Category Archives: Human Genetics

Idahos dairy industry is taking a unique and proactive approach to improving worker safety with a statewide on-farm training program.

Carol Ryan Dumas/Capital Press

David Douphrate, assistant professor of epidemiology, human genetics and environmental sciences at the University of Texas, answers questions during a panel on a new worker training program for Idahos dairy industry during the Idaho Milk Processors Association annual conference, while Robert Hagevoort, extension dairy specialist at New Mexico State University, looks on.

SUN VALLEY, Idaho Training a largely inexperienced, non-English-speaking workforce on Idahos dairies for the ultimate goal of worker safety has become a priority for both dairymen and the processors they supply.

Unfortunately, it took a fatality on a dairy to bring it to the table, Rick Naerebout, director of operations for the Idaho Dairymens Association, said during the Idaho Milk Processors Association annual conference last week.

That tragedy occurred in February 2016, when worker Ruperto Vazquez-Carrera, 37, drowned in a waste pond after mistakenly driving a feed truck into the pond in pre-dawn hours under flooded conditions.

IDFA quickly responded to prevent future tragedies by engaging with experts in worker safety and training to figure out how to get our arms around the issue of comprehensive training, Naerabout said.

We realized we have an opportunity to do more than check a box on safety and be proactive instead of reactive, he said.

The worker training and safety program has been in development for more than a year, and IDFA has hired a full-time worker training and safety specialist to lead it. The program rolled out this week, starting at dairies owned by IDA board members.

Processors are collaborating in the program and sharing in the cost, said Daragh Maccabee, senior vice president of procurement and dairy economics for Glanbia Nutritionals.

Processors met with IDA in April 2016 to discuss a path forward, wanting to participate in a meaningful way, he said.

While there are already good practices in place, the event which drew the attention of OSHA, the United Farm Workers of American and the media highlighted a need for more structure. The primary objective of the program is to provide a safe work environment, he said.

People safety is our No.1 priority, and Glanbia wants to support the producer community in a real way, he said.

As an industry, we need to be able to show to the world we are responsible, he said.

IDFA contracted worker safety and training experts David Douphrate, assistant professor of epidemiology, human genetics and environmental sciences at the University of Texas, and Robert Hagevoort, extension dairy specialist with New Mexico State University to develop a program.

Hagevoort said the U.S. dairy industry is experiencing growing pains, with the number of operations decreasing and herd size increasing, driven by economies of scale. It is also moving to automation, with a need for high-skilled workers.

Employment on dairies is not based on skill but on willingness, resulting in a lot of foreign workers unfamiliar with large animals. And its a population challenged by reading comprehension and retention, he said.

Training has to be consistent, repetitive and comprehensive and include both classroom and live training with animals. In addition to the what, the why of safety issues and animal handling must be explained, he said.

Idahos consortium can be beneficial in developing and evaluating training materials and training the trainer to train employees, he said.

Douphrate agreed, saying the focus needs to be on safety leadership and management.

You cant be everywhere on the farm, you have to delegate and need to equip supervisors, he said.

They need to be able to effectively train workers and evaluate whether that training is being retained and workers are applying what they learned, he said.

We want a proactive approach to address injuries and fatalities before they happen, he said.

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Idaho dairy industry elevates worker safety, training - Capital Press

Ever wonder why your friend, co-worker, or partner doesnt get as sick as you, even though they caught the same bug you did? Maybe they made some Faustian bargain that affords them greater protection to infections, or perhaps they are part of some top-secret government experiment that injects them with an array of antigens isolated from an alien race living in Area 51. While both theories are potential explanations, it seems likely that differences in response to infection lie in something a bit more scientificlike genetics. Now, a collaborative team of investigators from the University of Bonn, Germany, and the New York Genome Center has just published findings that map several genetic variants that affect how much gene expression changes in response to an immune stimulus.

Results from the new studypublished in Nature Communications in an article entitled Genetic Regulatory Effects Modified by Immune Activation Contribute to Autoimmune Disease Associationsoffer novel insights into the genetic contribution to varying immune responses among individuals and its consequences on immune-mediated diseases.

Our defense mechanisms against microbial pathogens rely on white blood cells that are specialized to detect infection," explained co-senior study investigator Veit Hornung, Ph.D., chair of immunobiochemistry at the Ludwig-Maxmilians-Universitt in Munich. Upon encounter of microbes, these cells trigger cellular defense programs via activating and repressing the expression of hundreds of genes.

We wanted to understand how genetic differences between individuals affect this cellular response to infection," added co-senior study investigator Johannes Schumacher, Ph.D., a research scientist at the Institute of Human Genetics within the University of Bonn.

The human immune system plays a central role in autoimmune and inflammatory diseases, cancer, metabolism, and aging. The researchers discovered hundreds of genes where the response to immune stimulus depended on the genetic variants carried by the individual.

"These genes include many of the well-known genes of the human immune system, demonstrating that genetic variation has an important role in how the human immune system works," noted lead study investigator Sarah Kim-Hellmuth, Ph.D., a postdoctoral researcher at the New York Genome Center. "While earlier studies have mapped some of these effects, this study is particularly comprehensive, with three stimuli and two-time points analyzed."

In the current study, the research team captured genetic variants whose effects on gene regulation were different depending on the different infectious state of the cells. These included four associations to diseases such as cholesterol level and celiac disease. Moreover, the researchers discovered a trend of genetic risk for autoimmune diseases such as lupus and celiac disease to be enriched for gene regulatory effects modified by the immune state.

"Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5-ppp-dsRNA) [lipopolysaccharide, muramyl dipeptide, and 5' triphosphate double-stranded RNA], and profile the transcriptomes at three-time points, the authors wrote. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS [genome-wide association study] loci and showed a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases.

Co-senior author Tuuli Lappalainen, Ph.D., assistant professor at Columbia University and core member of the New York Genome Center added that this data supports a paradigm where genetic disease risk is sometimes driven not by genetic variants causing constant cellular dysregulation, but by causing a failure to respond properly to environmental conditions such as infection."

Using the collected monocyte samples, the researchers treated the cells with three components that mimic infection with bacteria or a virus. They then analyzed how cells from different individuals respond to infection by measuring gene expression both during the early and late immune response. Integrating the gene expression profiles with genome-wide genetic data of each individual, they were able to map how genetic variants affect gene expression, and how this genetic effect changes with the immune stimulus.

Findings from this new study provide a highly robust and comprehensive dataset of innate immune responses and show wide variation among individuals exposed to diverse pathogens over multiple time points. The investigators identified population differences in immune response and demonstrated that immune response modifies genetic associations to disease. The research sheds light on the genomic elements underlying response to environmental stimuli and the dynamics and evolution of immune response.

"It's been known for a long time that most diseases have both genetic and environmental risk factors, concluded Dr. Lappalainen. But it's actually more complicated than that because genes and environment interact. As demonstrated in our study, a genetic risk factor may manifest only in certain environments. We are still in early stages of understanding the interplay of genetics and environment, but our results indicate that this is a key component of human biology and disease. The molecular approach that we took in our study can be a particularly powerful way for researchers to delve deeper into this question."

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Genetic Variance is Key to Individual Immune Response - Genetic Engineering & Biotechnology News

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On Aug. 3, the scientific article in Nature finally gave us some facts about the much-hyped experiments that involved editing the genomes of human embryos at the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. The story had broken in late July in Technology Review, spurring profuse hand-wringing and discussion. But until we saw the scientific paper, it was not clear what cells and methods were used, what genes were edited, or what the results were.

Now we know more, and while the paper demonstrates the possibility of genome editing of human embryos, it raises more questions than it answers. It is a useful demonstration of technical promise, though not an immediate prelude to the birth of a genome-edited baby. But the process by which the news emerged is also an ominous harbinger of the discombobulated way the debate about genetically altering human embryos is likely to unfold. We need open, vigorous debate that captures the many, often contradictory, moral views of Americans. Yet what we are likely to get is piecemeal, fragmented stories of breakthroughs with incomplete details, more sober publication in science journals that appear later, news commentary that lasts a few days, and very little systematic effort to think through what policy should be.

