulatory burden associated with smartphone-based diagnostic tools.

The algorithm the NIH uses developed by scientists atChildrens National Health System in Washington, D.C., seems to work pretty well so far: In 129 cases ofDown syndrome, it accurately detected the disorder94 percent of the time. For DiGeorge syndrome, the numbers were even higher: It had a 95 percent accuracy rate across all 156 cases.

Face2Gene declined to provide similar numbers for their technology. Since Face2Gene is a search and reference informational tool, the terms sensitivity and specificity are difficult to apply to our output, Gelbman cautioned.

But theres one big stumbling block for both of them, a problem that has dogged medical genetics for decades: Data for non-white populations is sorely lacking.

Should biologists stop grouping us by race?

In every single textbook, the ones we had [when I trained] in Germany and the major textbooks here in the US, there are photos of individuals of northern European descent, Muenke said. When I told this to my boss, he said there have to be atlases for children from diverse backgrounds. And there arent.There just arent. (Today there is that resource, based on Muenke and the NIHs work.)

So diagnosing diseases from a face alone presents an additional challenge in countries where the majority of the population isnt of northern European descent, because some facial areas that vary with ethnic background can often overlap with areas that signify a genetic disorder. Eventually, the software will also have to be able to tackle people with mixed ethnic backgrounds, too. We have thought about it but havent gone there yet, Muenke said.

For example, children with Down syndrome often have flat nasal bridges as do typically developing African or African-American children. Across different races and ethnicities of children there were only tworeliable identifiers that could be used to diagnose Down syndrome the angles between landmark points on the childs nose and eye, according to a paper Muenke and Marius Linguraru at Childrens National published with their colleagues earlier this year. All of the other typical features werent significantly more likely to show up when childrenwere compared toethnically matched controls.

In fact, using a Caucasian face as a reference can sometimes be the least representative choice. One of the findings that Im very interested in [in] our recent study was that the population that we found to be most different from the others, in terms of facial patterns characteristic of DiGeorge syndrome, was the Caucasian population, Linguraru said.

To continue to fix this problem, both the NIH and Face2Gene need help from more researchers who can upload more patients faces but thats easier said than done. Confirming a suspected disorder with genetic tests is standard practice today, and there are no genetic labs based in Africa registered in the NIHs Genetic Testing Registry. Asia and South America are also relatively underserved.

Those numbers also reflect the general patterns of distribution for medical geneticists.Most practitioners are located in North America and Europe, Gelbman said. Nigeria, for example, doesnt have a singlemedical geneticist in the entire country.

Its possible that might change, with time and effort. In addition to his work as a researcher, Muenke directs a program that brings health care professionals from developing countriesto the US for a month-long crash course in medical genetics. (The program is funded by the NIHs Fogarty International Center; President Trump eliminated funding for the center in his 2018 skinny budget proposal announced in March.)

For now, both algorithms have shown that they can handle a diverse patient set.FDNA scientists published a paper in January showing that their algorithm could better identify Down syndrome after being trained with a more diverse set of faces, andMuenke and Linguraru have also published papersthis yeardemonstrating their algorithms ability to identify genetic disorders correctly in children acrossa variety of ethnicbackgrounds.

As both groups work on recruiting more researchers, they are also working to push their tech forward. FDNA is working on establishing partnerships with pharmaceutical companies to start their commercial outreach. In theory, these partnerships could contribute to precision medicine efforts or help companies develop new therapies for rare diseases.

Meanwhile, Linguraru has his eyes on eventual FDA approval for the algorithm the NIH has used. The ultimate goal would be a simple tool that any doctor could use anywhere to get fast results and better diagnose their patients.

Kate Sheridan can be reached at kate.sheridan@statnews.com Follow Kate on Twitter @sheridan_kate

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Facial-recognition software finds new use: diagnosing genetic ... - Stat - STAT

ByAdam Allington

April 10, 2017 | 5:48 AM

The Food and Drug Administration has given the go-ahead to home genetics testing company 23andMe to inform customers whether they have an increased risk of diseases like Alzheimer's or Parkinsons.

