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Forkhead Box O3 (Foxo3) Anti-Aging Gene May Hold Key to Protect Inner Ear Hair Cells from Damage

Forkhead Box O3 (Foxo3) Anti-Aging Gene May Hold Key to Protect Inner Ear Hair Cells from Damage | Amazing Science | Scoop.it

Researchers have discovered that a protein implicated in human longevity may also play a role in restoring hearing after noise exposure. The findings, where were published in the journal Scientific Reports, could one day provide researchers with new tools to prevent hearing loss.

 

The study reveals that a gene called Forkhead Box O3 (Foxo3) appears to play a role in protecting outer hair cells in the inner ear from damage. The outer hair cells act as a biological sound amplifier and are critical to hearing. When exposed to loud noises, these cells undergo stress. In some individuals, these cells are able to recover, but in others the outer hair cells die, permanently impairing hearing. While hearing aids and other treatments can help recovered some range of hearing, there is currently no biological cure for hearing loss.

 

"While more than a hundred genes have been identified as being involved in childhood hearing loss, little is known about the genes that regulate hearing recovery after noise exposure," said Patricia White, Ph.D., a research associate professor in the University of Rochester Medical Center (URMC) Department of Neuroscience and lead author of the study. "Our study shows that Foxo3 could play an important role in determining which individuals might be more susceptible to noise-induced hearing loss."

 

Approximately one-third of people who reach retirement age have some degree of hearing loss, primarily due to noise exposure over their lifetimes. The problem is even more acute in the military, with upwards of 60 percent of individuals who have been deployed in forward areas experiencing hearing loss, making it the most common disability for combat veterans.

 

Foxo3 is known to play an important role in cell's stress response. For example, in the cardiovascular system, Foxo3 helps heart cells stay healthy by clearing away debris when the cells are damaged. Additionally, people with a genetic mutation that confers higher levels of Foxo3 protein have been shown to live longer.

 

White and her team carried out a series of experiments involving knock-out mice who were genetically engineered to lack the Foxo3 gene. The researchers found that, compared to normal mice, these animals were unable to recover hearing after being exposed to loud noises. The team also observed that during the experiment the Foxo3 knock-out mice lost most of their outer hair cells. In the normal mice, outer hair cell loss was not significant.

 

"Discovering that Foxo3 was important for the survival of outer hair cells is a significant advance," says senior author Patricia White. "We are also excited about the results because Foxo3 is a transcription factor, which regulates the expression of many target genes. We are currently investigating what its targets might be in the inner ear, and how they could act to protect the ear from damage."

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Amish Mutation in PAI-1 Protects Against Diabetes and May Extend Life

Amish Mutation in PAI-1 Protects Against Diabetes and May Extend Life | Amazing Science | Scoop.it

Amish men and women who carried a genetic mutation appeared to be in better cardiovascular health and had longer telomeres, a barometer of longevity.

 

The findings, published on Wednesday in the journal Science Advances, shed light on the processes underlying cellular aging and could lead to new therapies for chronic diseases, some experts say. The researchers are planning at least one follow-up trial that will recreate the effects of the mutation so they can study its impact on obese people with insulin resistance, a precursor to diabetes.

 

The mutation described in the new paper affects a mysterious protein called plasminogen activator inhibitor-1, or PAI-1, that is known primarily for its role in promoting blood clotting. The mutation was first identified in 1991 in a secluded Amish farming community in Berne, Ind. An estimated 5 percent of the community carries the mutation, which causes them to produce unusually low levels of PAI-1.

 

Scientists have long suspected that PAI-1 has other functions outside of clotting that relate to aging. Dr. Douglas Vaughan, a cardiologist at Northwestern medical school, noticed, for example, that mice that had been genetically engineered to produce high levels of the protein age fairly quickly, going bald and dying of heart attacks at young ages. People who have higher levels of the protein in their bloodstreams also tend to have higher rates of diabetes and other metabolic problems and to die earlier of cardiovascular disease.

 

Dr. Vaughan took a team of 40 researchers to their town, set up testing stations in a recreation center, and spent two days doing extensive tests on 177 members of the community, many of whom arrived by horse and buggy. The researchers pored over birth and death records and took extensive genealogical histories. They drew blood, did ultrasounds of their hearts, and rigorously examined their cardiac and pulmonary function.

 

“Some of the young men we collected blood from fainted because they had never had a needle stick in their life,” said Dr. Vaughan, who is chairman of medicine at the Northwestern University Feinberg School of Medicine. “These people live sort of an 18th century lifestyle and generally don’t take advantage of modern medicine. But they were so gracious and courteous and cooperative.”

 

What Dr. Vaughan and his colleagues discovered was striking. Amish carriers of the mutation live on average to age 85, about 10 years longer than their peers. Among the Amish who did not have the mutation, the rate of Type 2 diabetes was 7 percent. But for carriers of the mutation, the rate was zero, despite leading the same lifestyle and consuming similar diets. Tests showed that carriers of the mutation had 28 percent lower levels of insulin, a hormone whose chronic elevation can lead to Type 2 diabetes. “Diabetes is something that develops more as we age,” Dr. Vaughan said. “This is a terrific indicator that the mutation actually protected them from a metabolic consequence of aging.”

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Researchers Identify Liver Fibrosis-Causing Protein

Researchers Identify Liver Fibrosis-Causing Protein | Amazing Science | Scoop.it

An international team of scientists has identified a long-sought protein that causes liver fibrosis (scarring), paving the way for new treatments. The research was published in the journal Nature Genetics.

