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The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated | Genetics in Medicine

Until very recently, the fragmented distribution of patients across institutions hindered the discovery of new rare diseases. Clinicians working with a single, isolated patient could steadily eliminate known disorders but do little more. Families would seek clinicians with the longest history and largest clinic volume to increase their chances of finding a second case, but what does a physician do when N = 1 or if the phenotype is inconsistent across patients? These challenges are driving an increase in the use of NGS. Yet this technological advance presents new challenges of its own. Perhaps the most daunting, in our opinion, is the inability to share sequencing data quickly and universally. Standards and bioinformatic tools are needed that allow for a national repository where families or scientists can bring clinical results and NGS data for comparison. This challenge can be circumvented by tools already created for and by the Internet and social media.

Your genes could impact the quality of your marriage: Specific genes relevant to how partners provide and receive support from each other -- ScienceDaily

"However, what emerged as most relevant to overall marital quality for both partners was genotypic variation among husbands at a specific location on OXTR. Husbands with a particular genotype, which other researchers associated with signs of social deficits, were less satisfied with the support they were provided. Being less satisfied with the support they got from their wives was also associated with being less satisfied with their marriage. The researchers hope their findings provide the foundation for replication and additional study of OXTR as an enduring determinant of marital functioning, as well as encourage research more broadly evaluating the role of genetic factors in interpersonal processes important to overall marital quality. "Genes matter when it comes to the quality of marriage, because genes are relevant to who we are as individuals, and characteristics of the individual can impact the marriage," said Mattson. "Our findings were the first to describe a set of genetic and behavioral mechanisms for one possible route of the genetic influence on marriage. In addition, we added to the increasing awareness that the expression of genotypic variation differs greatly depending on context."

Male Y chromosomes not 'genetic wastelands' -- ScienceDaily

Using sequence data generated by new technology that reads long strands of individual DNA molecules, Chang and Larracuente developed a strategy to assemble a large part of the Y chromosome and other repeat-dense regions. By assembling a large portion of the Y chromosome, they discovered that the Y chromosome has a lot of duplicated sequences, where genes are present in multiple copies. They also discovered that although the Y chromosome does not experience crossing over, it undergoes a different type of recombination called gene conversion. While crossing over involves the shuffle and exchange of genes between two different chromosomes, gene conversion is not reciprocal, Larracuente says. "You don't have two chromosomes that exchange material, you have one chromosome that donates its sequence to the other part of the chromosome" and the sequences become identical.

Myriad Genetics to Acquire Counsyl for $375M | GenomeWeb

Myriad will merge Counsyl's reproductive health tests with its existing preventive care business unit into a new business unit called Myriad Women's Health, which will focus solely on OB-Gyns and reproductive healthcare providers. Myriad will also combine its women's health sales force of approximately 225 representatives with Counsyl's 80 sales professionals, enabling a threefold increase in physician reach for reproductive testing, according to Myriad.

An Expanded View of Complex Traits: From Polygenic to Omnigenic: Cell

In summary, many complex traits are driven by enormously large numbers of variants of small effects, potentially implicating most regulatory variants that are active in disease-relevant tissues. To explain these observations, we propose that disease risk is largely driven by genes with no direct relevance to disease and is propagated through regulatory networks to a much smaller number of core genes with direct effects. If this model is correct, then it implies that detailed mapping of cell-specific regulatory networks will be an essential task for fully understanding human disease biology.

An Expanded View of Complex Traits: From Polygenic to Omnigenic: Cell

core genes generally contribute just a small part of the total heritability and how most genes expressed in relevant cell types could make non-zero contributions to heritability. To resolve this, we propose that cell regulatory networks are highly interconnected to the extent that any expressed gene is likely to affect the regulation or function of core genes.

An Expanded View of Complex Traits: From Polygenic to Omnigenic: Cell

This debate was resolved in a seminal 1918 paper by R.A. Fisher, who showed that, if many genes affect a trait, then the random sampling of alleles at each gene produces a continuous, normally distributed phenotype in the population (Fisher, 1918). As the number of genes grows very large, the contribution of each gene becomes correspondingly smaller, leading in the limit to Fisher’s famous “infinitesimal model” (Barton et al., 2016).

