Category Archives: Human Genetics

NEW YORK, Nov. 02, 2020 (GLOBE NEWSWIRE) -- Prevail Therapeutics Inc. (Nasdaq: PRVL), a biotechnology company developing potentially disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases, today announced a decisive victory in the arbitration proceeding brought in 2019 by Alector Inc. against Prevails founder and Chief Executive Officer, Asa Abeliovich, M.D., Ph.D.

The arbitrator rejected all of Alectors principal claims against Dr. Abeliovich, including all claims alleging misappropriation or misuse of trade secrets. Significantly, the arbitrator rejected Alectors claims that Dr. Abeliovich used Alector trade secrets or confidential information in connection with his work on behalf of Prevail, as well as Alectors claim that it has rights to Prevails patents and patent applications. Prevail was not a party to this arbitration.

We appreciate the arbitrators thorough and independent review of this matter. This decision vindicates Dr. Abeliovich and rules in his favor on all significant issues, said Francois Nader, M.D., Non-Executive Chairman of Prevail. With this positive outcome, Prevail is looking forward to advancing our pipeline for the benefit of patients.

I am pleased with the decision, which confirms Prevails ownership of its intellectual property, said Dr. Abeliovich. Our team continues to advance our pipeline and remains committed to our critical mission of developing novel, urgently needed therapies for patients with neurodegenerative disorders such as Parkinsons disease and frontotemporal dementia.

The only relief granted to Alector by the arbitrator was permission to seek reimbursement for a portion of Alectors out-of-pocket costs and fees in connection with certain document retention-related claims. Alector will need to provide sufficient proof of such amounts.

About Prevail TherapeuticsPrevail is a clinical stage gene therapy company leveraging breakthroughs in human genetics with the goal of developing and commercializing disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases. The company is developing PR001 for patients with Parkinsons disease with GBA1 mutations (PD-GBA) and neuronopathic Gaucher disease (nGD); PR006 for patients with frontotemporal dementia with GRN mutations (FTD-GRN); and PR004 for patients with certain synucleinopathies.

Prevail was founded by Dr. Asa Abeliovich in 2017, through a collaborative effort with The Silverstein Foundation for Parkinsons with GBA and OrbiMed, and is headquartered in New York, NY.

Forward-Looking Statements Related to Prevail

Statements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Examples of these forward-looking statements include statements concerning the amount of costs and legal fees that Prevail may be required to reimburse. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These risks and uncertainties include, among others: Prevails novel approach to gene therapy makes it difficult to predict the time, cost and potential success of product candidate development or regulatory approval; Prevails gene therapy programs may not meet safety and efficacy levels needed to support ongoing clinical development or regulatory approval; the regulatory landscape for gene therapy is rigorous, complex, uncertain and subject to change; the fact that gene therapies are novel, complex and difficult to manufacture; and risks relating to the impact on our business of the COVID-19 pandemic or similar public health crises. These and other risks are described more fully in Prevails filings with the Securities and Exchange Commission (SEC), including the Risk Factors section of the Companys Quarterly Report on Form 10-Q for the period ended June 30, 2020, filed with the SEC on August 11, 2020, and its other documents subsequently filed with or furnished to the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Except to the extent required by law, Prevail undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Media ContactGina NugentTen Bridge Communications gina@tenbridgecommunications.com 617-460-3579

Investor Contactinvestors@prevailtherapeutics.com

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Prevail Therapeutics Announces Decisive Victory in Arbitration Brought by Alector against Prevail's CEO - GlobeNewswire

In the mid-18th century there was a period of intense innovation and codification in dog breeding, giving rise not only to a diversity of breeds, but the very concept of breed itself. During this boom, disparate dog lineages were deliberately crossed to enhance favourable traits or dilute undesirable ones This created a messy, intertwined relationship between different dog types, with the details of a breeds origin sometimes recorded only in oral history.

[So] researchers from the National Human Genome Research Institute in the US analysed DNA from 161 breeds to create a dog-breed family tree.

While the genomes of all dogs are 100% dog DNA, a small amount of the genome varies among breeds. These parts are responsible for the impressive spectrum of variation in size, shape and behaviour in domestic dogs. The researchers sequenced dog genomes at thousands of these variable sites. When blocks of them are identical across two different breeds, this indicates historic interbreeding between them.

These fresh results confirmed documented histories for some breeds. Heidi Parker, the lead researcher on the study and also a geneticist at NHGRI, said the results also showed evidence of crosses that were not documented or were otherwise unexpected.

We found out that the German shepherd was pretty much Italian, she said.

See the interactive infographic here

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Interactive: How Pomeranians, Poodles, Great Danes and 158 other dog breeds are genetically related to each other - Genetic Literacy Project

Libyan rock art that may date back 7000 years depicts a hunter and his dog.

By David GrimmOct. 29, 2020 , 2:00 PM

Sometime toward the end of the last ice age, a gray wolf gingerly approached a human encampment. Those first tentative steps set his species on the path to a dramatic transformation: By at least 15,000 years ago, those wolves had become dogs, and neither they nor their human companions would ever be the same. But just how this relationship evolved over the ensuing millennia has been a mystery. Now, in the most comprehensive comparison yet of ancient dog and human DNA, scientists are starting to fill in some of the blanks, revealing where dogs and humans traveled togetherand where they may have parted ways.