The science underlying this news cycle about human genome editing builds on a technique first developed six years ago by studying how bacteria alter DNA. CRISPR genome editing is the most recent, and most promising, way to introduce changes into DNA. It is faster, easier, and cheaper than previous methods and should eventually be more precise and controllablewhich is why it may one day be available for clinical use in people.

Though headlines about the study discussed designer babies, researchers prefer to emphasize how these techniques could help stop devastating genetic disorders. The Oregon experiments with human embryo cells corrected disease-associated DNA variants associated with heart muscle wasting that can cause heart failure. The treated embryos were alive for only a few days and were never intended to become a human baby. They were, however, human embryos deliberately created for the research.

U.S. guidance in this area is sparse and reflects the lack of societal consensus. In 1994, when the federal government was contemplating funding for research involving human embryos, the NIH Embryo Research Panel concluded that just this kind of experiment was ethically appropriate. But within hours of that reports release, then-President Bill Clinton announced he did not agree with creating embryos in order to do research on them.

The United States currently has just two policies relevant to genomic editing of human embryos. The first blocks federal funding: On April 28, 2015, Francis Collins, director of the National Institutes of Health, stated, NIH will not fund any use of gene-editing technologies in human embryos. This is not embedded in statute or formal executive order, but members of Congress are fully aware of it and it is, in effect, a federal policy. NIH can (and does) fund genome editing of nonembryonic cells that might be used to treat cancer and for other possible therapeutic purposes, but not embryonic cells that would have their effect by creating humans with germline alterations.

Second, Congress has prohibited the Food and Drug Administration from reviewing research in which a human embryo is intentionally created or modified to include a heritable genetic modification. This language comes from a rider to FDAs annual appropriations. Yet use of human embryonic cells for treatment should be subject to FDA regulation. So this language in effect means alterations of embryonic cells cannot be done in the United States if there is any intent to treat a human being, including implantation of an altered embryo into a womans uterus. This will remain true so long as the rider is included in FDAs annual appropriations. The federal government thus has two relevant policies, both of which take federal agencies out of the action: One removes NIH funding, and the other precludes FDA oversight of genome-edited human embryos.

This leaves privately funded research that has no direct therapeutic purpose, such as with the Oregon experiments. The funding came from OHSU itself; South Korean Basic Research Funds; the municipal government of Shenzhen, China; and several private philanthropies (Chapman, Mathers, Helmsley, and Moxie). The research complies with recommendations to study the basic cellular processes of genome editing, keeping an eye on possible future clinical use but only so long as the work does not attempt to create a human pregnancy.

By coincidence, on the same day the Nature paper came out, the American Journal of Human Genetics also published a thoughtful 10-page position statement about germline genome editing from the American Society for Human Genetics endorsed by many other genetic and reproductive medicine organizations from all over the world. It reviews recommendations of the National Academies of Sciences, Engineering, and Medicine, several international and U.S.-based organizations and commissions, and makes several recommendations of its own, concluding it is inappropriate to perform germline gene editing that culminates in human pregnancy, but also there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications. Indeed, the statement argues for public funding. Finally, it urges research to proceed only with compelling medical rationale, strong oversight, and a transparent public process to solicit and incorporate stakeholder input.

So is there a problem here? It is truly wonderful that medical and scientific organizations have addressed genome editing. It is, however, far from sufficient. Reports and scientific consensus statements inform the policy debate but cannot resolve it. All of the reports on genome editing call for robust public debate, but the simple fact is that embryo research has proven highly divisive and resistant to consensus, and it is far from clear how to know when there is enough thoughtful deliberation to make policy choices. Its significant that none of the reports have emerged from a process that embodied such engagement. The Catholic Church, evangelical Christians, and concerned civic action groups who view embryo research as immoral are not likely to turn to the National Academies of Sciences, Engineering and Medicine, the American Society for Human Genetics, the Hinxton Group, the Nuffield Council on Bioetics, or other scientific and medical organizations for their primary counsel. They may well listen to scientists, but religious and moral doctrine will get greater weight. Yet religious groups highly critical of embryo research are part of the political systemand whether we embrace this sort of genome editing in the United States is a political question, not a purely technical one.

Reports and scientific consensus statements inform the policy debate but cannot resolveit.

Addressing the political questions will be extremely difficult. The U.S. government is poorly positioned to mediate the policy debate in a way that recognizes and addresses our complex moral pluralism. NIH and FDA are two of the most crucial agencies, but current policies remove them from line authority, and with good reason, given that engaging in this debate could actually endanger the agencies other vital missions. International consensus about genome editing of human embryos remains no more likely than about embryo research in general: Some countries ban it while others actively promote and fund it. Private foundations dont have the mandate or incentive to mediate political debate about a controversial technology that rouses the politics of abortion. What private philanthropic organization would willingly take on such a thankless and politically perilous task, and what organization would be credible to the full range of constituencies?

So who can carry out the public engagement that everyone seems to agree we need? The likely answer is no one. This problem occurs with all debate about fraught scientific and technical innovations, but its particularly acute when it touches on highly ossified abortion politics.

The debate about genomic editing of human embryos is unlikely to follow the recommendations for systematic forethought proposed by illustrious research bodies and reports. Given the reactions weve seen to human embryonic stem-cell research in the past two decades, we have ample reason for pessimism. Rather, debate is more likely to progress by reaction to events as researchers make newsoften with the same lack of information we lived with for the last week of July, based on incomplete media accounts and quotes from disparate experts who lacked access to the details. Most of the debate will be quote-to-quote combat in the public media, leavened by news and analysis in scientific and medical journals, but surrounded by controversy in religious and political media. It is not what anyone designing a system would want. But the recommendations for robust public engagement and debate feel a bit vacuous and vague, aspirations untethered to a concrete framework.

Our divisive political system seems fated to make decisions about genomic editing of human embryos mainly amidst conflict, with experts dueling in the public media rather than through a thoughtful and well-informed debate conducted in a credible framework. As the furor over the Oregon experiments begins to dissipate, we await the event that will cause the next flare-up. And so it will continue, skipping from news cycle to news cycle.

History shows that sometimes technical advances settle the issues, at least for most people and in defined contexts. Furor about in vitro fertilization after Louise Brown, the first test tube baby, was born in 1978 gave way to acceptance as grateful parents gave birth to more and more healthy babies and welcomed them into their families. Initial revulsion at heart transplants gave way in the face of success. Anger about prospects for human embryonic stem-cell research might similarly attenuate if practical applications emerge.

Such historical examples show precisely why reflective deliberation remains essential, despite its unlikely success. Momentum tends to carry the research forward. Yet at times we should stop, learn more, and decide actively rather than passively whether to proceed, when, how, and with what outcomes in mind. In the case of genome editing of human embryos, however, it seems likely that technology will make the next move.

This article is part of Future Tense, a collaboration among Arizona State University, New America, and Slate. Future Tense explores the ways emerging technologies affect society, policy, and culture. To read more, follow us on Twitter and sign up for our weekly newsletter.

Read more from the original source:
Listening for the Public Voice - Slate Magazine

Credit: Online Mendelian Inheritance in Man

The leading genetic disease database has chosen a new name for a genetic condition, following complaints from a man whose son has the condition.

On Aug. 11, 2017, two days after our coverage of the situation, the Online Mendelian Inheritance in Man (OMIM) database changed the primary name of the phenotype associated with mutations in the RPS23 gene. The new name describes a set of features: Brachycephaly, Trichomegaly, and Developmental Delay, or BTDD.

Brachycephaly describes a condition where the back of the head is abnormally flat and trichomegaly refers to extra length, curling, pigmentation, or thickness of the eyelashes.

Marc Pieterse, of the Netherlands, has a son with the rare RPS23 mutation, one of two known patients in the world. The mutation affects ribosomes, cell components involved in protein production. On Aug. 9, we reported on Pieterses crusade against OMIMs original name for the condition, which dubbed it a syndrome. He has feared that calling it a syndrome would stigmatize his sons condition and tried to get the paper underpinning the OMIM entry retracted. The American Journal of Human Genetics has said it will not retract the paper.

Pieterse told us hes only partially pleased the name has been changed hes still unhappy that the original title, MacInnes Syndrome, remains listed as an alternate one.