 

The team led by Professor Jacob George and Dr. Mohammed Eslam of the Westmead Institute for Medical Research in Sydney, Australia, has unequivocally shown that variations in the interferon lambda 3 (INLF3) protein are responsible for tissue damage in the liver.

 

The researchers had previously identified that the common genetic variations associated with liver fibrosis were located on chromosome 19 between the IFNL3 and IFNL4 genes.

 

In the new study, they analyzed liver samples from 2,000 patients with hepatitis C, using state-of-the art genetic and functional analysis, to determine the specific IFNL protein responsible for liver fibrosis. They demonstrated that following injury there is increased migration of inflammatory cells from blood to the liver, increasing IFNL3 secretion and liver damage.

 

Notably, this response is determined to a great extent by an individual’s inherited genetic makeup. “This was a significant outcome that will help to predict risk of liver disease for individuals, enabling early intervention and lifestyle changes,” said Prof. George, who is the corresponding author of the study.

 

“We have designed a diagnostic tool based on our discoveries, which is freely available for all doctors to use, to aid in predicting liver fibrosis risk. This test will help to determine whether an individual is at high risk of developing liver fibrosis, or whether a patient’s liver disease will progress rapidly or slowly, based on their genetic makeup. This important discovery will play a vital role in reducing the burden of liver disease into the future,” he said. “This discovery holds great promise for the development of effective therapeutic treatments for liver disease,” added co-lead author Dr. Eslam.

 

“There is an urgent need for a safe pharmacologic therapy that can prevent of regress the progression of liver damage. There are currently no treatments available for patients with advanced fibrosis, and liver transplantation is the only treatment for liver failure,” he said. “Now that we’ve identified IFNL3 as the cause of liver scarring, we can work towards developing novel treatments specifically targeting this gene. This could be medicine targeting IFNL3 that is tailored to an individual’s genetic makeup, but could also include modifying usual treatment depending on whether a patient has IFNL3 risk genes.”

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Mice Provide Insight Into Genetics of Autism Spectrum Disorders

Mice Provide Insight Into Genetics of Autism Spectrum Disorders | Amazing Science | Scoop.it

While the definitive causes remain unclear, several genetic and environmental factors increase the likelihood of autism spectrum disorder, or ASD, a group of conditions covering a “spectrum” of symptoms, skills and levels of disability.

 

Taking advantage of advances in genetic technologies, researchers led by Alex Nord, assistant professor of neurobiology, physiology and behavior with the Center for Neuroscience at the University of California, Davis, are gaining a better understanding of the role played by a specific gene involved in autism. The collaborative work appears June 26 in the journalNature Neuroscience.

 

“For years, the targets of drug discovery and treatment have been based on an unknown black box of what’s happening in the brain,” said Nord. “Now, using genetic approaches to study the impact of specific mutations found in cases, we’re trying to build a cohesive model that links genetic control of brain development with behavior and brain function.”

 

The Nord laboratory studies how the genome encodes brain development and function, with a particular interest in understanding the genetic basis of neurological disorders.

 

There is no known specific genetic cause for most cases of autism, but many different genes have been linked to the disorder. In rare, specific cases of people with ASD, one copy of a gene called CHD8 is mutated and loses function. The CHD8 gene encodes a protein responsible for packaging DNA in cells throughout the body. Packaging of DNA controls how genes are turned on and off in cells during development. 

 

Because mice and humans share on average 85 percent of similarly coded genes, mice can be used as a model to study how genetic mutations impact brain development. Changes in mouse DNA mimic changes in human DNA and vice-versa. In addition, mice exhibit behaviors that can be used as models for exploring human behavior.


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Icelandic family of 10 suffering from psychosis helps to identify RBM12 as lead causative candidate

Icelandic family of 10 suffering from psychosis helps to identify RBM12 as lead causative candidate | Amazing Science | Scoop.it

A team from Iceland, Finland, and Germany have found evidence that links some forms of psychosis to mutations that lop off the end of the RNA-binding motif protein 12-coding gene RBM12.

 

As they reported in Nature Genetics, the researchers used genotyping and imputation-based long-range phasing to search for risky variants in a family from Iceland that included six individuals with of schizophrenia and two family members apiece with schizoaffective disorder or psychotic bipolar disorder. They also profiled seven psychosis-affected family members by whole-genome sequencing.

 

With genetic data from that family — and from a psychosis-affected family from Finland — the team narrowed in on a rare, psychosis-related truncation mutation in RBM12. Although that mutation did segregate with psychosis, it did not appear to be fully penetrant. Instead, the group reported that some individuals carrying the mutation did share non-psychosis-related psychiatric and neuropsychological features with their affected relatives.

 

"In addition to identifying RBM12 … the work reported here provides a template for future familial studies of psychosis, suggesting that the mutations involved are likely to be recent, may be incompletely penetrant for psychosis, but lead to related phenotypes in carriers unaffected by psychosis, and are likely to act in concert with other sequence variants," corresponding author Kari Stefansson, with Decode/Amgen and the University of Iceland, and his colleagues wrote.

 

Based on array-based genotypes, long-range phasing, and/or genome sequence data for the 10 individuals with psychosis from the first family, the researchers narrowed in on a shared nonsense mutation in the last coding exon of RBM12 that was verified with Sanger sequencing. The alteration did not turn up in the Genome Aggregation Database (gnomAD), they reported, and was identified in fewer than two dozen other Icelanders, all descended from the family in question.