Some experts are not convinced the information from 23andMe, which is known for selling tests allowing people to learn more about their ancestors, will be helpful to consumers, partly because genetic testing is so complex.

To do that [genetic testing] by mail order is fraught with certain problems, said James Evans, professor of genetics at the University of North Carolina. Evans said the tests are not the same as a diagnosis, and without input from a professional, people might not know how to interpret the data.

But others say theres no harm in having the information.

The idea that people should be protected from their own information strikes me as antiquated and paternalistic, said David Shaywitz, chief medical officer of DNAnexus, a company that manages large volumes of genomic data. But, he said, How useful is it going to be? I dont think it is going to be particularly informative.

Shaywitz said thats because even if someone were to test positive for a genetic variant, she or he may never develop the disease.

Read more here:
FDA clears 23andMe to sell genetics tests for diseases - Marketplace.org

The Teagasc INZAC flock, consisting of 180 ewes, is entering into its second full year of production.

The flock is comprised of 120 Irish Suffolk and Texel ewes split 50:50 between each breed and a flock of 30 New Zealand Texel and 30 New Zealand Suffolk ewes.

Dr. Fiona McGovern gave pedigree sheep breeders a run through of the operation earlier today, as part of a Sheep Ireland industry meeting.

McGovern, a UCD graduate, said the trial was established to validate the Replacement Index and to compare the difference between Irish and New Zealand ewe genetics.

As part of the trial, she said, the performance of Irish one-star (low) and five-star (elite) ewes under the Replacement Index is being compared.

Although the trial is primarily focused on maternal traits, data on a number of terminal traits is also being collected due to the overlapping nature of both indices.

These include lamb birth, 60-day and weaning weights. The length of time it takes the ewes progeny to reach slaughter or Days to Slaughter is also measured under the study.

McGovern added that the first of the animals involved in the study were brought onto the farm in 2014. 2016 was the first full year of the trial.

Currently the ewes are being grazed as three separate groups. These include an elite flock, consisting of 60 Irish Suffolk and Texel ewes all of which are five-star rated on the Replacement Index.

The trial also features a low flock, consisting of a mixture of 60 Irish Texel and Suffolk ewes. All of these ewes are rated as being one-star on the Replacement Index.

The third group the New Zealand ewes is also comprised of a mixture of Texel and Suffolk animals.

Each of the groups are split 50:50 between Suffolk and Texel genetics.

The three groups are grazed on a 15ha platform, which is subdivided into a 5ha farmlet for each individual group. Each farmlet carries 12 ewes/ha and receives 150kg of nitrogen/ha/year.

Early trial results show that the New Zealand flock had better performance in a number of areas, but it must be noted that the results presented are only from the first year of a four-year trial.

The trial results show that more New Zealand ewes held to the first service at breeding, while there was no significant difference between the low and elite ewe groups.

Looking at other key breeding metrics, there was no difference in the barren percentage, scan rate or lambing rate between the three ewe groups.

However, the New Zealand flock did produce more lambs (number of lambs born) when compared to the Irish low and elite flocks, which had almost identical results.

Interestingly, the New Zealand group had less lambing difficulty (dystocia) than either of the two Irish flocks, which once again posted similar performance figures.

From a production point of view, there was no difference between the birth, 40-day, weaning and drafting weights between the progeny of either group.

However, the lambs produced from the New Zealand and elite flocks did reach slaughter weight earlier than the low group.

The New Zealand and elite lambs took 155 days and 164 days respectively, to reach slaughter weight meaning that there was no significant difference between both groups. However, it took the low lambs 178 days to come to slaughter.

McGovern added that the last of the low lambs were sold off-farm in November and required concentrates to finish, while the last of the New Zealand lambs were drafted in September after 96% of these animals had received a grass-only diet.