Initially, OMIM had named the phenotype associated with RPS23 mutations after Alyson MacInnes, a researcher at the University of Amsterdams Academic Medical Center. The name had been selected by OMIM, following a standard procedure of using the last name of the last author of the scientific paper that described the link between the mutation and the set of features.

Pieterse told Retraction Watch that he doesnt think BTDD is a great name, but he likes it much better than the previous one:

I think in the long term, its not describing well what is going on. As an intermediate solution for this naming game, I can live with it. If they want to describe it in this way, I wont be upset about it.

However, OMIM lists MacInnes Syndrome as an alternative title, which Pieterse says he will not endure:

Take out the alternative name. You dont need an alternative name anymore now

I dont think its a big deal for OMIM to leave it out.

OMIM Director Ada Hamosh, a professor at Johns Hopkins University, is on vacation, her assistant told us. When we spoke to Hamosh for our original story, she told us that the names of phenotypes can change, but the database entry is likely to continue displaying past names:

[OMIM] is a complete record of everything that happened.

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Genetic disorder gets name change, but patient's father still not happy - Retraction Watch (blog)

I

t was a strange moment of triumph against racism: The gun-slinging white supremacist Craig Cobb, dressed up for daytime TV in a dark suit and red tie, hearing that his DNA testing revealed his ancestry to be only 86 percent European, and 14 percent Sub-Saharan African. The studio audience whooped and laughed and cheered. And Cobb who was, in 2013, charged with terrorizing people while trying to create an all-white enclave in North Dakota reacted like a sore loser in the schoolyard.

Wait a minute, wait a minute, hold on, just wait a minute, he said, trying to put on an all-knowing smile. This is called statistical noise.

Then, according to the Southern Poverty Law Center, hetook to the white nationalist website Stormfront to dispute those results. Thats not uncommon: With the rise of spit-in-a-cup genetic testing, theres a trend of white nationalists using these services to prove their racial identity, and then using online forums to discuss the results.

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But like Cobb, many are disappointed to find out that their ancestry is not as white as theyd hoped. In a new study, sociologists Aaron Panofsky and Joan Donovan examined years worth of posts on Stormfront to see how members dealt with the news.

Its striking, they say, that white nationalists would post these results online at all. After all, as Panofsky put it, they will basically say if you want to be a member of Stormfront you have to be 100 percent white European, not Jewish.

But instead of rejecting members who get contrary results, Donovan said, the conversations are overwhelmingly focused on helping the person to rethink the validity of the genetic test. And some of those critiques while emerging from deep-seated racism are close to scientists own qualms about commercial genetic ancestry testing.

Panofsky and Donovan presented their findings at a sociology conference in Montreal on Monday. The timing of the talk some 48 hours after the violent white nationalist rally in Charlottesville, Va. was coincidental. But the analysis provides a useful, if frightening, window into how these extremist groups think about their genes.

Stormfront was launched in the mid-1990s byDon Black, a former grand wizard of the Ku Klux Klan. His skills in computer programming were directly related to his criminal activities: He learned them while in prison for trying to invade the Caribbean island nation of Dominica in 1981, and then worked as a web developer after he got out. That means this website dates back to the early years of the internet, forming a kind of deep archive of online hate.

To find relevant comments in the 12 million posts written by over 300,000 members, the authors enlisted a team at the University of California, Los Angeles, to search for terms like DNA test, haplotype, 23andMe, and National Geographic. Then the researchers combed through the posts they found, not to mention many others as background. Donovan, who has moved from UCLA to the Data & Society Research Institute, estimated that she spent some four hours a day reading Stormfront in 2016. The team winnowed their results down to 70 discussion threads in which 153 users posted their genetic ancestry test results, with over 3,000 individual posts.

About a third of the people posting their results were pleased with what they found. Pretty damn pure blood, said a user with the username Sloth. But the majority didnt find themselves in that situation. Instead, the community often helped them reject the test, or argue with its results.

Some rejected the tests entirely, saying that an individuals knowledge about his or her own genealogy is better than whatever a genetic test can reveal. They will talk about the mirror test, said Panofsky, who is a sociologist of science at UCLAs Institute for Society and Genetics. They will say things like, If you see a Jew in the mirror looking back at you, thats a problem; if you dont, youre fine.' Others, he said, responded to unwanted genetic results by saying that those kinds of tests dont matter if you are truly committed to being a white nationalist. Yet otherstried to discredit the genetic tests as a Jewish conspiracy that is trying to confuse true white Americans about their ancestry, Panofsky said.

But some took a more scientific angle in their critiques, calling into doubt the method by which these companies determine ancestry specifically how companies pick those people whose genetic material will be considered the reference for a particular geographical group.

And that criticism, though motivated by very different ideas, is one that some researchers have made as well, even as other scientists have used similar data to better understand how populations move and change.

There is a mainstream critical literature on genetic ancestry tests geneticists and anthropologists and sociologists who have said precisely those things: that these tests give an illusion of certainty, but once you know how the sausage is made, you should be much more cautious about these results, said Panofsky.

Companies like Ancestry.com and 23andMe are meticulous in how they analyze your genetic material. As points of comparison, they use both preexisting datasets as well as some reference populations that they have recruited themselves. The protocol includes genetic material from thousands of individuals, and looks at thousands of genetic variations.

When a 23andMe research participant tells us that they have four grandparents all born in the same country and the country isnt a colonial nation like the U.S., Canada, or Australia that person becomes a candidate for inclusion in the reference data, explained Jhulianna Cintron, a product specialist at 23andMe. Then, she went on, the company excludes close relatives, as that could distort the data, and removes outliers whose genetic data dont seem to match with what they wrote on their survey.

But specialists both inside and outside these companies recognize that the geopolitical boundaries we use now are pretty new, and so consumers may be using imprecise categorieswhen thinking about their own genetic ancestry within the sweeping history of human migration. And users ancestry results can change depending on the dataset to which their genetic material is being compared a fact which some Stormfront users said they took advantage of, uploading their data to various sites to get a more white result.

J. Scott Roberts, an associate professor at the University of Michigan, who has studied consumer use of genetic tests and was not involved with the study, said the companies tend to be reliable at identifying genetic variants. Interpreting them in terms of health risk or ancestry, though, is another story. The science is often murky in those areas and gives ambiguous information, he said. They try to give specific percentages from this region, or x percent disease risk, and my sense is that that is an artificially precise estimate.

For the study authors, what was most interesting was to watch this online community negotiating its own boundaries, rethinking who counts as white. That involved plenty of contradictions.They saw people excluded for their genetic test results, often in very nasty (and unquotable) ways, but that tended to happen for newer members of the anonymous online community, Panofsky said, and not so much for longtime, trusted members. Others were told that they could remain part of white nationalist groups, in spite of the ancestry they revealed, as long as they didnt mate, or only had children with certain ethnic groups. Still others used these test results to put forth a twisted notion of diversity, one that allows them to say, No, were really diverse and we dont need non-white people to have a diverse society,' said Panofsky.

Thats a far cry from the message of reconciliation that genetic ancestry testing companies hope to promote.

Sweetheart, you have a little black in you, the talk show host Trisha Goddard told Craig Cobb on that day in 2013. But that didnt stop him from redoing the test with a different company, trying to alter or parse the data until it matched his racist worldview.

General Assignment Reporter

Eric is a general assignment reporter.

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White nationalists are flocking to genetic ancestry tests. Some don't like what they find - STAT

In 1944, a Columbia University doctoral student in genetics named Evelyn Witkin made a fortuitous mistake. During her first experiment in a laboratory at Cold Spring Harbor, in New York, she accidentally irradiated millions of E. coli with a lethal dose of ultraviolet light. When she returned the following day to check on the samples, they were all dead except for one, in which four bacterial cells had survived and continued to grow. Somehow, those cells were resistant to UV radiation. To Witkin, it seemed like a remarkably lucky coincidence that any cells in the culture had emerged with precisely the mutation they needed to survive so much so that she questioned whether it was a coincidence at all.

For the next two decades, Witkin sought to understand how and why these mutants had emerged. Her research led her to what is now known as the SOS response, a DNA repair mechanism that bacteria employ when their genomes are damaged, during which dozens of genes become active and the rate of mutation goes up. Those extra mutations are more often detrimental than beneficial, but they enable adaptations, such as the development of resistance to UV or antibiotics.