 

Along with experiments done to gauge expression of the RBM12 in lymphoblast cell lines from several individuals who did or did not carry mutated versions of the gene, the team scoured sequence databases for other suspicious looking changes in RBM12, narrowing in on another mutation in the gene in an individual from Finland who had been diagnosed with schizophrenia.

 

That individual also carried a chromosome 22 deletion already associated with psychosis, the authors noted. But the same deletion was not present in four siblings with psychosis who shared RBM12 with the first Finnish family member. Conversely, unaffected siblings did carry the chromosome 22 deletion. The RBM12 mutation did not turn up in the unaffected Finnish family members, though findings from the Icelandic family indicated that mutations in that gene are not fully penetrant. 

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What Can You Do With the World's Largest Family Tree of 13 Million People?

What Can You Do With the World's Largest Family Tree of 13 Million People? | Amazing Science | Scoop.it

Your family tree might contain a few curious revelations. It might alert you to the existence of long-lost third cousins. It might tell you your 10-times-great-grandfather once bought a chunk of Brooklyn. It might reveal that you have royal blood. But when family trees includes millions of people—maybe even tens of millions of people—then we’re beyond the realm of individual stories.

 

When genealogies get so big, they’re not just the story of a family anymore; they contain the stories of whole countries and, at the risk of sounding grandiose, even all of humanity.

 

Last week, scientists using data from Ancestry.com and Geni.com each unveiled papers analyzing the genealogies for patterns like migrations, lifespan, and when people stopped marrying family members. Ancestry.com sells both subscriptions to its genealogy research site and a popular genetic test through its subsidiary AncestryDNA. Its geneticists— along with a historian—used the genetic data of 770,000 AncestryDNA customers along with the genealogy records of their ancestors to map migrations in North America.

 

The team first analyzed the DNA tests to find clusters of closely related people in the present. Then, they matched up the people in those clusters with genealogy records containing 20 million people, which included the birthplaces of several generations of ancestors. With that, they could march backwards in time to see how those ancestors migrated across the U.S.

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Molecular patterns of complex diseases

Molecular patterns of complex diseases | Amazing Science | Scoop.it

The Helmholtz Zentrum München has published results of the largest genome-wide association study on proteomics to date. An international team of scientists reports 539 associations between protein levels and genetic variants in ‘Nature Communications’. These associations overlap with risk genes for 42 complex diseases.

 

Genome-wide association studies (GWAS) provide an opportunity to associate concentration changes in certain proteins or metabolic products with gene loci. Knowledge of these genes makes it possible to establish connections to complex diseases. Scientists utilize the fact that to date, hundreds of associations between genetic variants and complex diseases have been demonstrated. These associations are immensely important because they do help uncover the underlying molecular mechanisms.

 

"In the world's largest proteomics GWAS to date, we worked with colleagues* to examine blood samples from 1,000 participants in the KORA study**," reports Dr. Gabi Kastenmüller. She is acting director and head of the Metabolomics Group at the Institute of Bioinformatics and Systems Biology (IBIS) at the Helmholtz Zentrum München. The team quantified a total of 1,100 proteins. Dr. Christian Gieger, head of the Molecular Epidemiology Research Unit (AME) at the Helmholtz Zentrum München, adds: "We found 539 independent associations between protein levels and genetic variants." These overlap with genetic risk variants for 42 complex conditions, such as cardiovascular diseases and Alzheimer's disease.

 

"Our results provide new insights into the biological processes that are influenced by a very wide range of complex diseases and that can be used as a basis for the development of new strategies to predict and prevent these diseases," Gieger states. The team is now planning to investigate the exact mechanisms behind the new gene-protein associations.


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Set of uncombable hair genes discovered (PADI3, TGM3 and TCHH)

Set of uncombable hair genes discovered (PADI3, TGM3 and TCHH) | Amazing Science | Scoop.it
Some children suffer from completely tangled hair, which cannot be combed at all. In German, the phenomenon bears the apt name “uncombable hair syndrome” or even “Struwwelpeter syndrome”. Researchers have identified mutations in three genes that are responsible for this.

 

Scientists from a total of eight countries were involved in the work. The results were published in the American Journal of Human Genetics.

 

Many parents know from their own experience that it is not always easy to comb children's hair. Yet with patience and nerves of steel, even the toughest of knots can usually be undone. In the case of "uncombable hair syndrome," brushes and combs don't stand even the hint of a chance. Those affected have extremely frizzy, dry, generally light blonde hair with a characteristic shine, which successfully resists any attempt to tame it. These symptoms are most pronounced in childhood and then ease over time. In adulthood, the hair can more or less be styled normally.

 

Virtually nothing has so far been known about the causes -- particularly because the phenomenon is relatively rare. It was described in the specialist literature for the first time in 1973; since then, around one hundred cases have been documented worldwide. "However, we assume that there are much more people affected," explains Professor Regina Betz from the Institute for Human Genetics at the University of Bonn. "Those who suffer from uncombable hair do not necessarily seek help for this from a doctor or hospital." Nevertheless, it is known that the anomaly occurs more frequently in some families -- it thus appears to have genetic causes.