The rest is here:
New Zealand genetics delivering the goods in Athenry - Agriland

Action Points

Molecular screening of different tumor types led to a matched targeted treatment strategy for a subset of patients with advanced, hard-to-treat cancers, although only a minority of those who were successfully screened and treated derived clinical benefit from the approach, a single-center, single-arm, open-label trial indicated.

Out of a cohort of 1,035 patients, a molecular portrait could be identified in 89% of them, among whom an actionable target was detected in almost half of the group at 49%, reported Fabrice Andre, MD, PhD, of Gustave Roussy Cancer Institute in Villejuif, France, and colleagues. This subsequently led to 199 patients actually receiving a treatment course matched to their specific genomic alternation.

And in this subgroup of patients, clinical benefit as reflected by the percentage of patients who achieved a progression-free survival (PFS) interval on matched therapy (PFS2) that was 1.3-fold longer than the PFS interval achieved on prior therapy (PFS1) was documented in one-third of them, 11% of them being objective responses.

"There are controversies about whether the use of high-throughput genomics could improve outcomes in patients with hard-to-treat cancers," explained Andre and colleagues in Cancer Discovery. "In the present study, we have shown that tumor sequencing improves outcome in 33% of patients with advanced cancers," they added. "Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach."

The Molecular Screening for Cancer Treatment Optimization (MOSCATO) 01 trial involved both adult and pediatric patients with a variety of tumor types. The most common tumors included digestive cancer followed by lung cancer, urological cancers, breast cancer, and head and neck cancer. The median number of prior lines of therapy was 4 and tumor biopsies were successfully taken in the majority of patients.

The approaches used to obtain molecular portraits for the 843 patients in whom such a portrait was identified included targeted sequencing and array comparative genomic hybridization analysis. As investigators noted, both RNA sequencing and whole-exome sequencing were added during the course of the study. "The vast majority of the patients received matched therapy in the context of phase I/II trials," Andre noted. Complete responses were documented in two patients or 1% of those who received matched treatment.

There were also 20 partial responses, 10% of the treated cohort. Disease stabilized in 52% of the group and 17% had progressive disease. "The median follow-up for progression-free survival on matched therapy or PFS2 was 20 months," researchers noted, "and median PFS2 was estimated at 2.3 months." The estimated median overall survival was 11.9 months.

"There are several ways to further improve the efficacy of precision medicine," Andre suggested. First, researchers need better ways with which to identify genomic alterations. For example, although both RNA and whole-exome sequencing were done in a large proportion of patients in the MOSCATO trial, "they were not useful to drive patients to therapy," as he pointed out. Researchers also need to be able to more accurately identify which patients might gain from a genomics approach.

Lastly, scientists need to identify targeted combinations of therapies that might improve clinical outcomes, especially for patients who have more than one driver alteration.

Commenting on the study, Leif Ellisen, MD, PhD, of Massachusetts General Hospital Breast Cancer Center in Boston, felt that overall, the MOSCATO 01 trial was an encouraging study.

"There are a few things that you have to remember about this study in particular and the field in general," Ellisen said. To some degree the "deck was stacked" against the study because patients who previously received standard therapy -- including targeted agents against well-established actionable targets -- were excluded from this trial.

"In other words, the study had already culled out known successes of genotype-driven therapy," Ellisen emphasized.

He also pointed out that the median number of prior therapies was four, so investigators were pitted against advanced disease known to be more aggressive and resistant to treatment. "But the bigger picture is that systematically doing genotypic-directed therapy is really a means to a larger end and that larger end is allowing us to collect the data about the relationship between the genotype of a tumor and response to therapy that informs us how we should treat future patients."

If physicians 30 years ago abandoned chemotherapy for patients with advanced cancer on the grounds that only a minority of them responded to it, "we would never have made any progress in oncology," he added.

"This is really the same story -- because only a minority of patients who benefit from this approach today does not mean that the data we are collecting and correlating with responses is not going to be the thing that allows us to make advances tomorrow as we refine our predictions and more patients can benefit in the future."

The study was supported by Genentech and Sanofi.