Its a really cool study, says Wolfgang Haak, an archaeogeneticist at the Max Planck Institute for the Science of Human History. Were finally starting to see how the dog story and the human story match up.

Dogs are one of the biggest enigmas of domestication. Despite decades of study, scientists still havent figured out when or where they arose, much less how or why it happened. A 2016 study concluded that dogs may have been domesticated twice, once in Asia and once in Europe or the Near East, but critics said there wasnt enough evidence to be sure. A few years later, researchers reported signs of dogs in the Americas as early as 10,000 years ago, yet those canines appear to have vanished without a genetic trace. Other studies have found evidence of ancient dogs in Siberia and elsewhere, but scientists dont know how they got there or how theyre related.

To fill in some of the blanks, two big names in dog and human genetics teamed up: Greger Larson, an evolutionary biologist at the University of Oxford, and Pontus Skoglund, a paleogenomicist at the Francis Crick Institute. Larsen, Skoglund, and colleagues sifted through more than 2000 sets of ancient dog remains dating back nearly 11,000 years from Europe, Siberia, and the Near East. In the process, they added 27 ancient dog genomes to the five already on record. They then compared those with the genomes of 17 humans living in the same places and times as the dogs.

The dog DNA alone revealed some surprises. As early as 11,000 years ago, there were already five distinct dog lineages; these gave rise to canines in the Near East, northern Europe, Siberia, New Guinea, and the Americas, the team reports today in Science. Because dogs had already diversified so much by that time, domestication had to occur long before then, Skoglund says. That fits with archaeological evidence: The oldest definitive dog remains come from Germany about 15,000 to 16,000 years ago.

Remarkably, pieces of these ancient lineages are still present in todays pooches. Chihuahuas can trace some of their ancestry to early American dogs, for example, whereas Huskies sport genetic signatures of ancient Siberian dogs, the team found. If you see a bunch of different dogs in a dog park, Skoglund says, they may all have different ancestries that trace all the way back 11,000 years (see figure below).

Todays dogs can trace their ancestry to canines that lived up to 11,000 years ago.

When the researchers compared their dog DNA with modern and ancient wolf DNA, they got another surprise. Most domesticated animals pick up genetic material from their wild relativeseven after domesticationbecause the two species often live in close proximity and can still mate (think pigs and wild boars). But dogs show no such gene flow from wolves. Instead, the wolves gained new DNA from the dogsa one-way street.

Larson chalks this up to the intimate relationship between dogs and humans. If your pig or chicken becomes a bit wilder thanks to an infusion of feral DNA, it doesnt matter, because youre going to eat them anyway, he explains. But dogs that go native make bad guards, hunting companions, and friends. If youre a dog and you have a bit of wolf in you, thats terrible, Larson says. People will get rid of the dog.

The wolf-dog analysis also suggests dogs evolved only once, from a now-extinct wolf population. Still, Larson, who led the 2016 study on multiple domestication events, says more data are needed to seal the deal.

Then the scientists brought humans into the mix. They selected human DNA samples from the same places and eras for which they had ancient canine DNA, and traced the genetic history of each. Its like you have an ancient text in two different languages, and youre looking to see how both languages have changed over time, Skoglund says.

In many places, the team found a strong overlap between human and dog genomes. For example, farmers and their pups in Sweden about 5000 years ago both trace their ancestry to the Near East. This suggests early farmers took their dogs with them as agriculture spread throughout the continent. Writ large, as humans moved, they moved with their dogs, Larson says.

But sometimes the stories didnt match up. Farmers in Germany about 7000 years ago also came from the Near East and also lived with dogs. But those animals seem more similar to hunter-gatherer pups, which came from Siberia and Europe.

That suggests many early migrants adopted local dogs that were better adapted to their new environment, Haak says. The benefits were many, adds Peter Savolainen, a geneticist at the Royal Institute of Technology and an expert on dog origins. They were cute. You could use them. You could even eat them.

Savolainen calls the study very thorough, and adds its fantastic that the researchers were able to bring together so many data. But he has long argued that dogs arose in Southeast Asia and says the work is incomplete without samples from that corner of the globe. Without those, you could be missing an important part of the picture.

For now, Larson says his team is analyzing a ton of wolf and dog genomes. He and his colleagues have also begun to look at ancient skull shape and genetic markers that could give clues to what early dogs looked like. Whatever he finds, hes counting on being surprised. We have to expect the unexpected, he says, because thats all ancient DNA ever gives us.

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How dogs tracked their humans across the ancient world - Science Magazine

SAN DIEGO, Oct. 27, 2020 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (Nasdaq: BNGO) announced that human genetics researchers using the Saphyr system will present their results at the American Society of Human Genetics (ASHG) Annual Meeting, being held virtually at http://www.ashg.org between October 27-30. The impact of structural variation analysis using the Saphyr system will be demonstrated at ASHG with 18 oral and poster presentations which cover an expanding array of diseases like cancer predisposition, microdeletion syndromes, repeat expansion disorders, neurodegenerative diseases, disorders of sex development and a variety of other genetic diseases. Additionally, these presentations show Saphyrs abilities to elucidate the exact structure of complex genomic rearrangements such as large inversions, chromothripsis and low copy repeats.