 

Betz is a specialist for rare hereditary hair disorders. A few years ago, she was approached at a conference by a British colleague. He had recently examined a family with two affected children. The Bonn-based human geneticist's interest was piqued. "Via contact with colleagues from around the world, we managed to find nine further children," she explains. The scientists in Bonn sequenced all the genes of those affected. When comparing large databases, they thus came across mutations in three genes that are involved in forming the hair.

 

The changed genes bear the identifiers PADI3, TGM3 and TCHH. The first two contain the assembly instructions for enzymes, while the third -- TCHH -- contains an important protein for the hair shaft. In healthy hair, the TCHH proteins are joined to each other with extremely fine strands of keratin, which are responsible for the shape and structure of the hair. During this process, the two other identified genes play an important role: "PADI3 changes the hair shaft protein TCHH in such a way that the keratin filaments can adhere to it," explains the lead author of the study, Dr. Fitnat Buket Basmanav Ünalan. "The TGM3 enzyme then produces the actual link."

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The Genetic Components of Rare Diseases

The Genetic Components of Rare Diseases | Amazing Science | Scoop.it

In fall 2015, the conclusion of the 1000 Genomes Project revealed 88 million variants in the human genome. What most of them mean for human health is unclear. Of the known associations between a genetic variant and disease, many are still tenuous at best. How can scientists determine which genes or genetic variants are truly detrimental?

 

Patients with rare diseases are often caught in the crosshairs of this uncertainty. By the time they have their genome, or portions of it, sequenced, they’ve endured countless physician visits and tests. Sequencing provides some hope for an answer, but the process of uncovering causal variants on which to build a treatment plan is still one of painstaking detective work with many false leads. Even variants that are known to be harmful show no effects in some individuals who harbor them, says Adrian Liston, a translational immunologist at the University of Leuven in Belgium who works on disease gene discovery.

 

Exome sequencing, which covers the 1 percent to 2 percent of the genome that codes for protein, typically turns up some 30,000 genetic variants, which need to be carefully assessed. Advances in bioinformatics tools have allowed researchers to rapidly whittle numerous variants or genes down to a manageable list. From there, other web-based platforms are helping investigators build a case for causation. These steps are important, Liston says, because testing a gene candidate in animal models or cell lines consumes a vast amount of resources.

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First gene mutation explaining development of multiple sclerosis found

First gene mutation explaining development of multiple sclerosis found | Amazing Science | Scoop.it

MS is a neurodegenerative disease in which the immune system attacks the myelin that protects nerve fibers, upsetting the flow of information between the brain and the body. It affects about 2 million people worldwide, and in its more severe, progressive form, no good treatments are available.

 

About 10% to 15% of MS cases appear to have a hereditary component, but until now researchers conducting genetic studies have found only weak associations between the risk of developing MS and particular gene variants. In contrast, people who carry the newly discovered mutation have a 70% chance of developing the disease, the team determined.

 

In the current study, the investigators reviewed materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. They looked at a family that had multiple cases of the disease--five cases over two generations--and did exome sequencing to look for rare coding mutations that were present in all family members who had the disease.

 

After identifying a gene of interest, they went back to the database and found the same mutation in another family with multiple cases of MS. Interestingly, all patients in these families with the mutation presented with the progressive form of MS. "The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," says neuroscientist Weihong Song, Canada Research Chair in Alzheimer's Disease at UBC and the study's other senior author. Together with other members of the same family, LXRA controls transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity.

 

Mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production. "There is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development," Song says.

 

"One thing that's important to note is that although this mutation is present in only about 1 in 1,000 people with MS, by doing association analysis we've also found common variants in the same gene that are risk factors for progressive MS," Vilariño-Güell adds. "So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them."

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The gene hunters 

The gene hunters  | Amazing Science | Scoop.it

Criss-crossing the globe on a quest for unusual DNA, researchers have discovered a rare mutation that promises insights into both epilepsy and autism — and points to a treatment.


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Scientists find link between genome and microbiome in Crohn’s disease patients

Scientists find link between genome and microbiome in Crohn’s disease patients | Amazing Science | Scoop.it
Genes linked to Crohn’s disease, an inflammatory bowel disease, might make people’s immune cells miss out on helpful messages sent by friendly gut bacteria.

 

Good gut bacteria might not help people with Crohn’s disease.

Protective microbial messages go unread in mice and in human immune cells with certain defective genes, researchers report online May 5 in Science. The findings are the first to tie together the roles of genes and beneficial microbes in the inflammatory bowel disease, says biologist Brett Finlay of the University of British Columbia in Vancouver, who was not involved in the new work.

 

“This is a major step forward in this area,” he says. Human genes and friendly microbes work together to control inflammation, he says. “And when you muck that up, things can go awry.”

 

In Crohn’s disease, the immune system riles up too easily, trigging chronic inflammation. Scientists don’t know why exactly people’s immune systems go haywire. But researchers have linked the disease to glitches in nearly 200 genes, including ATG16L1 and NOD2, which typically help kill bad bacteria in the gut.

 

Researchers have also reported that people with Crohn’s have a different collection of gut microbes compared with that of healthy people, says study coauthor and Caltech microbiologist Sarkis Mazmanian.But though “there’s a huge body of literature on the genome and on the microbiome,” he says, “no one knew what the interplay was between the two.”

 

So his team explored a potential link using a friendly gut microbe called Bacteroides fragilis. The bacteria send out calming messages that tell the immune system to tone down inflammation. Like letters inside envelopes, these messages travel in protective pouches called outer membrane vesicles, or OMVs.

