Daily Archives: May 25, 2022

ByJill Rosen

TIME today named Michael Schatz, a computational biologist and one of the world's leading genomics experts, to its 2022 list of the 100 most influential people for his contributions to the first complete sequencing of the human genome, "the most complete look yet at the genetic script underlying the very nature of who we are as human beings."

A Bloomberg Distinguished Professor of computer science and biology at Johns Hopkins University, Schatz harnesses the power of computing to better understand human and agricultural genetics. His ongoing work to demystify the structure and function of genomes is leading directly to deeper knowledge of human diseases, targeted medical treatments and improved plants and crops.

Schatz shares TIME's honor with Telomere-to-Telomere Consortium colleagues Adam Phillippy, Karen Miga and Evan Eichler.

"Dr. Schatz embodies the highest aspirations of universities like Johns Hopkins and the impact they can make on the world," said Johns Hopkins University President Ron Daniels. "He has pushed the boundaries of computational biology to decode successfully one of the greatest mysteries of our species. This extraordinary feat of international interdisciplinary research will fuel scientific and medical advancements for decades to come."

Twenty years ago, Schatz was working in cybersecurity when he abruptly changed his career trajectory to genomics, inspired by breakthroughs coming from the Human Genome Project, the first attempt to decipher the human genome. Being integral to the ultimate completion of that project has been a dreamy affirmation of both that choice and what has become his life's work, being a pioneer in the "genomics revolution."

"The telomere-to-telomere project has been a capstone result for my 20-year endeavor to improve and complete the human genome," Schatz said. "Moving forward, I'm excited to consider how we will be able to use this new genome and the genomic technologies we developed to build it to improve so many aspects of society, from agriculture to health care, and especially our understanding of cancer.

"I also feel enormous gratitude to all my students, postdocs, lab members, colleagues and mentors that helped me to reach this recognition. I feel like I am accepting this award on behalf of all of them as much as for myself. And finally, I see this as a call to give back to the community to help support those that historically have not been able to participate in the genomics revolution."

As a Bloomberg Distinguished Professor, Schatz has appointments in both the Whiting School of Engineering and the Krieger School of Arts and Sciences, where divisional leadership was thrilled to learn about the TIME 100 honor.

"Mike is a dedicated and visionary researcher, whose discoveries will have a profound impact on basic research and on clinical practice," said Whiting Dean T.E. "Ed" Schlesinger. "Our ability to understand and quantify an individual's genome represents a major breakthrough, both in terms of understanding DNA's role in disease risk and in realizing the promise of personalized medicine. This is a well-deserved honor for Mike and his colleagues and I have no doubt that his achievements will benefit generations to come."

Ron Daniels

President, Johns Hopkins University

Added Krieger Dean Christopher S. Celenza: "This is well-deserved recognition for one of our remarkable scientists. His extraordinary work with the team assembling the first complete sequence of a human genome is profound. I know his research will create opportunities for new, life-changing discoveries."

Schatz joined Johns Hopkins in 2016, coming from Cold Spring Harbor Laboratory on Long Island in New York, where he was an associate professor in the Simons Center for Quantitative Biology, served as the co-director of the Undergraduate Research Program, and co-led the Cancer Genetics & Genomics Program in the CSHL Cancer Center.

Earlier this year it was announced that a team Schatz co-led had created a cloud-based platform that grants researchers easy access to one of the world's largest genomics databases. Known as AnVIL (Genomic Data Science Analysis, Visualization, and Informatics Lab-space), the new platform gives any researcher with an Internet connection access to thousands of analysis tools, patient records, and more than 600,000 genomes.

Vice Provost for Research Denis Wirtz said that type of collaborative spirit is typical of Schatz, whom he calls a "scientific tour de force."

"In addition to being a remarkable scientist, Mike is also a tremendous colleague and collaborator," Wirtz said. "This is an incredible recognition of the type of team science that is defining the future of research."

Lauren Gardner, a civil and systems engineering professor in the Whiting School of Engineering, made TIME's list in 2020 for her work developing the university's COVID-19 dashboard, which became the Coronavirus Resource Center.

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Michael Schatz among 'TIME 100' most influential people in the world - The Hub at Johns Hopkins

Their team, the Telomere-to-Telomere (T2T) Consortium, published their work in Science magazine in March 2022, detailing how they filled in gaps in the sequence of the human genome. (The article had another Terp author, computer scientist Sergey Koren 02, M.S. 05, Ph.D. 12.)

The T2T researchers used a mixture of new "long read" DNA sequencing technologies to map a gap-free sequence of the roughly 3 billion bases (or letters) in human DNA.

In making the announcement for Time, Jennifer Doudna, a biochemist and winner of the 2020 Nobel Prize in Chemistry, wrote that the team had uncovered the human genomes dark matter, which had been missed by earlier genome sequencing.

The Human Genome Project, which announced it had finished decoding the basic chemical instructions for life in 2003, skipped a significant section of the genome composed of highly repetitive sequences that were mostly considered junk DNA at the time. Researchers today know theres more to it than that, making T2Ts work crucial.