‘Omnigenic’ Model Suggests That All Genes Affect Every Complex Trait | Quanta Magazine

“What we realized was that the signal for height was coming from almost the whole genome,” he said. If the genome were a long string of ornamental lights, and every DNA snippet linked to height were illuminated, more than 100,000 lights would be shining all the way down the string. That result contrasted starkly with the general expectation that GWAS findings would be clustered around the most important genes for a trait.

‘Omnigenic’ Model Suggests That All Genes Affect Every Complex Trait | Quanta Magazine

Starting about 15 years ago, geneticists began to collect DNA from thousands of people who shared traits, to look for clues to each trait’s cause in commonalities between their genomes, a kind of analysis called a genome-wide association study (GWAS). What they found, first, was that you need an enormous number of people to get statistically significant results — one recent GWAS seeking correlations between genetics and insomnia, for instance, included more than a million people. Second, in study after study, even the most significant genetic connections turned out to have surprisingly small effects. The conclusion, sometimes called the polygenic hypothesis, was that multiple loci, or positions in the genome, were likely to be involved in every trait, with each contributing just a small part. (A single large gene can contain several loci, each representing a distinct part of the DNA where mutations make a detectable difference.)

Heavy drinking may change DNA, leading to increased craving for alcohol: Genetic vicious cycle may reinforce risky drinking behavior -- ScienceDaily

Scientists at Rutgers and Yale University School of Medicine focused on two genes implicated in the control of drinking behavior: PER2, which influences the body's biological clock, and POMC, which regulates our stress-response system. By comparing groups of moderate, binge and heavy drinkers, the researchers found that the two genes had changed in the binge and heavy drinkers through an alcohol-influenced gene modification process called methylation. The binge and heavy drinkers also showed reductions in gene expression, or the rate at which these genes create proteins. These changes increased with greater alcohol intake. Additionally, in an experiment, the drinkers viewed stress-related, neutral or alcohol-related images. They also were shown containers of beer and subsequently tasted beer, and their motivation to drink was evaluated. The result: alcohol-fueled changes in the genes of binge and heavy drinkers were associated with a greater desire for alcohol.

BARBARIANS AT THE GATE: CONSUMER-DRIVEN HEALTH DATA COMMONS AND THE TRANSFORMATION OF CITIZEN SCIENCE

This article explores how these mechanisms, imbedded in major federal research and privacy regulations, enshrine institutional data holders—entities such as hospitals, research institutions, and insurers that store people’s health data—as the prime movers in assembling large-scale data resources for research and public health. They rely on approaches—such as de-identification of data and waivers of informed consent—that are increasingly unworkable going forward. They shower individuals with unwanted, paternalistic protections—such as barriers to access to their own research results—while denying them a voice in what will be done with their data.

BARBARIANS AT THE GATE: CONSUMER-DRIVEN HEALTH DATA COMMONS AND THE TRANSFORMATION OF CITIZEN SCIENCE

Data resources are a central currency of twenty-first-century science, and the question is, “Who will control them?”

The F.D.A. vs. Personal Genetic Testing | The New Yorker

A fifty-five-year-old who is confused and depressed and learns that he carries two copies of the risk gene and stands an eighty-per-cent chance of getting Alzheimer’s might reach for a gun, which is the kind of scenario that some genetic counsellors worry about.

23andMe Is Sharing Genetic Data with Drug Giant - Scientific American

Only about 10,000 of the 1 million Americans with Parkinson’s disease have the disease because of LRRK2. So, GlaxoSmithKline has to test about 100 Parkinson’s patients to find just one potential candidate. However, 23andMe has already provided 250 Parkinson’s patients who have agreed to be re-contacted for GlaxoSmithKline’s clinical trials, which may help the pharmaceutical company develop the drug much faster, Forbes reported.