The scientific importance and quality of the studies utilizing Saphyr and presented at ASHG have increased year over year, said Erik Holmlin, Ph.D., CEO of Bionano. As more scientists present and publish their important discoveries made with Saphyr, an increasing number of potential future Saphyr users become aware of its prowess in uncovering novel genetic variants that contribute to cancer and genetic disease, which could drive more adoption and utilization for basic genetic research and clinical studies alike.

Below is a summary of key presentations to be given at ASHG 2020 featuring the use of Bionanos optical genome mapping technology:

Live Presentation October 29, 2020, 11:45AM-12:00PMDeciphering Genomic InversionsChristopher M. Grochowski, Baylor College of MedicineGenomic inversions are a class of structural variation (SV) relevant in evolution, speciation, and human disease but challenging to detect and resolve using current genomic assays. While short-read WGS can detect a fraction of copy number neutral inversions, those mediated by repeats or accompanied by CNVs remain challenging. The utilization of multiple technologies and visualization of unbroken DNA through long molecule approaches facilitate detection ofin cisevents and resolution of SVs containing two or more breakpoint junctions.

The following Co-Labs, Poster Sessions and Abstracts are available for on-demand viewing during and after ASHG 2020:

Bionano Laboratory Co-Lab Session: Resolving Complex Haplotypes Implicated in Alzheimers and Other Neurodegenerative Diseases.Mark T. W. Ebbert, Neuroscience Department, Mayo ClinicAlzheimers disease is genetically complex with no meaningful therapies or pre-symptomatic disease diagnostics. Most of the genes implicated in Alzheimers disease do not have a known functional mutation, meaning there are no known molecular mechanisms to help understand disease etiology.

In this co-lab session, Mark T. W. Ebbert of the Mayo Clinic will discuss his teams work toward identifying functional structural mutations that drive disease in order to facilitate a meaningful therapy and pre-symptomatic disease diagnostic. Some of the genes and regions implicated in Alzheimers disease are genomically complex and cannot be resolved with short-read sequencing technologies. These regions include MAPT, CR1, and the histocompatibility complex (including the HLA genes).

3342 Bionano Poster Session: High Throughput Analysis of Disease Repeat Expansions and Contractions by Optical MappingErnest Lam, Sr Manager Bioinformatics, Bionano GenomicsRepeat expansions and contractions are associated with degenerative disorders such as facioscapulohumeral muscular dystrophy (FSHD). Southern Blotting is the gold standard for long repeat analysis but has many limitations. Optical genome mapping allows for efficient analysis of diseases associated with repeat expansion and contraction.

2190 Bionano Poster Session: Rapid Automated large Structural Variation Detection in Mouse Genome by Whole Genome SequencingJill Lai, Sr Applications Scientist, Bionano GenomicsIdentifying SVs for key model organisms such as mouse and rat is essential for genome interpretation and disease studies but has been historically difficult due to limitations inherent to available genome technologies. We updated the Saphyr analysis pipeline such that copy number variant (CNV) and SV analyses could now be applied to mouse and other non-human species, and constructed a control SV database for annotating variants, and identified strain-specific SVs/CNVs as well as variation shared among strains.

Additional presentations/abstracts featuring optical genome mapping:

3208 - Long-read sequencing and optical mapping decipher structural composition ofATXN10repeat in kindred with spinocerebellar ataxia and Parkinsons diseasePresented by Birgitt Schuele, Associate Professor, Department of Pathology, Stanford University School of Medicine

3270 - Uniparental isodisomy, structural and noncoding variants involved in inherited retinal degeneration (IRD) in three pedigreesPresented by Pooja Biswas, Ophthalmology Department, University of California, San Diego

Data CoLab: Whole Genome Map Assembly and Structural Variation Analysis with Hitachi Human Chromosome ExplorerPresented by Hitachi-High-Tech America, Inc.

2123 - High-throughput sequencing and mapping technologies applied to 10 human genomes with chromothripsis-like rearrangementsPresented by Uir Souto Melo, Mundlos Lab, Max Planck Institute for Molecular Genetics, Berlin, Germany

2165 -nanotatoR: A tool for enhanced annotation of genomic structural variantsPresented by Emmanuele Delot, Center for Genetic Medicine Research, Childrens National Hospital, Washington, DC

2998 - Highly variable structure and organization of the human 3q29 subtelomeric segmental duplicationsPresented by Umamaheswaran Gurusamy, Cardiovascular Research Institute, University of California San Francisco

2304 - Enlightening the dark matter of the genome: Whole genome imaging identifies a germline retrotransposon insertion inSMARCB1in two siblings with atypical teratoid rhabdoid tumorPresented by Mariangela Sabatella, Princess Mxima Center for Pediatric Oncology, Utrecht, Netherlands