 

Feeding OMVs to mice typically protects them from developing inflamed colons, or colitis — but not mice lacking the Crohn’s-linked genes ATG16L1 and NOD2. When researchers treated those mice with a colitis-causing chemical, they succumbed to the disease, even after eating OMVs.

 

Mice with defective versions of ATG16L1 and NOD2 “can’t reap the benefits of the beneficial microbiota,” Mazmanian says.Immune cells from human patients with the defective genes didn’t respond to OMVs either.

 

The findings suggest that the genes that kill bad bacteria also work with good bacteria to keep people’s immune systems from going out of control, says gastroenterologist Balfour Sartor of the University of North Carolina School of Medicine in Chapel Hill. The work “opens up a new mechanism for protection,” he says.

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Do 'genetic superheroes' exist? Or did media overhype Resilience Project?

Do 'genetic superheroes' exist? Or did media overhype Resilience Project? | Amazing Science | Scoop.it
Genetic Superheroes. Hitting the genetic lottery. 13 Incredibly lucky people. Bulletproof genomes.

 

That’s just a few of the ways people have described the results from a recent analysis of the genomes of over half a million people which found that 13 lucky people have disease causing mutations, but don’t exhibit any symptoms.

 

The study is the largest effort, to date, to identify so called ‘resilient’ individuals. These are healthy people who possess a mutation in their genome that is known to be disease causing. Many believe the DNA of these resilient people hold the key to treating genetic diseases, like cystic fibrosis, that today are incurable.

 

The existence of these 13 genetic Herculeses has created much excitement in the media:

  • STAT: Genetic ‘unicorns’ defy their own DNA — and hint at treatments
  • NPR: How Do ‘Genetic Superheroes’ Overcome Their Bad DNA?
  • BBC‘Superhero DNA’ Keeps Diseases at Bay

 

But did the study really identify a few lucky winners of the genome lottery? What’s the real story here? The study published in the journal Nature Biotechnology by a team of international scientists led by researchers at Icahn School of Medicine at Mount Sinai in New York City searched the genomes of 589,306 people—all over the age of 30—for 874 genes that are linked to 584 genetic diseases. All of these diseases begin to affect a person during childhood, like cystic fibrosis, Tay-sachs and Pfeiffer syndrome.

 

The team obtained these sequences from a variety of previous studies, but most of the data—nearly 400,000 samples—came from the at-home, personal genetics test 23andMe. (On the 23andMe consent forms, customers can select a box to allow their DNA to be used in such research.) Pooling all of this data, the scientists identified 15,597 potentially resilient individuals, but after a rigorous screen of these candidates, they eliminated almost all of them, settling on just 13, they believed were resilient.

 

The study is considered, by the Resilience Project leaders to be a ‘proof of concept’ study which means they modestly set out to prove their methods could identify resilient individuals. The study’s leader, Stephen Friend, says the idea to look for resilient people came out of frustration from the lack of success he had in looking at the problem from the other way. He and other biotech researchers usually search for genetic variants common in a number of sick individuals and then look for ways to fix the defect, but Friend admits they have been largely unsuccessful using this approach. He hopes that by looking for resilient people instead, he will discover why they are resilient and then use that knowledge to treat those who do exhibit symptoms.

 

But some have begun to question the validity of the resilience of these candidates, which could blow a hole in the conclusions. The study was a retrospective analysis, meaning the authors looked over data from other studies to establish connections, but they did not personally examine any of the participants. More importantly, for many they never can. In several of the studies they borrowed data from, recontact was not even considered when asking for participant consent. For participant’s samples from 23andMe, the consent for recontact falls into a gray area because the company does not specifically ask for permission to recontact on its consent form.

 

Nature Biotechnology published an independent commentary from Daniel MacArthur, a geneticist who teaches at Harvard University and conducts research at Massachusetts General Hospital. MacArthur explains why this data collection flaw hurts the study’s validity: "Perhaps most unfortunately, the researchers could not recontact the majority of resilient individuals for further study because of a lack of necessary consent forms. This means that some of their resilient cases may be mirages (the result of undisclosed disease cases, sample swaps, or somatic mosaicism), and this lack of consent precluded the collection of further clinical and genetic data to explore possible resilience mechanisms."

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Boy Or Girl? It's In The Father's Genes, but the Gene is not Known Yet

Boy Or Girl? It's In The Father's Genes, but the Gene is not Known Yet | Amazing Science | Scoop.it
A study of hundreds of years of family trees suggests a man's genes play a role in him having sons or daughters. Men inherit a tendency to have more sons or more daughters from their parents. This means that a man with many brothers is more likely to have sons, while a man with many sisters is more likely to have daughters.

 

A Newcastle University study involving thousands of families is helping prospective parents work out whether they are likely to have sons or daughters.

 

The work by Corry Gellatly, a research scientist at the university, has shown that men inherit a tendency to have more sons or more daughters from their parents. This means that a man with many brothers is more likely to have sons, while a man with many sisters is more likely to have daughters.

 

The research involved a study of 927 family trees containing information on 556,387 people from North America and Europe going back to 1600. "The family tree study showed that whether you’re likely to have a boy or a girl is inherited. We now know that men are more likely to have sons if they have more brothers but are more likely to have daughters if they have more sisters.