Full transcript: 23andMe CEO Anne Wojcicki answers genetics and privacy questions on Too Embarrassed to Ask - Recode

It’s hard because health care is spectacularly fragmented. An oncology team at Stanford doesn’t do the same things as an oncology team at Memorial Sloan Kettering and to protect it under the Practice of Medicine, and they have different ways that they engage with their patients. Everything is spectacularly fragmented. For us, one of the things that I’m really proud of that we saw is I have millions of people now on a single platform that I know are all interested in their DNA and their health. I think there’s a huge potential for us to help, again, engage all of our customers and potentially work with all of the innovative tech companies out here and give them a platform.

How Fasting Can Improve Overall Health - Neuroscience News

“The reorganization of gene regulation by fasting could prime the genome to a more permissive state to anticipate upcoming food intake and thereby drive a new rhythmic cycle of gene expression. In other words, fasting is able to essentially reprogram a variety of cellular responses. Therefore, optimal fasting in a timed manner would be strategic to positively affect cellular functions and ultimately benefiting health and protecting against aging-associated diseases.”

You become what you believe

A week later, the participants were given a result, based not on their actual data, but rather on one of two groups into which they had been randomly placed. Some were told they had the form of a gene called CREB1 that makes a person tire easily; others were told they had the high-endurance version. Then they ran on the treadmill again. This time, those who had been told they had the low-endurance version of CREB1 did worse on the test, even if they had the other variant. Compared with their results on the first test, on average their bodies removed toxic carbon dioxide less efficiently, their lung capacity dropped, and they stopped running 22 seconds sooner, the team reports today in Nature Human Behavior. And those who thought they had the high-endurance form of the CREB1 gene ran slightly longer on average before feeling hot and tired, regardless of what gene variant they had. “Simply giving people this information changed their physiology,” Turnwald says. The team also tested a second group of 107 people for its version of FTO, a gene that influences how full we feel after eating. Some versions can also predispose people to obesity. Participants ate a small meal and rated their fullness. After being told, at random, that they had a version of FTO that made them hungrier than average or one that made them easily sated, participants ate the same meal. Those told they had the “hungry” version of the gene didn’t feel any different. But those who were told they had the other version felt less hungry on average after eating; they also had higher blood levels of a hormone that indicates a feeling of fullness.

Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial | The American Journal of Clinical Nutrition | Oxford Academic

Loge relative weight change over the intervention phase was −7.1% ± 0.7% (mean ± SEM) with ICR, −5.2% ± 0.6% with CCR, and −3.3% ± 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was −5.2% ± 1.2% with ICR, −4.9% ± 1.1% with CCR, and −1.7% ± 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers.

Sea invertebrate sheds light on evolution of human blood, immune systems -- ScienceDaily

"The mammalian and Botryllus blood-forming systems also share hundreds of homologous genes, even though the two species are separated by over 500 million years of evolution," said former postdoctoral scholar Benyamin Rosental, PhD. Rosental shares lead authorship of the study with graduate student Mark Kowarsky. The senior authors are Irving Weissman, MD, the Virginia and D.K. Ludwig Professor for Clinical Innovation in Cancer Research and professor of pathology and of developmental biology; Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics; and senior research scientist Ayelet Voskoboynik, PhD. The researchers isolated the Botryllus stem cells that are the foundation of its blood and immune system, as well as the progenitor cells they make on their way to becoming adult blood and immune cells. "Out of all the invertebrates, the Botryllus blood stem cells and progenitors are the most similar to vertebrate blood cells, so it is possible, if not likely, that they are the 'missing link' between vertebrates and invertebrates," said Weissman, who also directs the Stanford Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center at Stanford.

The link between cannabis use and psychotic-like experiences is largely the result of genetic factors

Karcher and her colleagues found that cannabis use was positively associated with psychotic-like experiences, even after controlling for a number of demographic variables and other substance use measures. But genetic factors accounted for 69.2% to 84.1% of the association. “The study indicates that the relationship between psychotic-like experiences and marijuana use is largely the result of shared genetics,” she explained to PsyPost.