The question that has tormented some evolutionary biologists ever since is whether nature favored this arrangement. Is the upsurge in mutations merely a secondary consequence of a repair process inherently prone to error? Or, as some researchers claim, is the increase in the mutation rate itself an evolved adaptation, one that helps bacteria evolve advantageous traits more quickly in stressful environments?

The scientific challenge has not just been to demonstrate convincingly that harsh environments cause nonrandom mutations. It has also been to find a plausible mechanism consistent with the rest of molecular biology that could make lucky mutations more likely. Waves of studies in bacteria and more complex organisms have sought those answers for decades.

The latest and perhaps best answer for explaining some kinds of mutations, anyway has emerged from studies of yeast, as reported in June in PLOS Biology. A team led by Jonathan Houseley, a specialist in molecular biology and genetics at the Babraham Institute in Cambridge, proposed a mechanism that drives more mutation specifically in regions of the yeast genome where it could be most adaptive.

Its a totally new way that the environment can have an impact on the genome to allow adaptation in response to need. It is one of the most directed processes weve seen yet, said Philip Hastings, professor of molecular and human genetics at Baylor College of Medicine, who was not involved in the Houseley groups experiments. Other scientists contacted for this story also praised the work, though most cautioned that much about the controversial idea was still speculative and needed more support.

Rather than asking very broad questions like are mutations always random? I wanted to take a more mechanistic approach, Houseley said. He and his colleagues directed their attention to a specific kind of mutation called copy number variation. DNA often contains multiple copies of extended sequences of base pairs or even whole genes. The exact number can vary among individuals because, when cells are duplicating their DNA before cell division, certain mistakes can insert or delete copies of gene sequences. In humans, for instance, 5 to 10 percent of the genome shows copy number variation from person to person and some of these variations have been linked to cancer, diabetes, autism and a host of genetic disorders. Houseley suspected that in at least some cases, this variation in the number of gene copies might be a response to stresses or hazards in the environment.

In 2015, Houseley and his colleagues described a mechanism by which yeast cells seemed to be driving extra copy number variation in genes associated with ribosomes, the parts of a cell that synthesize proteins. However, they did not prove that this increase was a purposefully adaptive response to a change or constraint in the cellular environment. Nevertheless, to them it seemed that the yeast was making more copies of the ribosomal genes when nutrients were abundant and the demand for making protein might be higher.

Houseley therefore decided to test whether similar mechanisms might act on genes more directly activated by hazardous changes in the environment. In their 2017 paper, he and his team focused on CUP1, a gene that helps yeast resist the toxic effects of environmental copper. They found that when yeast was exposed to copper, the variation in the number of copies of CUP1 in the cells increased. On average, most cells had fewer copies of the gene, but the yeast cells that gained more copies about 10 percent of the total population became more resistant to copper and flourished. The small number of cells that did the right thing, Houseley said, were at such an advantage that they were able to outcompete everything else.

But that change did not in itself mean much: If the environmental copper was causing mutations, then the change in CUP1 copy number variation might have been no more than a meaningless consequence of the higher mutation rate. To rule out that possibility, the researchers cleverly re-engineered the CUP1 gene so that it would respond to a harmless, nonmutagenic sugar, galactose, instead of copper. When these altered yeast cells were exposed to galactose, the variation in their number of copies of the gene changed, too.

The cells seemed to be directing greater variation to the exact place in their genome where it would be useful. After more work, the researchers identified elements of the biological mechanism behind this phenomenon. It was already known that when cells replicatetheir DNA, the replication mechanism sometimes stalls. Usually the mechanism can restart and pick up where it left off. When it cant, the cell can go back to the beginning of the replication process, but in doing so, it sometimes accidentally deletes a gene sequence or makes extra copies of it. That is what causes normal copy number variation. But Houseley and his team made the case that a combination of factors makes these copying errors especially likely to hit genes that are actively responding to environmental stresses, which means that they are more likely to show copy number variation.

The key point is that these effects center on genes responding to the environment, and that they could give natural selection extra opportunities to fine-tune which levels of gene expression might be optimal against certain challenges. The results seem to present experimental evidence that a challenging environment could galvanize cells into controlling those genetic changes that would best improve their fitness. They may also seem reminiscent of the outmoded, pre-Darwinian ideas of the French naturalist Jean-Baptiste Lamarck, who believed that organisms evolved by passing their environmentally acquired characteristics along to their offspring. Houseley maintains, however, that this similarity is only superficial.

What we have defined is a mechanism that has arisen entirely through Darwinian selection of random mutations to give a process that stimulates nonrandom mutations at useful sites, Houseley said. It is not Lamarckian adaptation. It just achieves some of the same ends without the problems involved with Lamarckian adaptation.

Ever since 1943, when the microbiologist Salvador Luria and the biophysicist Max Delbrck showed with Nobel prize-winning experiments that mutations in E. coli occur randomly, observations like the bacterial SOS response have made some biologists wonder whether there might be important loopholes to that rule. For example, in a controversial paper published in Nature in 1988, John Cairns of Harvard and his team found that when they placed bacteria that could not digest the milk sugar lactose in an environment where that sugar was the sole food source, the cells soonevolved the ability to convert the lactose into energy. Cairns argued that this result showed that cells had mechanisms to make certain mutations preferentially when they would be beneficial.

Go here to read the rest:
Beating the Odds for Lucky Mutations - Quanta Magazine

In an article published in American Journal of Human Genetics on 3 August 2017, an international group of 11 organisations with genetics expertise has issued a joint position statement, setting out 3 key positions on the question of human germline genome editing:

(1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy.

(2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research.

(3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.

This serendipitously timed statement comes on the heels of Shoukhrat Mitalipov and colleagues at Oregon Health and Science Universitys publication of an article in Nature reporting the successful use of CRISPR/Cas9 in human embryos to correct a mutation in a gene called MYBPC3 that causes a potentially fatal heart condition known as hypertrophic cardiomyopathy. The publication of this article has drawn the attention of the wider mainstream media and reignited the public debate as to the desirability, feasibility and ethics of editing the human genome in an inheritable way.

Gene editing - putting the paper in context

Whilst debates about the ethics of gene editing (both somatic and germline) go back decades, human germline genome editing has never before been realistically possible from a technical standpoint. That has changed with the advent of the CRISPR/Cas9 system, whose efficiency and ease of use has not only opened up the field of gene editing to a far larger number of companies and laboratories than previously, but has brought the editing of specific genes in a human embryo out of the realms of fantasy into reality. The potential for such technology to improve quality of life and prevent suffering caused by debilitating genetically inherited diseases has captured the imagination of many, particularly people living with currently intractable genetic conditions, their friends and family. However, the power of the technology has also conjured up the familiar spectres of playing God, the uncertainty of long term effects on individuals (and what it means to be human itself), marginalisation of the disabled or genetically inferior and the potential for inequality to manifest itself genetically as well as socioeconomically.

Germline cell editing poses significantly more concerning ethical and regulatory issues than somatic cell editing. The latter will only result in uninheritable changes to the genome of a population of cells in the particular individual treated, whilst the former involves genetic changes that will be passed down, for better or worse, to the individuals offspring.

In early 2015, the first study demonstrating that CRISPR/Cas9 could be used to modify genes in early-stage human embryos was published. Although the embryos employed for those experiments were not capable of developing to term, the work clearly demonstrated that genome editing with CRISPR/Cas9 in human embryos can readily be performed. That report stimulated many scientists and organisations to clarify their stance on the use of genome-editing methods. The United Kingdom and Sweden have both approved experiments for editing DNA of a human embryo but not those that involve implanting embryos. In the UK, Human Fertilisation and Embryology Authority (HFEA) has approved an application by developmental biologist Kathy Niakan, at the Francis Crick Institute in London, to use CRISPR/Cas9 in healthy human embryos. Currently, such experiments cannot be done with federal funding in the United States given a congressional prohibition on using taxpayer funds for research that destroys human embryos. Congress has also banned the U.S. Food and Drug Administration from considering a clinical trial of embryo editing. As would be expected, the safety requirements for any human clinical genome-editing application are extremely stringent.