2318 - FaNDOM: Fast Nested Distance-based seeding of Optical MapsPresented by Siavash Raeisi Dehkordi, Computer Science & Engineering, University of California San Diego, La Jolla

3023 - Structural hypervariability of low copy repeats on chromosome 22 is human specificPresented by Lisanne Vervoort, Department of Human Genetics, KU Leuven, Leuven, Belgium

3024 - Telomere-to-telomere assembly and complete comparative sequence analysis of the human chromosome 8 centromereReviewer's Choice Award RecipientPresented by Glennis Logsdon, Genome Sciences, University of Washington, Seattle, WA

3311 - Comprehensive structural variant identification with optical genome mapping and short-read sequencing for diagnosis of disorders/differences of sex development (DSD)Reviewer's Choice Award RecipientPresented by Hayk Barseghyan, Center for Genetic Medicine Research, Children's National Hospital, Washington, DC

3318 - De novo mutation and skewed X-inactivation in girl with BCAP31-related syndromePresented by H.J. Kao, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

3560 - Resolving genomic structures inMECP2Duplication Syndrome provides insight into genotype-phenotype correlationsReviewer's Choice Award RecipientPresented by Davut Pehlivan, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

2157 -methometR: quantification of long-range haplotype specific methylation levels from Optical Genome MapsPresented by Surajit Bhattacharya, Center for Genetic Medicine Research, Childrens Research Institute, Childrens National Hospital, Washington, DC

About Bionano GenomicsBionano is a genome analysis company providing tools and services based on its Saphyr system to scientists and clinicians conducting genetic research and patient testing, and providing diagnostic testing for those with autism spectrum disorder (ASD) and other neurodevelopmental disabilities through its Lineagen business. Bionanos Saphyr system is a platform for ultra-sensitive and ultra-specific structural variation detection that enables researchers and clinicians to accelerate the search for new diagnostics and therapeutic targets and to streamline the study of changes in chromosomes, which is known as cytogenetics. The Saphyr system is comprised of an instrument, chip consumables, reagents and a suite of data analysis tools, and genome analysis services to provide access to data generated by the Saphyr system for researchers who prefer not to adopt the Saphyr system in their labs. Lineagen has been providing genetic testing services to families and their healthcare providers for over nine years and has performed over 65,000 tests for those with neurodevelopmental concerns. For more information, visitwww.bionanogenomics.com or http://www.lineagen.com.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: the timing and content of the presentations identified in this press release; the effectiveness and utility of Bionanos technology in basic genetic research and clinical settings; the contribution of Saphyr to uncovering novel genetic variants that contribute to cancer and genetic disease; the benefits of Bionanos optical mapping technology and its ability to facilitate genomic analysis in future studies; and Bionanos strategic plans. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape and the introduction of competitive products; changes in our strategic and commercial plans; our ability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions to obtain funding to support adoption or continued use of our technologies; the loss of key members of management and our commercial team; and the risks and uncertainties associated withour business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2019 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management's assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations Contact:Ashley R. RobinsonLifeSci Advisors, LLC+1 (617) 430-7577arr@lifesciadvisors.com

Media Contact:Darren Opland, PhDLifeSci Communications+1 (617) 733-7668darren@lifescicomms.com

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Prowess of Bionano Genomics' Saphyr System in Uncovering Novel Genetic Variations That Cause Cancer and Genetic Disease in Full Display at ASHG 2020 -...

Oct. 26, 2020 10:00 UTC

SAN DIEGO--(BUSINESS WIRE)-- Boundless Bio, a biotechnology company developing innovative therapeutics directed to extrachromosomal DNA (ecDNA) in aggressive cancers, today will present research highlighting powerful components of its proprietary Spyglass platform at the 2020 American Society of Human Genetics (ASHG) Annual Meeting.

The poster, titled A Robust Imaging and Single-Cell Sequencing Platform to Characterize Tumor Extrachromosomal DNA (ecDNA) in Response to Therapeutic Intervention, describes elements of Boundless Bios broad platform for interrogating ecDNA biology. These elements couple automated cellular imaging with comprehensive single-cell genomic sequencing. The tools are part of an essential toolkit for understanding how ecDNA responds when cancers are treated with various therapeutic pressures and can be broadly applied to track how oncogenes amplify and where they are expressed following therapeutic intervention. Tumors driven by oncogene amplification are aggressive, have poor prognosis, and have proven elusive for targeted therapies. ecDNA frequently harbor oncogene amplifications and promote resistance to cancer treatment by enhancing genomic diversity and enabling cancer cells to rapidly adapt in response to therapeutic pressures.

We are building our Spyglass platform to serve as the first robust, objective, and high-resolution tool for characterizing ecDNA and how they respond to therapeutic pressures, said Jason Christiansen, Chief Technology Officer of Boundless Bio. This new research presented at ASHG demonstrates that our platform can successfully track how the behavior of ecDNA in cancer shifts in the face of treatment; these insights are enabling us to develop more effective, highly-targeted treatments for patients with cancers driven by ecDNA.