 

However, in women, you just can’t predict it," Mr Gellatly explains. Men determine the sex of a baby depending on whether their sperm is carrying an X or Y chromosome. An X chromosome combines with the mother’s X chromosome to make a baby girl (XX) and a Y chromosome will combine with the mother’s to make a boy (XY).

 

The Newcastle University study suggests that an as-yet undiscovered gene controls whether a man’s sperm contains more X or more Y chromosomes, which affects the sex of his children. On a larger scale, the number of men with more X sperm compared to the number of men with more Y sperm affects the sex ratio of children born each year.

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Are we at the dawn of choosing human embryos by health, height, and future intelligence?

Are we at the dawn of choosing human embryos by health, height, and future intelligence? | Amazing Science | Scoop.it
Will you be among the first to pick your kids’ IQ? As machine learning unlocks predictions from DNA databases, scientists say parents could have choices never before possible.

 

 

Nathan Treff was diagnosed with type 1 diabetes at 24. It’s a disease that runs in families, but it has complex causes. More than one gene is involved. And the environment plays a role too.

So you don’t know who will get it. Treff’s grandfather had it, and lost a leg. But Treff’s three young kids are fine, so far. He’s crossing his fingers they won’t develop it later.

 

Now Treff, an in vitro fertilization specialist, is working on a radical way to change the odds. Using a combination of computer models and DNA tests, the startup company he’s working with, Genomic Prediction, thinks it has a way of predicting which IVF embryos in a laboratory dish would be most likely to develop type 1 diabetes or other complex diseases. Armed with such statistical scorecards, doctors and parents could huddle and choose to avoid embryos with failing grades.

 

IVF clinics already test the DNA of embryos to spot rare diseases, like cystic fibrosis, caused by defects in a single gene. But these “preimplantation” tests are poised for a dramatic leap forward as it becomes possible to peer more deeply at an embryo’s genome and create broad statistical forecasts about the person it would become.

 

The advance is occurring, say scientists, thanks to a growing flood of genetic data collected from large population studies. As statistical models known as predictors gobble up DNA and health information about hundreds of thousands of people, they’re getting more accurate at spotting the genetic patterns that foreshadow disease risk. But they have a controversial side, since the same techniques can be used to project the eventual height, weight, skin tone, and even intelligence of an IVF embryo.

 

In addition to Treff, who is the company’s chief scientific officer, the founders of Genomic Prediction are Stephen Hsu, a physicist who is vice president for research at Michigan State University, and Laurent Tellier, a Danish bioinformatician who is CEO. Both Hsu and Tellier have been closely involved with a project in China that aims to sequence the genomes of mathematical geniuses, hoping to shed light on the genetic basis of IQ.

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Scientists Discover First Genes for Insomnia

Scientists Discover First Genes for Insomnia | Amazing Science | Scoop.it

Insomnia is among the most frequent complaints in general practice. Even after treatment, poor sleep remains a persistent vulnerability for many people. A research team led by Vrije Universiteit Professor Danielle Posthuma has come closer to unraveling the biological mechanisms that cause the predisposition for insomnia.

 

“Our findings are the start of a path towards an understanding of insomnia at the level of communication within and between neurons, and thus towards finding new ways of treatment,” Vrije Universiteit Professor Van Someren, co-author of the study.

 

“As compared to the severity, prevalence and risks of insomnia, only few studies targeted its causes. Insomnia is all too often dismissed as being ‘all in your head.’ Our research brings a new perspective. Insomnia is also in the genes.”

 

To identify genetic factors for insomnia complaints, Prof. Posthuma, Prof. Someren and their colleagues performed a genome-wide association study and a genome-wide gene-based association study in 113,006 individuals. As a result, the researchers identified seven genes associated with insomnia.

 

“These genes play a role in the regulation of transcription, the process where DNA is read in order to make an RNA copy of it, and exocytosis, the release of molecules by cells in order to communicate with their environment,” the authors said.

 

“One of the identified genes, MEIS1, has previously been related to two other sleep disorders: periodic limb movements of sleep (PLMS) and restless legs syndrome (RLS).”

 

“Variants in the MEIS1 gene seem to contribute to all three disorders,” they added. “Strikingly, PLMS and RLS are characterized by restless movement and sensation, respectively, whereas insomnia is characterized mainly by a restless stream of consciousness.”

 

The team also found a strong genetic overlap with other traits, such as anxiety disorders, depression and neuroticism, and low subjective wellbeing. “This is an interesting finding, because these characteristics tend to go hand in hand with insomnia,” said study first author Anke Hammerschlag, a PhD student at Vrije Universiteit. “We now know that this is partly due to the shared genetic basis.”

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One in five 'healthy' adults seems to carry disease-related genetic mutations

One in five 'healthy' adults seems to carry disease-related genetic mutations | Amazing Science | Scoop.it

Some doctors dream of diagnosing diseases—or at least predicting disease risk—with a simple DNA scan. But others have said the practice, which could soon be the foundation of preventative medicine, isn’t 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 genes—such genome screening goes far beyond that currently recommended by the American College of Medical Genetics and Genomics (ACMG), which suggests informing people of results for just 59 genes known or strongly expected to cause disease.


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Scientists identify single-gene mutations (CARD11) that lead to atopic dermatitis

Scientists identify single-gene mutations (CARD11) that lead to atopic dermatitis | Amazing Science | Scoop.it

Researchers have identified mutations in a gene called CARD11 that lead toatopic dermatitis, or eczema, an allergic skin disease. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and other institutions discovered the mutations in four unrelated families with severe atopic dermatitis and studied the resulting cell-signaling defects that contribute to allergic disease. Their findings, reported in Nature Genetics, also suggest that some of these defects potentially could be corrected by supplementation with the amino acid glutamine.