However, earlier this year, US-based National Academy of Sciences (NAS) and the National Academy of Medicine (NAM), published a report that concluded using genome-editing technology, such as CRISPR/Cas9, to make alterations to the germline would be acceptable if the intention was to treat or prevent serious genetic disease or disorders, and the procedure was proven to be safe ( significant and, to an extent, subjective hurdles to be overcome).

The ASHG position paper

The position paper was the product of a working group established by the American Society of Human Genetics (ASHG), including representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counsellors. These groups, as well as the American Society for Reproductive Medicine, Asia Pacific Society of Human Genetics, British Society for Genetic Medicine, Human Genetics Society of Australasia, Professional Society of Genetic Counsellors in Asia, and Southern African Society for Human Genetics, endorsed the final statement. The group, composed of a combination of research and clinical scientists, bioethicists, health services researchers, lawyers and genetic counsellors, worked together to integrate the scientific status of and socio-ethical views towards human germline genome editing.

As part of this process, the working group reviewed and summarised nine existing policy statements on gene editing and embryo research and interventions from national and international bodies, including The International Society for Stem Cell Research (2015) Statement on Human Germline Genome Modification, The Hinxton Group (2015) Statement on Genome Editing Technologies and the statement released following the International Summit on Human Gene Editing (2015) co-hosted by the National Academy of Sciences, National Academy of Medicine, Chinese Academy of Sciences and The Royal Society (UK). It was observed that differences in these policies include the very definition of what constitutes a human embryo or a reproductive cell, the nature of the policy tool adopted to promote the positions outlined, and the oversight/enforcement mechanisms for the policy. However, by and large, the majority of available statements and recommendations restrict applications from attempting to initiate a pregnancy with an embryo or reproductive cell whose germline has been altered. At the same time, many advocate for the continuation of basic research (and even preclinical research in some cases) in the area. One notable exception is the US National Institutes of Health, which refuses to fund the use of any gene-editing technologies in human embryos. Accordingly, due to the lack of public funding in the US, work such as that done by Mitalipovs group must be privately funded.

The working group considered that ethical issues around germline genome editing largely fall into two broad categories those arising from its potential failure and those arising from its success. Failure exposes individuals to a variety of health consequences, both known and unknown, while success could lead to societal concerns about eugenics, social justice and equal access to medical technologies.

The 11 organisations acknowledged numerous ethical issues arising from human germline genome editing, including:

Having touched on each of these issues, the group then outlined its consensus positions:

1. At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy.

It was noted that there is not yet a high quality evidence base to support the use of germline genome editing, with unknown risk of health consequences and ethical issues still to be explored and resolved by society.

The group observed that two major categories of safety concerns are (i) the effect of unwanted or off-target mutations, and (ii) the potential unintended effects of the desired on-target base changes (edits) being made. It noted that it is reasonable to presume that any human genome-editing therapeutic application will require stringent monitoring of off-target mutation rates, but there remains no consensus on which methods would be optimal for this, or what a desirable maximum off-target mutation rate would be when these techniques are translated clinically. The working-group thus outlined its views on the minimum necessary developments that would be required (at least from a safety perspective) before germline genome editing could be used clinically:

2. Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research.

The group agreed that conducting basic scientific [techniques?] involving editing of human embryos and gametes can be performed ethically via compliance with applicable laws and policies, and that any study involving in vitro genome editing on human embryos and gametes should be conducted under rigorous and independent governance mechanisms, including approval by ethics review boards and meeting any other policy or regulatory requirements. Public funding for such research was seen as important in ensuring that such research is not driven overseas or underground, where it would be subject to less regulation, oversight and transparency.

3. Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.

Even if the technical data from preclinical research reaches a stage where it supports clinical translation of human germline genome editing, the working group stresses that many more things need to happen before translational research in human germline genome editing is considered. The criteria identified by the group in this position cut across medical, ethical, economic and public participation issues and represent the setting of an appropriately high and comprehensive standard to be met before human germline genome editing may be applied clinically. The group acknowledges the challenges of public engagement with such technical subject matter but encourages new approaches to public engagement and engagement of broader stakeholder groups in the public discussion.

The ethical implications of altering the human germline has been the subject of intense discussion in recent years, with calls for such work to be put on hold until the process of genome editing is better understood. ASHG supports somatic genome editing and preclinical (in vitro human and animal) germline genome research but feels strongly that it is premature to consider human germline genome editing in any translational manner at this time.

The working group concludes that Many scientific, medical, and ethical questions remain around the potential for human germline genome editing. ASHG supports somatic genome editing and preclinical (in vitro human and animal) germline genome research but feels strongly that it is premature to consider human germline genome editing in any translational manner at this time. We encourage ethical and social consideration in tandem with basic science research in the upcoming years.

This appears a reasonable position largely in line with the recommendations from the major national and international groups surveyed by the working group. It balances the need to encourage further basic research and validation with strong awareness of the ethical and societal implications of human germline genome editing, setting a high bar before such technology should be translated to the clinic. No doubt, however, the debate will continue, particularly in respect of public funding for such work. Whether the US will maintain their stance against public funding, in the face of international competition, and potential loss of talent and investment, remains to be seen.

For more information about the science of CRISPR, its wide range of applications in life sciences and beyond, and latest developments in the field, please see Allen & Overys dedicated CRISPR microsite.

Original post:
Human Germline Genome Editing - Genetics bodies weigh in on debate with position paper - Lexology (registration)

15 Aug 2017

Genetic forces drive a sizable portion of Alzheimers disease, yet only a fraction of cases thus far are explained by known mutations. A handful of recent papers used genomic sequencing to fish out new variants that, while exceedingly rare, pack a wallop in those who carry them. In the July 24 JAMA Neurology, researchers led by Margaret Pericak-Vance at the University of Miami in Florida reported that mutations in four endolysosomal transport genes boosted risk of early onset AD (EOAD). A few weeks earlier, a large collaboration of French researchers reported rare new TREM2, ABCA7, and SORL1 variants in Neurobiology of Aging, while scientists led by Henne Holstege at VU University Medical Center in Amsterdam characterized the pathogenicity of SORL1 variants and even proposed classifying this endosomal sorting protein as the fourth autosomal-dominant AD gene. A team led by Dominique Campion at University of Rouen, France, dug deep into the well-trodden territory of the three autosomal-dominant genesAPP, PS1, and PS2and uncovered de novo pathogenic variants that cropped up in people with no family history of AD. Last but not least, Anne Rovelet-Lecrux, also at Rouen, linked a duplication in the tau gene to people with an AD diagnosis who lacked Aplaques.

Together, the studies move the field a step closer to filling in the missing genetic influence on AD, and could provide new targets for therapeutic strategies, commented Liana Apostolova at the University of Indiana in Bloomington. There are more genetic risk factors in hiding that have yet to be discovered, and these studies suggest were on the right track, she toldAlzforum.

In the JAMA Neurology study, first author Brian Kunkle and colleagues report on their search for rare variants with large effects on AD risk. Reasoning that people with EOAD are likely carriers of damaging genetic mutations, they conducted whole-exome sequencing in 51 non-Hispanic white EOAD patients, plus 53 people from 19 Caribbean Hispanic families with EOAD; all had tested negative for known causal mutations in APP, PS1, and PS2. The scientists combed the exomes for variants predicted to have damaging effects, then attempted to validate each variants association with AD using exome genotyping data from a separate cohort of 1,500 EOAD patients, 7,000 LOAD patients, and 7,000 controls. Developed by the Alzheimers Disease Genetics Consortium (ADGC), the exome chip used to genotype this separate cohort contains more than 200,000 variants, most of which are functional, rare, single nucleotidemutations.