Study Details

Utilizing key analytical tool elements of the Spyglass platform, scientists studied colorectal cancer cells with amplified oncogenes in the presence and absence of cytotoxic chemotherapy, demonstrating the ability to robustly characterize changes in ecDNA and chromosomally-amplified genes at the phenotypic and molecular level.

The researchers studied Colo320DM cells, containing a mixture of the MYC oncogene on ecDNA and chromosomally amplified gene populations; Colo320HSR cells with a pure chromosomally amplified MYC population; and DLD1 cells as a non-amplified control. Each arm was treated for 2 weeks with a cytotoxic chemotherapeutic agent. Cells in metaphase were collected, stained with DAPI and probed for the MYC oncogene by Fluorescence In Situ Hybridization (FISH). Whole-slide images (~10mm2) were collected using automated imaging; and custom-built software was used to automatically identify and quantify ecDNA in individual metaphase spreads. Relative changes in MYC FISH signal and localization were used to quantify the changes in ecDNA and chromosomal amplification populations before and after drug treatment.

In addition, single-cell sequencing techniques revealed molecular level information about the amplified gene regions that is complementary to the spatial information provided by image analysis. Regions of increased gene expression and open chromatin around the MYC gene are indicative of ecDNA and were not identified in the chromosomally amplified line. Further, although chromosomally amplified regions exist in both model lines, molecular level evidence demonstrated divergence in this region not discernable by imaging. When treated with cytotoxic chemotherapy, the ecDNA population was reduced and the chromosomally amplified region was selected. Together these tools demonstrated Boundless Bios ability to monitor and quantify dynamic changes in ecDNA in cancer cells under selective pressure.

About ecDNA Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA containing functional genes, including oncogenes, that are separated from tumor cell chromosomes. ecDNA rapidly replicate within cancer cells, causing high numbers of oncogene copies and can be passed to daughter cells asymmetrically during cell division, driving tumor heterogeneity. Cancer cells have the ability to increase or decrease copy number of oncogenes located on ecDNA to enable survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells primary mechanisms of recurrence and treatment resistance. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

About Boundless Bio Boundless Bio is a next-generation precision oncology company interrogating a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies to patients with previously intractable cancers.

For more information, visit http://www.boundlessbio.com.

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About Boundless Bios Spyglass Platform Boundless Bios Spyglass platform is a comprehensive suite of proprietary ecDNA-driven and pair-matched tumor models along with proprietary imaging and molecular analytical tools that enables Boundlesss researchers to interrogate ecDNA biology and maintain a robust pipeline of novel oncotargets essential to the function of cancer cells that are enabled by ecDNA. The Spyglass platform facilitates Boundless innovation in the development of precision therapeutics specifically targeting ecDNA-driven tumors, thereby enabling selective treatments for patients whose tumor genetic profiles make them most likely to benefit from our novel therapeutic candidates.

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Boundless Bio Presents Research Showcasing its Imaging and Single-Cell Sequencing Platform for Extrachromosomal DNA (ecDNA) Detection at the 2020...

Counting the years: Older parents are no more likely than younger ones to pass on large genetic mutations to their children.

10,000 Hours / Getty Images

Most of the large, spontaneous genetic mutations tied to autism are passed down from fathers. But, unlike with smaller mutations, a mans age is unlikely to significantly up the rate at which they occur.

Researchers presented the unpublished work today at the 2020 American Society of Human Genetics conference, which is taking place virtually because of the coronavirus pandemic.

Spontaneous, or de novo, mutations can occur in a sperm or egg cell, or very early on in an embryos development. Many of these changes involve a single DNA letter, or base pair, and are known as point mutations. They tend to accumulate over time in sperm and eggs and may contribute to higher rates of autism among children born to older parents, especially older fathers.

Larger mutations, such as deletions or duplications of DNA sequences, have also been linked to autism, but they are rarer and require sizeable cohorts to study. The new work examined structural variants involving 50 or more base pairs in two large groups of autistic people and their families.

Its likely that studies of even larger groups will find that parental age does raise the odds of passing down structural variants, says co-lead investigator Aaron Quinlan, professor of human genetics and biomedical informatics at the University of Utah in Salt Lake City. But the new findings from his lab make it clear that age plays a much smaller role for them than it does for point mutations.

The results are fairly good evidence that if there is a parental age effect, it is weak, he says.

The researchers analyzed the genomes of 2,363 people with autism, as well as 1,938 of their non-autistic siblings and both parents. They compared rates of structural variants, excluding those that involve entire chromosomes. The families have no known history of autism.

They found that more than one in five autistic people has a structural variant, compared with fewer than one in six non-autistic people.

In both autistic people and controls, about three-quarters of the mutations occurred in DNA passed down by the fathers cells rather than the mothers.

But the fathers of children with and without structural variants do not differ significantly in age, the researchers found.

They did not analyze the relationship between a mothers age and likelihood of mutations, but because mothers and fathers in the cohort were of similar ages, the researchers can infer a similar effect.

In a smaller group of 165 autistic people and 85 unaffected people all carrying structural variants the researchers confirmed an association between paternal age and the number of point mutations in people with autism and in controls.