Andre disclosed no relevant relationships with industry. One or more coauthors disclosed relationships with Roche/Genentech, AstraZeneca, Lilly, Servier, Merck, Pfizer, Eisai, Actelion, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Haliodx, Novartis, Sanofi, Pharmamar, and Pierre Fabre.

Ellisen disclosed no relevant relationships with industry.

2017-04-08T16:00:00-0400

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Mixed Results with Genetics-Guided Cancer Therapy - MedPage Today

NEW YORK (GenomeWeb) Cancer Genetics said today that it has been hired by Effector Therapeutics to provide clinical biomarker services for Effector's lead product candidate, eFT508 a highly selective oral small molecule inhibitor of MNK1 and MNK2.

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Cancer Genetics to Evaluate Biomarkers for Effector Therapeutics - GenomeWeb

Genetic testing company 23AndMe is back with a controversial new offering, after the U.S. Food and Drug Administration on Thursday green-lighted the companys request to market a fresh batch of direct-to-consumer tests. Soon, with a simple saliva swab dropped in the mail, customers will be able to get answers about their genetic risk for developing 10 maladiesincluding Parkinsons disease and late-onset Alzheimers.

The FDA approval will likely reignite a long-simmering debate about when and how such tests should be used. Even when there are strong links between certain gene variants and medical conditions, genetic information often remains difficult to interpret. It must be balanced against other factors including health status, lifestyle and environmental influences, which could sharpen or weaken risk. If disease risk news is delivered at homewithout a genetic counselor or doctor on hand to offer contextmany geneticists fear it can lead to unnecessary stress, confusion and misunderstandings.

Against that backdrop, the FDAs decision came with caveats: Results obtained from the tests should not be used for diagnosis or to inform treatment decisions, the agency said in a statement. It added that false positive and false negative findings are possible.

But geneticist Michael Watson, executive director of the American College of Medical Genetics and Genomics, thinks consumers will have trouble making such distinctions and says he doubts people will view them as a mere novelty. Watson also worries 23AndMes wares may create other problems: Follow-up testing for some of these conditions may be quite pricey, he says, and insurance companies might not cover that cost if a person has no symptoms. He also notes that some of the conditions involved may have no proved treatments, leaving consumers with major concernsand few options to address them, aside from steps like making some lifestyle changes.

The makeup of 23AndMes reports to consumers is still being finalized, but the company says it does not expect to grade or rank a persons risk of developing any of the 10 conditions approved for analysis. Instead it will simply report a person has a gene variant associated with any of the maladies and is at an increased risk, the company told Scientific American.

The FDA decision may significantly widen the companys market and top off a years-long debate about what sort of genetic information should be available to consumers without professional medical oversight. After the FDAs 2013 decision to stop 23AndMe from sharing data about disease risk with its customers, the company was still able to offer them information about their genetic ancestry. It has also been selling consumer tests for genes that would indicate whether people are carriers for more than 30 heritable conditions, including cystic fibrosis and Tay-Sachs disease.

This month 23AndMe plans to release its first set of genetic health-risk reports for late-onset Alzheimers disease, Parkinsons disease, hereditary thrombophilia (a blood-clotting disorder), alpha 1-antitrypsin deficiency (a condition that raises the risk of lung and liver disease), and a new carrier status report for Gauchers disease (an organ and tissue disorder). Reports for other tests will follow, the company says.

In considering whether to approve the tests, the FDA says it reviewed studies that demonstrated the 23AndMe procedures correctly and consistently identified variants associated with the 10 conditions. Further data from peer-reviewed scientific literature demonstrated the links between these gene variants and conditions, and supported the underlying science.

The FDA also announced on Thursday that it plans to offer the company exemptions for similar genetic tests in the future, without requiring them to be submitted for premarket review. That decision could leave the door open to offering tests for other conditions that have questionable reproducibility, says Jim Evans, a genetics and medicine professor at the University of North Carolina School of Medicine.

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Too Much Information? FDA Clears 23AndMe to Sell Home Genetic Tests for Alzheimer's and Parkinson's - Scientific American