In their original sequencing cohort, the researchers identified mutations in known or suspected EOAD genes, including SORL1, PS1, PS2, TREM2, and MAPT. Some were known; others were new variants in genes previously tied to LOAD, including HLA-DRB1, ABCA7, and RIN3. Suspicious mutations also cropped up in genes without an AD record. A missense mutation in TCIRG1, present in a non-Hispanic white person with EOAD and segregating with EOAD in three Hispanic families, was twice as frequent in EOAD than in controls in the validation cohort. Deleterious mutations in PSD2 appeared in multiple unrelated cases in the sequencing cohort, and associated with EOAD in the validation cohort, at least when considered in the aggregate. Mutations in RIN3 and RUFY1 appeared in the discovery cohort, but their EOAD association in the validation group was nominal. Importantly, all four genes function in different parts of the endolysosomal transport pathway, which is essential for clearing cellular debris and unwanted proteins, includingA.

The researchers found additional rare mutations in EOAD patients, but these were not on the exome chip used for the validation cohort. For example, of 151 potentially damaging variants that appeared in the original exome sequencing cohort, only 43 were included on the exomechip.

While this filtering process allows researchers to test whether a variant is truly linked to disease, it also precludes consideration of totally new, potentially damaging mutations, said Holstege. The mutations that are most damaging are also the most rare, Holstege told Alzforum. If you filter them out in this way, you quench yoursignal.

Holstege took a different tack to find and classify rare SORL1 variants. Rather than filtering out undocumented variants, Holstege and colleagues made them their bread and butter. In the May 24 European Journal of Human Genetics, they reported 115 SORL1 variants from the exomes of a Dutch cohort of 640 AD cases and 1,268 controls. Fifteen of these variants were common, and not associated with AD. The other 100 were rare, occurring in less than 0.01 percent of the population. Of those, 19 were predicted to be strongly damaging, based on high scores on CADD, an algorithm that considers more than 100 variant characteristics to predict how likely a given mutation is to alter protein function orexpression.

Strikingly, 16 of these suspicious variants only appeared in a single person within the entire cohort, and 14 of those had AD. None of the variants were included in prior exome genotyping studies, so the researchers could not draw upon past data to validate whether they truly associated with the disease. Instead, the researchers developed a pathogenicity scale. Weaving in data from more than 3,000 exomes sequenced separately, the researchers classified a total 181 SORL1 variants based on their combined CADD scores and rarity. They categorized those that had high CADD scores and were very rare as pathogenic. Estimated pathogenicity decreased from likely pathogenic to uncertain to likely benign to benign as variants became less damaging and morecommon.

The scientists found that a combination of high CADD scores and extremely low allele frequency selected out those SORL1 variants that occurred much more often in cases than in controls. The 13 variants with the highest pathogenicity resulted in truncations of SORL1, and occurred only in AD cases. The researchers predicted they would cause dominantly inherited AD, though none have yet been traced in familypedigrees.

Holstege and colleagues proposed that SORL1 take a spot alongside PS1, PS2, and APP as an autosomal-dominant AD gene. Pathogenic SORL1 mutations occurred in 2 percent of the AD cases in this study, placing them at a higher frequency than other ADAD genes. Like PS1, PS2, and APP, SORL1 protein strongly influences A, as it protects APP from amyloidogenic processing and ushers A to lysosomes for disposal (see Sep 2007 news; Feb 2014 news).

Classifying SORL1 as an ADAD gene would raise new questions. How to provide genetic counseling to affected families? Should mutation carriers be eligible to join the Dominantly Inherited Alzheimers Network (DIAN)? Clinical-grade genetic tests for SORL1 variants would be needed, a challenge developers may postpone until further data has confirmed the mutations are pathogenic, commented Apostolova. She added that while Holsteges pathogenicity scale is an exciting tool that should be used in future studies, validation of each mutation in other cohorts, as well as functional evidence in animal and cell culture studies, should be required to elevate SORL1 to ADAD status. Rovelet-Lecrux agreed that designating SORL1 an ADAD gene will have to await discovery of multigenerational families in which SORL1 segregates with disease in an autosomal-dominant pattern. Until we accumulate more genetic evidence, we cannot tell SORL1 mutation carriers how likely they are to develop disease, shesaid.

A new study led by Rouens Campion and co-authored by Rovelet-Lecrux further supports pathogenicity of SORL1 variants, even if it does not provide evidence of multigenerational segregation. As reported July 13 in the Neurobiology of Aging, the researchers detected SORL1 missense and protein-truncating variants that associated strongly with early onset disease by doing whole-exome and genome sequencing of a French cohort of 852 EOAD, 927 LOAD, and 1,273 control cases. All but one of 13 protein-truncating variants occurred only in EOAD cases, and eight of 10 cases with available family information had a history of the disease. Besides SORL1, TREM2 and ABCA7 also harbored potentially damaging EOAD-associated variants in this sample. The researchers estimated that variants in these three genes accounted for 1.42, 1.17, and 1.33 percent of EOAD heritability, respectively. By comparison, ApoE4 accounted for 9.12percent.

New Finds in Old Genes While many pathogenic mutations in PS1, PS2, and APP have been traced in family pedigrees, additional rare variants in these established ADAD genes may yet be discovered. In search of them, researchers led by Rouens Campion sequenced these genes in 129 sporadic cases of early onset AD, as well as in 53 affected families. Published March 28 in PLOS Medicine, the findings included data from participants who joined the ongoing French study after 2012, when the researchers had published a similar analysis (Wallon et al., 2012).In all, first author Hlne-Marie Lanoisele and colleagues identified 44 PS1, two PS2, and 20 APP mutations, as well as five APP duplications; 12 of the PS1 and one PS2 mutation had not been reportedpreviously.

The most striking finding was the existence of de novo mutations in PS1. Indeed, seven of 12 new mutations occurred in sporadic cases of EOAD. In three of these mutations, the researchers were able to confirm that the carriers parents did not carry the new mutation. Rovelet-Lecrux, a co-author on the paper, said that the prevalence of de novo mutations in ADAD genes is likely underestimated, because routine genetic screening for these mutations is done only in familial AD cases. The de novo find underscores the importance of checking for pathogenic mutations even in patients without a family history of AD, especially people with an early age at onset, Holstege commented. Similar to the situation with rare SORL1 variants, researchers will need to decide how to categorize carriers of new and de novo mutations in established ADAD genes, shesaid.

Finally, results from a slightly older study led by Rovelet-Lecrux pose a different kind of classification conundrum. The authors deployed whole-exome sequencing to hunt specifically for copy number variations (CNVs) such as duplications and deletions in 335 genes predicted to influence A processing, clearance, or aggregation. The researchers found CNVs in 30 out of 522 people with EOAD, but only 18 out of 584 controls. Most of these CNVs occurred in a single person in the cohort, and they included novel deletions in the PS1, ABCA7, and SLC30A3 genes previously tied toAD.

A surprising finding reared its head in four AD cases, who all had a duplicationin a region of chromosome 17 including MAPT, the gene encoding none other than tau. The duplication appeared in two sporadic cases of EOAD and two with a family history. DNA available from one of those families confirmed that the duplication segregated with EOAD. Even though these four carriers had symptoms consistent with AD, the three who underwent amyloid-PET imaging had negative scans, to Rovelet-Lecruxs surprise. All four duplication carriers had abnormal levels of CSF p-tau and tau, and three of them also had abnormal concentrations of A42. The researchers also found nearly double the amount of tau mRNA in the blood of carriers than incontrols.

Together, the findings suggest that despite the lack of A plaques visible on PET, carriers of a tau duplication have a clinical disorder markedly similar to AD. The abnormality of CSF A42 in three of the duplication carriers suggests that they could have accumulated A just below the level of PET detection, a sub-threshold aggregation the researchers speculated could even be somehow caused by elevatedtau.

Do these tau duplication carriers have AD? Not if you consider A accumulation as a defining feature of the disease, said Apostolova. Indeed, in the paper, the researchers defined their disease as a tau-related dementia, proposing that it could account for a significant proportion of early onset dementia cases with no genetic explanation. While some researchers view A as a mere forerunner to the more destructive tau pathology, which they consider the main event in AD, Rovelet-Lecrux shied away from separating A from AD, saying that AD is ultimately diagnosed via its neuropathological hallmarks of A plaques and tau tangles. She believes it will be important to screen EOAD patients without A plaques for tau pathology, especially in the future once both A- or tau-targeted therapies exist.JessicaShugart

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The Search for the Missing AD Heritability Turns Up New Rare Variants - Alzforum

Using health insurance claims data from more than 480,000 people in nearly 130,000 families, researchers have created a new classification of common diseases based on how often they occur among genetically-related individuals.