Point mutations and structural variants have different underlying mechanisms: The former tend to occur randomly during cell division and genome replication, whereas the latter are the result of cells repairing breaks in the chromosome.

The rate at which those [chromosome breaks] occur dont really change as a function of age, Quinlan says.

The findings may lead to a better understanding of the role of structural variations in autism and other complex conditions in which genetics play a large role, says Jonathan Belyeu, a graduate student in Quinlans lab. Belyeu presented the findings.

Theoretically, if we can identify where these variants are occurring, it will point us to genes that are important for the overall [condition], Belyeu says.

For more reports from the 2020 American Society of Human Genetics annual meeting, please click here.

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Parental age plays small role in large mutations tied to autism - Spectrum

At least 10% of patients with life-threatening coronavirus diseases 2019 (COVID-19) pneumonia have antibodies that attack their own interferons, according to a new study by a team of international investigators.

The study, published in Science, found that 101 out of 987 patients with severe COVID-19 pneumonia had IgG autoantibodies that neutralize the ability of type 1 interferons to block SARS-CoV-2 infection.

This was a huge surprise, much unexpected, corresponding author Paul Bastard, affiliated with Inserm, University of Paris Imagine Institute and St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University, told Contagion. Very surprising how it mimics genetic inborn errors of immunity. Extremely surprising too that individuals with complete genetic defects in key interferon genes (as described in Zhang Q and al., Science, 2020) were adult patients who had not suffered previously from severe viral infections.

In a separate study, the team detailed genetic variants contributing to life-threatening COVID-19 pneumonia. Loss-of-function variants at 13 human loci known to govern TLR3- and IRF7-dependent type 1 interferon immunity to influenza virus were examined. Genetic defects leading to impaired production or response to type 1 interferons were reported in 23 patients (3.5%).

The twin studies come from lab of Jean-Laurent Casanova, MD, PhD, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University, and the COVID Human Genetic Effort, a international collaboration aiming to determine how human genetics determine severe COVID-19.

The antibody study included 987 patients with critical COVID-19, 663 asymptomatic or pauci-symptomatic patients with COVID-19, and 1227 healthy controls. Autoantibodies were found in none of the patients with asymptomatic or mild COVID-19 and in only 4 of the healthy participants. Based on this, the estimated prevalence of these autoantibodies in the general population is 0.33%.

The study also could help explain why men have been more adversely affected by COVID-19 than women, finding that 95 of the 101 patients with the autoantibodies were men.

The neutralizing autoantibodies are believed to have been present before SARS-CoV-2 infection and caused the severity of the disease. They were identified in 2 patients before infection and 3 patients with APS-1, a serious but rare immune diseased marked by a high concentration of antibodies against interferons, had life-threatening COVID-19.

It would be important to implement routine testing for auto-antibodies in all patients infected with COVID-19 to be able to implement adequate treatments and preventive measures. And perform genetic testing in the patients with unexplained severe COVID-19, Bastard said.

Treatment could include early injected or nebulized IFN- because autoantibodies that work against that type of interferon are rare among those affected, while treatment with IFN- is unlikely to be affective, the study said.

Early intervention might be key. Once patients are hospitalized, it might be too late for treatment to show benefits. The World Health Organization Solidarity Trial recently released results indicating that interferon-beta therapy didnt lower mortality nor the need for ventilation among more than 2,000 people who received the drug.

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Autoantibodies Block Interferons in 10% of Severe COVID-19 Cases - Contagionlive.com

Insitro founder and CEO Daphne Koller (left) and CFO Mary Rozenman (right). Photo courtesy of Insitro.

San Francisco-based Insitro announced today that it has entered a five-year discovery collaboration agreement with Bristol Myers Squibb to discover and develop novel therapies for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Through this collaboration, Insitro will utilize its proprietary platform, Insitro Human (ISH), to create induced pluripotent stem cell (iPSC) derived disease models for both diseases. This platform applies machine learning, human genetics and functional genomics to create predictive in vitro models. ISH can potentially provide insight into how these diseases progress within patients. Bristol Myers Squibb will have the option to select from targets identified by Insitro to advance through clinical development and commercialization.

Neurodegenerative disorders like ALS and FTD have historically been a challenging therapeutic area, with no disease modifying treatments today. We are excited to partner with Bristol Myers Squibb and its world-class neuroscience leaders, who share our vision of leveraging human genetics, machine learning, and high-throughput biology and chemistry in order to identify and provide new treatments for patients suffering from these devastating diseases, said Daphne Koller, founder and chief executive officer of Insitro. Since founding Insitro just over two years ago, we have demonstrated our capabilities in building predictive models to discover novel targets and patient segments. We have also developed new approaches to machine-learning-enabled therapeutics design, which we look forward to deploying to discover treatments for novel targets emerging from this collaboration.

Insitro is set to receive $50 million as an upfront payment, and it will be eligible to receive an additional $20 million in near term operational milestones.