 

The scientists analyzed the genetic sequences of patients with severe atopic dermatitis and identified eight individuals from four families with mutations in the CARD11 gene, which provides instructions for production of a cell-signaling protein of the same name. While some people with these mutations had other health issues, such as infections, others did not, implying that mutations in CARD11 could cause atopic dermatitis without leading to other medical issues often found in severe immune system syndromes.

The scientists next set out to understand how the newly discovered CARD11 mutations contribute to atopic dermatitis.

 

Each of the four families had a distinct mutation that affected a different region of the CARD11 protein, but all the mutations had similar effects on T-cell signaling. With cell culture and other laboratory experiments, the researchers determined that the mutations led to defective activation of two cell-signaling pathways, one of which typically is activated in part by glutamine.  

 

Growing cultured T cells from patients with CARD11 mutations with excess glutamine boosted mTORC1 activation, a key part of one of the affected pathways, suggesting the potential to partially correct the cell-signaling defects that may contribute to atopic dermatitis. The scientists now are planning a study to assess the effect of supplemental glutamine and leucine, another amino acid that activates mTORC1, in people with atopic dermatitis with and without CARD11 mutations.

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Diabetes in your DNA? Scientists zero in on the genetic signature of risk

Diabetes in your DNA? Scientists zero in on the genetic signature of risk | Amazing Science | Scoop.it

Why do some people get Type 2 diabetes, while others who live the same lifestyle never do?

 

For decades, scientists have tried to solve this mystery – and have found more than 80 tiny DNA differences that seem to raise the risk of the disease in some people, or protect others from the damagingly high levels of blood sugar that are its hallmark.

But no one “Type 2 diabetes signature” has emerged from this search. Now, a team of scientists has reported a discovery that might explain how multiple genetic flaws can lead to the same disease.

 

They’ve identified something that some of those diabetes-linked genetic defects have in common: they seem to change the way certain cells in the pancreas “read” their genes. The discovery could eventually help lead to more personalized treatments for diabetes. But for now, it’s the first demonstration that many Type 2 diabetes-linked DNA changes have to do with the same DNA-reading molecule. Called Regulatory Factor X, or RFX, it’s a master regulator for a number of genes.

 

The team reporting the findings in a new paper in the Proceedings of the National Academy of Sciences(link is external) comes from the University of Michigan, National Institutes of Health, Jackson Laboratory for Genomic Medicine, University of North Carolina, and the University of Southern California.

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How a tiny mutation in the ARHGAP11B gene helped grow our big human brain

How a tiny mutation in the ARHGAP11B gene helped grow our big human brain | Amazing Science | Scoop.it

After splitting from the chimpanzee lineage, a single letter of our genome switched to another – and likely shaped the evolutionary expansion of the human.

 

The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication ofARHGAP11A, which encodes a Rho guanosine triphosphatase–activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence.

 

Scientists now show that these 55 nucleotides are deleted by mRNA splicing due to a single C→G substitution that creates a novel splice donor site. They reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.

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Carlos Garcia Pando's comment, December 11, 2016 12:23 PM
Is this a case of progressive evolution? I think this is a clear case of random error: just a sigle base change (C for G) with such a great impact.
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Catalog of genetic information from 60,000 people reveals unexpected surprises

Catalog of genetic information from 60,000 people reveals unexpected surprises | Amazing Science | Scoop.it

More than one million people have now had their genome sequenced, or its protein-coding regions (the exome). The hope is that this information can be shared and linked to phenotype — specifically, disease — and improve medical care. An obstacle is that only a small fraction of these data are publicly available:

 

 

In an important step, we report this week the first publication from the Exome Aggregation Consortium (ExAC), which has generated the largest catalogue so far of variation in human protein-coding regions. It aggregates sequence data from some 60,000 people. Most importantly, it puts the information in a publicly accessible database that is already a crucial resource (http://exac.broadinstitute.org).

 

There are challenges in sharing such data sets — the project scientists deserve credit for making this one open access. Its scale offers insight into rare genetic variation across populations. It identifies more than 7.4 million (mostly new) variants at high confidence, and documents rare mutations that independently emerged, providing the first estimate of the frequency of their recurrence. And it finds 3,230 genes that show nearly no cases of loss of function. More than two-thirds have not been linked to disease, which points to how much we have yet to understand.

 

The study also raises concern about how genetic variants have been linked to rare disease. The average ExAC participant has some 54 variants previously classified as causal for a rare disorder; many show up at an implausibly high frequency, suggesting that they were incorrectly classified. The authors review evidence for 192 variants reported earlier to cause rare Mendelian disorders and found at a high frequency by ExAC, and uncover support for pathogenicity for only 9. The implications are broad: these variant data already guide diagnoses and treatment (see, E. V. Minikel et al. Sci. Transl. Med. 8, 322ra9; 2016 and R. Walsh et al. Genet. Med. http://dx.doi.org/10.1038/gim.2016.90; 2016).

 

These findings show that researchers and clinicians must carefully evaluate published results on rare genetic disorders. And it demonstrates the need to filter variants seen in sequence data, using the ExAC data set and other reference tools — a practice widely adopted in genomics.