Researchers hope the work, published this week in Nature Genetics, will help physicians make better diagnoses and treat root causes instead of symptoms.

Understanding genetic similarities between diseases may mean that drugs that are effective for one disease may be effective for another one, says senior author Andrey Rzhetsky, professor of medicine and human genetics at the University of Chicago. And for those diseases with a large environmental component, that means we can perhaps prevent them by changing the environment.

The results of the study suggest that standard disease classificationscalled nosologiesbased on symptoms or anatomy may miss connections between diseases with the same underlying causes. For example, the new study showed that migraine, typically classified as a disease of the central nervous system, appeared to be most genetically similar to irritable bowel syndrome, an inflammatory disorder of the intestine.

Rzhetsky and a team of researchers analyzed records from Truven MarketScan, a database of de-identified patient data from more than 40 million families in the United States. They selected a subset of records based on how long parents and their children were covered under the same insurance plan within a time frame most likely to capture when children were living in the same home with their parents. They used this massive data set to estimate genetic and environmental correlations between diseases.

Next, using statistical methods developed to create evolutionary trees of organisms, the team created a disease classification based on two measures. One focused on shared genetic correlations of diseases, or how often diseases occurred among genetically-related individuals, such as parents and children. The other focused on the familial environment, or how often diseases occurred among those sharing a home but who had no or partially matching genetic backgrounds, such as spouses and siblings.

The results focused on 29 diseases that were well represented in both children and parents to build new classification trees. Each branch of the tree is built with pairs of diseases that are highly correlated with each other, meaning they occur frequently together, either between parents and children sharing the same genes, or family members sharing the same living environment.

The large number of families in this study allowed us to obtain precise estimates of genetic and environmental correlations, representing the common causes of multiple different diseases, says Kanix Wang, a graduate student and lead author of the study. Using these shared genetic and environmental causes, we created a new system to classify diseases based on their intrinsic biology.

Genetic similarities between diseases tended to be stronger than their corresponding environmental correlations. For the majority of neuropsychiatric diseases, such as schizophrenia, bipolar disorder, and substance abuse, however, environmental correlations are nearly as strong as genetic ones. This suggests there are elements of the shared, family environment that could be changed to help prevent these disorders.

The researchers also compared their results to the widely used International Classification of Diseases Version 9 (ICD-9) and found additional, unexpected groupings of diseases. For example, type 1 diabetes, an autoimmune endocrine disease, has a high genetic correlation with hypertension, a disease of the circulatory system. The researchers also saw high genetic correlations across common, apparently dissimilar diseases such as asthma, allergic rhinitis, osteoarthritis, and dermatitis.

The study received support from the Defense Advanced Research Projects Agency (DARPA) Big Mechanism program, the National Institutes of Health, and a gift from Liz and Kent Dauten. Additional authors are from the University of Chicago, Microsoft Research, and Vanderbilt University.

Source: University of Chicago

See the article here:
Insurance claims reveal new links among diseases - Futurity: Research News

Nine more graduates of Lockport High School have been named "Distinguished Alumni" by the LHS Foundation.

The 11th annual recognition ceremony for honorees will be held at 7 p.m. Aug. 24 at the high school auditorium. A reception precedes the ceremony at 6:30 p.m. in the art gallery and foyer. All community members are welcome.

The 2017 honorees are listed here.

Anthony Caridi

Anthony Caridi, class of 1980, is recognized as the state of West Virginias most popular sports voice.As the play-by-play announcer of the West Virginia University Mountaineers, he has described the action of some of the schools greatest athletic accomplishments including victories in the Orange, Sugar and Fiesta bowls, along with an NCAA Final Four appearance.

A multiple winner of the West Virginia Sportscaster of the Year award, Caridi has hosted his own nightly statewide sports talk show on the Metro News Radio Network since 1986.

As a founding member of Emmy Award-winning Pikewood Creative, Caridi is responsible for generating new business development, fostering client relationships and directing the Pikewood team in its creative trajectory.

Caridi was raised in his familys grocery business in Lockport. He attended Syracuse University and graduated from the S.I. Newhouse School of Public Communication with a degree in broadcast journalism.

This past December, he released his first childrens book, Where, Oh Where, Oh Where Could we Go? which takes readers on a whimsical trek around West Virginia.

Tony and his wife Joan have three children: Michael, who has a degree in finance and works in Morgantown, and twins Andrew and Matthew, who just finished their freshman year at WVU.

Mary E. Poole Dale

The late Mary Elizabeth (Bette) Poole Dale, class of 1935, was a pioneer in the elder care field and her legacy lives on through the local not-for-profit Dale Association.

Dale was an early advocate for the elderly. She created the first senior center in the United States that provided direct mental health services for adults. Lockport Senior Centre became a national model of the multi-purpose senior center.Dale was an acclaimed speaker at conferences and seminarswell beyond the limits of New York state.In 1995, Lockport Senior Centre was renamed in her honor.

Dale died in 2007.

Jack J. Florio Jr.

Jack J. Florio Jr., class of 1979, and his wife Rebecca are the owners of Micro Graphics, a printing and sign company on Main Street. Florio founded the business in 1989, while he was attending college in Florida, studying computer engineering and working in the college computer lab.

Florio paid close attention to the graphic design classes taught in the lab and mastered the curriculum quickly. The college soon hired him as a technical adviser, to help instruct computer graphics. Seeing the industry's potential, Florio invested in a Xerox copier and a laser printer and landed clients includingShands Teaching Hospital, University of Florida and Daytona International Speedway.

Upon his return to Western New York, Florio went to work for Roswell Park Cancer Institute, developing the Gilda Radner Ovarian Cancer Registry and the AIDS Database Registry and utilizing his skills for various departments from radiology and pathology to medical illustration, marketing and the print shop. Simultaneously, he was rebuilding Micro Graphics, with which he eventually went full time.

While building up his business, it was normal for Florio to work two or three jobs at a time. He did CAD for General Motors and EDS and has worked as an auto mechanic for Texaco and Gulf Oil, a pre-press and web press operator for the Union-Sun & Journal, a software instructor for DuPont Paint, and a manager of CopyMax and the old Friendly's restaurant in Lockport.

Florio and his wife have been the sole organizers of the Mother's Day Breast Cancer Canal Walk for over 20 years. The walk has raised over $500,000 for cancer support. Florio also partners with the Salvation Army every year to send oversized Christmas cards to U.S. troops overseas.

The Florios' son Michael works in the computer animation field in New York City.

Ronald Franco

Ronald Franco, class of 1982, met his future wife and fellow Distinguished Alumnus, Deborah Qualiana, while attending track practice as an eighth grader.He graduated as senior class president, then attended the Air Force Academy and Syracuse University, and earned a degree in aerospace engineering.

A graduate of Officer Training School, Franco flew supersonic jets during his year at undergraduate pilot training and qualified for Fighter-Attack-Reconnaissance assignment. He returned to Western New York to serve with the Niagara Falls-based 328th Tactical Airlift Squadron and flew: combat missions to liberate Kuwait during Desert Storm and in Iraq and Afghanistan during Operation Iraqi Freedom; humanitarian aid flights to Somalia and the Kurds; UN support missions in Bosnia and Serbia; international cooperation missions in Egypt and Japan; and Special Forces support in Central and South America. He was awarded the USAF Air Medal and Aerial Achievement Medal.

In 1999, Franco was hired by American Airlines. He is a recipient of the Outstanding Checkride Award and recently upgraded to Captain on the Airbus 321 aircraft. He has over 8,000 hours of flight time in jet aircraft.

Last year, Francospent two months at NASAs Johnston Space Center in Houston taking part in the Human Exploration Research Analog. He and three other men completed a simulated deep-space mission to help facilitate the national space program's goal of sending a manned mission to Mars.

Franco is a past member for the Lockport Common Council, representing the 2nd Ward. Currently he serves on the board of directors of Challenger Learning Center and is a member of the Explorers Club in Manhattan.

Franco has completed two marathons was a member of the winning team in the Lockport 100 Mile Relay Race, which commemorated the 1967 world record. He also has volunteered with the disabled veterans sled hockey team.