We believe that machine learning and data generated by novel experimental platforms offer the opportunity to rethink how we discover and design novel medicines, said Richard Hargreaves, Ph.D., senior vice president, head of neuroscience TRC research and early development, Bristol Myers Squibb. There is an unmet medical need for therapies to treat ALS and FTD and we are excited by the prospect of working with Insitros team towards our shared goal of identifying transformative treatments for patients with these devastating diseases.

Insitro recently strengthened its machine learning-based drug discovery capabilities through the acquisition of Haystack Sciences back on Oct. 22. Haystack focuses on synthesizing, breeding and analyzing large, diverse combinatorial chemical libraries encoded by unique DNA sequences called DNA-encoded libraries (DELs). Insitro intends on leveraging the DEL technology to collect massive small molecule data.

We are thrilled to have the Haystack team join Insitro, Koller said at the time of the announcement. For the past two years, Insitro has been building a company focused on the creation of predictive cell-based models of disease in order to enable the discovery of novel targets and evaluate the benefits of new or existing molecules in genetically defined patient segments. This acquisition enables us to expand our capabilities to the area of therapeutic design and advances us towards our goal of leveraging machine learning across the entire process of designing and developing better medicines for patients.

Haystacks platform combines several elements, including the capability to synthesize small molecule collections. With these advantages, Insitro will be better equipped to develop multi-dimensional predictive models for small molecule design.

I am excited by the opportunity to join a company with such a uniquely open and collaborative culture and to work with and learn from colleagues in data science, machine learning, automation and cell biology, said Richard E. Watts, co-founder and chief executive officer of Haystack Sciences. The capabilities enabled by joining our efforts are considerably greater than the sum of the parts, and I look forward to helping build core drug discovery efforts at Insitro.

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Insitro and BMS Team Up to Pave the Way for New ALS and FTD Treatments - BioSpace

Yale Daily News

Advocating for the transition of medicine away from race-based practices and toward a more race-conscious approach, Yale Medical School MD-PhD student Jessica Cerdea GRD 21, Yale Emergency Medicine physician Jennifer Tsai and Howard University PhD student Marie Plaisime recently co-authored an editorial for The Lancet, a peer-reviewed medical journal, this month about reforming medical education for future doctors.

The editorial characterizes the current practice of medicine as race-based, stating that physicians often infer that race has inherent biological significance, whereas in actuality race is merely a social construct. The authors say the future of medicine should move from this race-based approach to a race-conscious approach, with the end goal being a reduction in health inequities across racial lines. They advocated for emphasizing institutional inequities in healthcare during medical education, which they said would raise the cultural competency of future physicians.

Race-based medicine uses and treats race as an essential biological variable that has utility in medical education and clinical practice, Cerdea said. Race-conscious medicine understands that race is a social and power construct that changes for political utility over time, and that it is a poor proxy for human genetic variation. Instead, the more salient variable when it comes to differences in human groups that have been socially categorized in this way is the experience of racism and racialization This idea that there are biological differences between racial groups comes from colonization. This is how white supremacy operates.

The editorial was published in The Lancet after the prominent medical journal released a statement supporting the Black Lives Matter movement and its continuing commitment to advancing racial equality. This editorial was also published following a summer of racial unrest and protests around the country that advocated for putting an end to police brutality against Black Americans. The timing of the publication was significant to the authors.

Certainly we were motivated by the very apparent murders of George Floyd, Ahmaud Arbery and Breonna Taylor, among others, Tsai said. But also because this is a very long-standing problem that I think all three of us have been working on, thinking about and advocating against beforehand.

The article presented a wide range of examples in which race heavily influences physicians medical assessment of patients, such as the Atherosclerotic Cardiovascular Disease risk calculator equation. This online tool determines a given patients risk of having a cardiovascular event within ten years, Cerdea said. These calculations involve categorizing the patient as either Black or not Black. If the patient is Black, the predicted risk is significantly increased, and the patient is more likely to start taking a certain medication earlier than patients of other racial groups.

The prescription dosage for certain drugs can also vary based on racial groups. According to Cerdea, medical practitioners consider East Asian people to have different metabolisms, which means that a drug like Eltrombopag, a bone marrow stimulant, is started at half the normal dose for these people. This type of race-based medicine is condemned in the article.

You cant know someones pharmacokinetics, or the way that they metabolize a drug, by looking at them, or by their race, Cerdea said. Thats the problem with race-based medicine.

The Lancet piece includes different policy recommendations for researchers, clinicians and practitioners. According to Plaisime, It was crafted with care towards its intended audience of physicians, picking and choosing words that would be most accessible. The most important step in moving forward, Tsai said, is to change the curriculum of medical schools to be more race-conscious.

The authors also wrote this editorial from the perspective of their own experiences as women of color within the American healthcare system. Cerdea is Italian and Chilean with Indigenous Mapuche ancestry, Plaisime is Haitian American and Tsai is Taiwanese American.

As a Black woman, for sure there have definitely been times where Ive been treated differently based on how I appeared in the clinical room, how I was spoken to, Plaisime said. Also being the daughter of Haitian immigrants, I know first-hand what its like to have your accent judged. Not just one isolated event that kind of sparked this, its my story, and I want to make sure that all people receive equitable care.