 

The ExAC project plans to grow over the next year to include 120,000 exome and 20,000 whole-genome sequences. It relies on the willingness of large research consortia to cooperate, and highlights the huge value of sharing, aggregation and harmonization of genomic data. This is also true for patient variants — there is a need for databases that provide greater confidence in variant interpretation, such as the US National Center for Biotechnology Information’s ClinVar database.

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Mystery Solved: Muffs and Beard in Chickens

Mystery Solved: Muffs and Beard in Chickens | Amazing Science | Scoop.it
Hip humans aren't the only ones growing outrageous facial hair. Some chickens do, too. And now, geneticists in China have discovered the cause.

 

Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. A group of scientists have now used genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele is causing the Mb phenotype which is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to the tandem repeat around 1.70 Mb away on GGA27. The duplications contain a total of seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens only, strongly suggesting that HOXB8 directs this regional feather-development.

 

In conclusion, the results provide an interesting example of how genomic structural rearrangements of homeobox genes alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation.

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Five genes identified that give your nose its shape

Five genes identified that give your nose its shape | Amazing Science | Scoop.it

Whether you have a huge honker, a puny proboscis, or a snubbed schnoz, the shape of your nose is in your genes. Now, researchers have sniffed out five of those stretches of DNA that control nose and chin shape. The team sequenced the genomes of more than 6000 men and women in Central and South America and used photographs of the participants to categorize 14 of their facial features—from cheekbone protrusion to lip shape. Then, the scientists analyzed whether any of the features were associated with certain genes. GLI3 and PAX1, both known to be involved in cartilage growth, were linked to the breadth of a person’s nostrils;DCHS2, also related to cartilage, controlled nose pointiness; RUNX2, which drives bone development, was associated with the width of the nose bridge, the upper area of the nose; and EDAR, which has previously been linked to ear and tooth shape and hair texture, affected chin protrusion. The results, published online today in Nature Communications, may help shed light on how the human face evolved and why different ethnicities have distinct facial features. Moreover, the research could help forensic scientists reconstruct faces based on genetic samples.

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There is no single 'clever gene' – there are thousands

There is no single 'clever gene' – there are thousands | Amazing Science | Scoop.it

Thousands of genes are involved in intelligence, according to a new study which effectively shatters any hopes of eugenicists that babies can be genetically designed to be clever. In one of the largest studies of the human genome to date, a group of 253 scientists from around the world identified 74 genetic variants that are associated with the number of years spent in formal education.

 

Humans’ genetic make-up is believed to be responsible for at least 20 per cent of the difference in educational attainment between individuals, with the rest down to social factors and the environment in which they are raised. But the researchers found that the largest effect of any one genetic variant was tiny – just 0.035 per cent. This suggests that there must be at least several thousand of genes that are involved.

 

An Oxford University geneticist asked to comment on the research said it was a “great relief” because it showed there was little chance that people would be able to genetically modify children to be smart. The researchers, who published a paper in the journal Nature, said that the total effect of the 74 genetic variants on educational attainment was 0.43 per cent.

 

One of the authors of the paper, Dr Daniel Benjamin, an associate professor at the University of Southern California, said: “The fact that the genetic variant we identify with the largest effect accounts for only 0.035 of one per cent of the variation tells us that there must be at least thousands of genetic variants that influence education but have not yet been detected.” However he said the “most exciting result” of their research was that they could construct an index of genetic variants from across the genome, called a polygenic score, that could predict about six per cent of the variation.

 

“That’s not large enough to be useful for predicting any particular individual’s educational attainment, but it’s important because it is large enough to be useful in social science studies, which focus on average behavior in the population,” Dr Benjamin said.


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Campaign for Social Science's curator insight, May 12, 2016 4:35 AM

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Thousands of genes are involved in intelligence, according to a new study which effectively shatters any hopes of eugenicists that babies can be genetically designed to be clever.
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Skeletal stem cells form the blueprint of the face structure

Skeletal stem cells form the blueprint of the face structure | Amazing Science | Scoop.it

Timing is everything when it comes to the development of the vertebrate face. In a new study published in PLoS Genetics, USC Stem Cell researcher Lindsey Barske from the laboratory of Gage Crump and her colleagues identify the roles of key molecular signals that control this critical timing.

 

Previous work from the Crump and other labs demonstrated that two types of molecular signals, called Jagged-Notch and Endothelin1 (Edn1), are critical for shaping the face. Loss of these signals results in facial deformities in both zebrafish and humans, revealing these as essential for patterning the faces of all vertebrates.

 

Using sophisticated genetic, genomic and imaging tools to study zebrafish, the researchers discovered that Jagged-Notch and Edn1 work in tandem to control where and when stem cells turn into facial cartilage. In the lower face, Edn1 signals accelerate cartilage formation early in development. In the upper face, Jagged-Notch signals prevent stem cells from making cartilage until later in development. The authors found that these differences in the timing of stem cells turning into cartilage play a major role in making the upper and lower regions of the face distinct from one another.

 

"We've shown that the earliest blueprint of the facial skeleton is set up by spatially intersecting signals that control when stem cells turn into cartilage or bone. Logically, therefore, small shifts in the levels of these signals throughout evolution could account for much of the diversity of shapes we see within the skulls of different animals, as well as the wonderful array of facial shapes seen in humans," said Barske, lead author and A.P. Giannini postdoctoral research fellow.

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