Seeing and smelling food prepares the mouse liver for digestion -- ScienceDaily

A previous study published in Cell in 2015 by another team of researchers found that sensory perception of food by lab mice was enough to trigger the neural pathways normally fueled by eating. Specifically, perceiving food inhibited AgRP neurons, which stimulate appetite, and activated POMC neurons, which induce satiety and suppress eating. The new study built on that research, focusing on how the changes in these neural pathways sent signals that affected metabolic activities in the liver. Here, the researchers found that within five minutes of lab mice perceiving food, the changes in POMC neuron activity were enough to induce a rapid signaling cascade that activated the mTOR and xbp1 signaling pathways. These pathways are normally activated when the liver takes up amino acids from digested food and help increase the protein folding capacity of the endoplasmic reticulum (ER), which assembles proteins from the amino acids found in food.

What if the Placebo Effect Isn’t a Trick? - The New York Times

The subjects were randomly divided into four groups, following standard clinical-trial protocol, and received a daily dose of either vitamin E, aspirin, vitamin E with aspirin or a placebo. A subset also had their DNA sampled — which, Hall realized, offered her a vastly larger genetic database to plumb for markers correlated to placebo response. Analyzing the data amassed during the first 10 years of the study, Hall found that the women with the low-COMT gene variant had significantly higher rates of heart disease than women with the high-COMT variant, and that the risk was reduced for those low-COMT women who received the active treatments but not in those given placebos. Among high-COMT people, the results were the inverse: Women taking placebos had the lowest rates of disease; people in the treatment arms had an increased risk.

Genetic risk factor for CTE detected: Findings may offer insight into how the disease occurs -- ScienceDaily

Researchers from Boston University School of Medicine (BUSM) and the VA Boston Healthcare System (VABHS) studied 86 former contact-sport athletes whose brains were donated to the VA-BU-CLF brain bank and found to have evidence of CTE, but no other pathology. The athlete brains were examined for genetic variation in TMEM106B, a gene thought to be involved in the brain's inflammation system. Overall, the genetic variation was not different in those with CTE compared to those without. "However, among the athletes with CTE, variation did predict increased CTE pathology and brain inflammation. Additionally, the risk allele increased the likelihood of developing dementia by 2.5 times suggesting the variant might predict an increased risk for developing the symptoms of CTE," explained first author Jonathan Cherry, PhD, postdoctoral fellow in neurology at BUSM.

Review reveals ambiguous understanding of genetic privacy in US study participants: Privacy often conflated with confidentiality, control, and security -- ScienceDaily

Participants were frequently concerned about the amount of control they retained over their personal information, the use of their data by third parties, and confidentiality issues. Many were worried they could be harmed if genetic information was divulged to third parties like employers or insurers. However, participants often felt benefits such as getting information from genetic tests were more important than protecting privacy.

Just a few drinks can change how memories are formed -- ScienceDaily

One of the downstream dominos in the signaling pathway affected by alcohol is a gene called dopamine-2-like receptor, which makes a protein on neurons that recognizes dopamine, the "feel-good" neurotransmitter. "The dopamine-2-like receptor is known to be involved in encoding whether a memory is pleasing or aversive," Petruccelli said. And alcohol hijacks this conserved memory pathway to form cravings. In the case of the alcohol reward pathway studied, the signaling cascade didn't turn the dopamine receptor gene on or off, or increase or decrease the amount of protein made, Kaun said. Instead, it had a subtler effect -- it changed the version of the protein made by a single amino acid "letter" in an important area. "We don't know what the biological consequences of that small change are, but one of the important findings from this study is that scientists need to look not only at which genes are being turned on and off, but which forms of each gene are getting turned on and off," Kaun said. "We think these results are highly likely to translate to other forms of addiction, but nobody has investigated that."

Dads' Nicotine Use May Cause Cognitive Problems for Children and Grandchildren - Neuroscience News

Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.