Julie Zenger Hain

Julie Zenger Hain, class of 1980, is an expert in the field of genetics.

She's a graduate of St. Lawrence University, where she earned a degree in biology and psychology and was inducted in Phi Beta Kappa. Subsequently, she earned a Ph.D. in human genetics and a bachelor's degree in nursing at the Medical College of Virginia of Virginia Commonwealth University. Her post-doctoral work in medical genetics and cytogenetics was completed at Henry Ford Hospital in Detroit, and she achieved board certification from the American Board of Medical Genetics. From there she developed the genetics program at Oakwood Hospital in Dearborn, Michigan, which provides laboratory and clinical genetic services to the Oakwood Health System, now Beaumont Health.

Since her career at Oakwood, Zenger Hain has worked to educate physicians, patients and the public regarding the power of genetics in health care. She has been an active participant with the Michigan Department of Health and Human Services genetic and genomic initiatives, volunteering her time to assist the development and implementation of public policy aimed at enhancing genetic services to all Michigan residents.

Zenger Hain is co-chair of the Michigan Cancer Genetics Alliance, a collaborative network of genetics professionals, patient advocates, oncology experts, health plan employees, state and local public health workers and others with an interest in cancer genomics. She has collaborated on multiple state and community grants aimed at delivering genetic services to underserved populations and served on the Wayne State Institutional Review Board to foster safe research practices for human study participants.

She is also a mentor for the Womens Institute for National Global Success, which provides guidance to young women seeking to enter careers in the sciences.

Zenger Hainand her husband, Jon, have a son and daughter. They currently reside in Troy, Michigan.

Cindi McEachon

Cindi McEachon, class of 2000,defied the odds as a teenage mother. After giving birth to her daughter, Emilee, in her sophomore year, she stayed in school and earned her diploma, then went on to complete post graduate studies. Today she's a volunteer youth mentor with numerous organizations and serves as the executive director of Peaceprints of WNY.

After high school, McEachon earned an associate's degree from Niagara County Community College, a bachelor's degree from the University of Buffalo and a Master of Business and Science degree from Medaille College.

According to her nominator, McEachon is passionate and often bull-headed; when she sets her mind to something, she never looks back. When she was 17, she moved out on her own and balanced full-time work, school and parenting, motivated by the "teen parent" stigma that she carried.

McEachon was appointed director of Peaceprints in 2014. Peaceprints works with incarcerated men, youths and their families. McEachon hopes to raise awareness about the U.S. epidemic of mass incarceration and put a stop to "school-to-prison pipeline" in Buffalo.

Currently, McEachon is the executive vice president of the Junior League of Buffalo and board secretary of Homespace Corporation and For Our Daughters Inc. She's an active member of Women on the Rise and the Erie County Reentry Task Force, a volunteer coach for Girls on the Run Buffalo, a teen mentor for Homespace Corporation and coordinator of the annual Christmas cookie drive for Buffalo City Mission. She has been a Kenan Center youth soccer coach, a Brownie troop leader and a life coach mentor; and enjoys running marathons and half marathons.

McEachon has two daughters, Emilee, 19, and Lily, 12. She and Christopher Summers will be married on Sept. 9.

James Sansone

James Sansone, class of 1960, is a local attorney, accomplished musician and tireless civic booster.

Sansone earned a bachelor's degree in linguistics from SUNY at Buffalo in 1964, then went to Buffalo Law School where he received a Bachelor of Laws degree and, in 1968, a Juris Doctorate. He has been a practicing attorney ever since; and has been a confidential law clerk to the Niagara County and Surrogates Court judges, an administrative law judge for New York State. Currently he's the Newfane town attorney and town prosecutor, mortgage counsel to Cornerstone Community FCU and pro bono counsel to Olcott Volunteer Fire Company and EquiStar Therapeutic Riding in Newfane.

Sansone, an accomplished trumpet player, has played professionally since he was 12 years old. He has been a volunteer bugler for American Legion and VFW since 1953, playing Taps on Veterans Day and Memorial Day and at servicemen's funerals. He's a teacher and mentor to young trumpet players and has played in many high school musicals throughout Western New York. Every year, with his trumpet, he leads the (July 4) Patriots Day children's parade in Olcott. He organizes the summertime Olcott Beach Gazebo Concert Series and volunteers his music services for an array of charitable organizations including Olcott Beach Carousel Park, Olcott Lions Club,Batavia School for the Blindand Lawyers for the Arts.

Sansone has been a member of the Newfane Tourism Board since 2003. He's a member of Olcott Lions Club,a life member of Local 97-106 of the musicians' union,a past Eucharistic Minister for St. Josephs church in Lockport and Niagara USA Chamber's 2012 Small Business Person of the Year.

Jack B. Walters

Jack B. Walters, class of 1946, is an engineer, retired Iowa state public servant and the author of four books.

Waltersenlisted in the Army Air Corps when he turned 18, on July 30, 1946, and served in Japan for three years. He was the lead enlisted officer of a statistical control unit where he advanced to the rank of staff sergeant. Using the G.I. Bill, he obtained a bachelor's degree in electrical engineering at the University of Buffalo.

Walters married fellow LHS graduate Carolyn Highhouse in 1954 and began a lengthy career with Firestone. He was a staff engineer in Akron, Ohio, a senior engineer in Pottstown, Pa., a plant engineer in Hamilton, Ontario, and a plant manager in Calgary, Alberta, Akron, Ohio, and Firestone's largest tire factory in Des Moines, Iowa. The Walters had three children, Amy, Andy and Steve, who died in a plane accident in 1997.

Walters became director of general services for the state of Iowa in 1983, upon appointment by Gov. Terry Branstad. Hismost notable efforts included starting exterior restoration of the Capitol building and design and construction of the $25 million Historical and Library Building. He served in the post for eight years, until his wife died from cancer.

Walters retired to Tucson, Arizona, where he discoveredthe Southern Arizona Hiking Club. The goal of members is to climb to the top of 315 area mountains and Walters did it in five years. Afterward, he became a guide and helped others in their quest. Later, the club set a 400-peak goal; and with encouragement from his friend Roxanna Baker, he accomplished the new goal in 2008, at age 79. Walters still hikes today.

Copies of Walters' four published books are available at Lockport Public Library.

Edward C. Weeks

The late Edward C. Weeks, class of 1953, was an innovator in the adult care field in New York state.

At LSHS, Weeks played football and was a member of the swim team. He went on to the University of Buffalo, where he earned a degree in physical therapy, andmarried Margaret Reddington in 1958. (They had four children, Sean, Patricia, Bridge and Mark. Margaret Weeks died in 1979.)

Weeks did a tour of duty with the Army from 1958 to 1960, serving as a physical therapistat the 98th General Hospital in Neubrucke, Germany.After his discharge, he worked as a physical therapist at Mercy Hospital in Buffalo, St. Josephs Hospital in Cheektowaga and Niagara Lutheran Home, where he established a physical therapy department. Impressed by his leadership skills, home management persuaded him to move into an administrative role.

After three years at Niagara Lutheran, Weeks was appointed administrator of Carlton House Nursing Home; and when that facility was sold to becomepart of what is now Roswell Park Cancer Institute, he became the administrator of Newfane Health Care Facility. In 1976, Weeks took over as administrator of Episcopal Church Home, where he rose to president and chief executive officer.

As an administrator, Weeks was always looking for better ways to care for elderly with illness and dementia. He developed many "firsts" in Western New York and New York state: respite care, long-term home health care, HIV/AIDS home care, restraint-free nursing home care, adult day health care, inter-generational child care and, ultimately, the first Continuing Care Retirement Community (CCRC) in the state.

Weeks lobbied for state legislation to permit operation of life-care communities, which resulted in him developing Canterbury Woods in Amherst. The project introduced the area to continuing care, which offers a range of options from independent living to skilled nursing, all on one campus.

Weeks married Alana Parisi in 1997 and added five stepchildren to his family: Jason, Cale, Aron, Matthew and Ryan. His hobbies included golfing and sailing. He died in 2015.

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LHS Foundation names 9 more Distinguished Alumni - Lockport Union-Sun & Journal