The authors also emphasized that even research studies are subjected to racialization, despite undergoing objective screening processes instituted by peer-reviewed journals. Although race has no inherent biological significance, countless epidemiological studies include race as a critical variable when mapping out the prevalence of certain diseases.

In their article, the authors urged clinical research journals to include instructions in their publication guidelines that denounce the use of race as a proxy for biological variables such as genetics, pharmacokinetics and metabolism.

Prestigious publications continue to allow research that [uses] problematic versions of race in their research, Tsai said. They still allow that to be published, which means this kind of data and this kind of thinking is continually generated and perpetuated.

Plaisime, who is a medical sociologist studying the impacts of race and racism in clinical decision-making processes, explained that biologizing race is harmful. Prior to this collaboration, she had published a piece about the implications of using race in medicine.

She emphasized the need for using evidence-based treatments that do not rely solely on race as a factor of consideration, as this can often be detrimental to members of racial minority groups.

The different biomarkers and tools they use arent necessarily based on science, but more on racist assumptions, Plaisime said. My work was based on how that kind of training impacts later on how patients receive care, and how medical students are trained.

Cerdea and Plaisime are both Robert Wood Johnson Foundation Health Policy Research Scholars, and Tsai is completing her residency at the Yale New Haven Hospital.

Anjali Mangla | anjali.mangla@yale.edu

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Members of medical community call for shift from race-based to race-conscious medicine - Yale Daily News

Scientists in Vienna have developed a new human tissue screening technique that has identified previously unknown genes involved in causing microcephaly, a rare genetic disorder, and that could one day be used to identify unknown genes tied to other conditions.

In a study published Thursday in Science, researchers screened lab-grown human brain tissues for 172 genes thought to be associated with microcephaly, a condition in which babies are born with smaller-than-normal brains and have severe mental impairments. The search revealed 25 new genes linked to this rare neurological condition, adding to the 27 already known genes tied to microcephaly. The researchers also uncovered the involvement of certain pathways that were previously unknown to be connected to the disease.

This is a proof of concept, said Jrgen Knoblich, a molecular biologist at the Austrian Academy of Sciences Institute of Molecular Biotechnology and co-author of the study. With our ability to query many diseased genes at the same time and ask which ones are relevant in a human tissue, we can now study other diseases and other organs.

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For decades scientists have relied on small animals as models to make sense of how a human brain develops. But it turns out that our brains are not blown-up versions of a rodent brain. Mice and rat brain surfaces, for instance, are smooth, unlike the shrivelled walnut look of a human brain, with its countless folds. Also, these rodents are born with a somewhat complete brain, in which most neurons are in place, although they continue to form new connections after birth. In a human child, on the other hand, there are a massive number of neurons that form and populate the cortex after birth.

There are some processes that happen in our brain and not in mice brains that are responsible for human brains becoming so big and powerful, Knoblich said. This generates a very big medical problem, which is how do we study processes that are only happening in humans.

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To address this problem, several scientists including Knoblich developed human brain organoids that are no bigger than a lentil, created from stem cells, and function just like a working human brain. With an interest in studying neurodevelopmental disorders like microcephaly, Knoblichs team used these miniature substitute brains to look for clues about the genes that may hamper brain development.

Typically, scientists conduct genetic screening by inactivating select genes one by one to understand their contribution to bodily functions. But screens of human genes are restricted to cells grown in petri dishes in two dimensions, in which cells dont interact very much.

Microcephaly is a tissue disease and we couldnt really study it in 2D, said Christopher Esk, a molecular biologist at the Austrian Academy of Sciences Institute of Molecular Biotechnology and co-lead author of the study.

So, the researchers developed a technique called CRISPR-Lineage Tracing at Cellular resolution in Heterogeneous Tissue, which uses the gene-editing technology to make cuts in DNA and knockout genes in combination with a barcoding technology that tracks parent stems and their progeny cells as the 3D brain organoid develops.

Using an organoid developed from cells of a microcephalus patient, they kept an eye out for mutations that gave rise to fewer cells and thus a small brain in comparison with a healthy one.

The researchers used CRISPR-LICHT to simultaneously screen 172 potential microcephaly causing gene candidates and found 25 to be involved.

Among them was a gene called Immediate Early Response 3 Interacting Protein 1 in the endoplasmic reticulum, which is the protein processing station within a cell. This protein processing is required to properly process other proteins, among them extracellular matrix proteins, which are in turn important for tissue integrity, and thus brain size, Esk said.

Kristen Brennand, a stem cell biologist at the Icahn School of Medicine at Mount Sinai in New York, who wasnt involved in the study, said she appreciated how the research captured this causal link. Clinical genetics can identify mutations in patients, but fall short of identifying causal mutations that definitively underlie disease risk, she said.

Going forward, Knoblich and his colleagues hope to use CRISPR-LICHT to screen many more genes that may be associated with other brain development disorders. Weve done it for microcephaly, and were already doing it for autism, he said. But the method can be applied to any type of organoid or any type of disease and any cell type.

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New screening tool could turn up genes tied to developmental disorders - STAT