The complete human genome sequence is an invaluable resource that may provide new insights into the origin of diseases and how we can treat them, Doudna said. It also offers the most complete look yet at the genetic script underlying the very nature of who we are as human beings.

Phillippy is head of the genome informatics section at the institute, where his lab has developed numerous widely used tools for the problems of genome assembly, alignment, clustering, forensics and metagenomics.

Schatz is a Bloomberg Distinguished Professor of computer science and biology at Johns Hopkins, where he uses computing to better understand human and agricultural genetics, leading to deeper knowledge of human diseases, targeted medical treatments and improved plants and crops.

The success of the T2T project demonstrates the power of interdisciplinary science and represents the culmination of decades of advances in computational techniques for analyzing genomes, many of which were pioneered by Adam and Mike, said Mihai Pop, a professor of computer science, director of the University of Maryland Institute for Advanced Computer Studies and a co-adviser to Schatz.

Pop said that during their time at CBCB, Phillippy and Schatz fostered a collegial and collaborative environment that still characterizes the centeran environment that has contributed to the success of many other outstanding scientists.

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Alums Named to Time Magazine's 2022 List of 100 Most Influential - Maryland Today

Genome Insight CEO Ju Young-seok received the Human Genome Organizations (HUGO) Chen Award of Excellence.

HUGO awards the Chen Award of Excellence annually to two young scientists who have extraordinary work or suggested a new treatment in human genomics.

Ju, a professor at the Korea Advanced Institute of Science and Technology (KAIST), is the second Korean to win the award after V. Narry Kim, a professor at Seoul National University (SNU).

Ju was selected as the 2020 Chen Award of Excellence recipient, but the awarding ceremony was postponed due to the Covid-19 pandemic. Ju received the award on Tuesday.

This is a second winning award as a Korean, and I am honored. I will strive to advance whole-genome sequencing (WGS) and the related industry, Ju said at the awarding ceremony.

Ju will have a chance to present a lecture at the Human Genome Meeting, hosted by HUGO, in Tel Aviv, Israel.

Ju is a physician-scientist who graduated from SNU College of Medicine. He serves as a professor at the Graduate School of Medical Science and Engineering at KAIST.

In January 2020, Ju and another physician-scientist, Lee Jeong-seok, co-founded Genome Insight.

Genome Insight specializes in analyzing and interpreting WGS big data, designed to provide accurate diagnosis and customized treatment for cancer and rare diseases caused by genetic mutations. The company is headquartered in San Diego in the U.S., and its R&D center is located in Seoul and Daejeon, Korea.

A Taiwanese physician-scientist established Chen Award, Yuan-Tsong Chen.

Chen is director of the Institute of Biomedical Sciences at Academia Sinica, Taiwan, and a professor of pediatrics and genetics at Duke University Medical Center, the U.S.

HUGO also gives Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research to one scientist who made an outstanding performance in human genomics. The awardee gets $10,000. In 2017, SNUs Kim won the award as the first Korean.

HUGO also awards the Chen Award of Excellence to two young scientists with a monetary award of $5,000 each. One award goes to a person residing outside Asia and the other to someone residing in Asia whose career years have not passed 15 years since receiving their highest earned degree.

HUGO is a non-profit international organization established in 1988. It conducts international academic exchanges and builds a joint research database. It played a crucial role in the Human Genome Project completed identifying all the nucleotide sequences of the human genome in 2003.

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Genome Insight CEO Ju wins Chen Award as 2nd Korean - KBR

Several decades of nutrition research have shown us that no one-size diet fits all and since we are all unique, healthcare nutrition which applies to all doesn't fit everyone. Many factors come into play as to why it may happen but the main reason has something to do with our genes or genetic makeup.

Genomic testing determines the interplay between genes, nutrition and health. It helps personalise the diet and nutrition and provides you with a blueprint for optimal health and wellness.

What do genomic tests evaluate?

Genomic tests identify the specifics of our DNA, in terms of change in our chromosomes, associated genes and/or protein . Nutrigenetic DNA tests examine the genes and variants of these genes involved in specific nutrients and their metabolism.

What can genomic testing tell you?

Genomic testing can reveal a wide range of information, from your ancestry to your health and family history. For instance, genetic testing can screen and diagnose complex diseases, find out the risk and predisposition to disease, identify hereditary disease patterns and even help in creating a course on treatment, revealing a proclivity for nutrient deficiency or toxicity, food sensitivities and even whether you're at risk for nutrition-related diseases.

In an interview with HT Lifestyle, Dr Saima Naz Khan, Senior Manager- Scientific Affairs at Genes2Me Pvt Ltd, revealed, Every individual requires a balanced diet which should comprise macronutrients (carbohydrates, proteins, fats and fibers) and micronutrients (minerals and vitamins) but no individual neither requires nor responds to the exact amount of these nutrients; therefore, theres no one-size-fits-all diet. While several factors are at play, genetics plays a crucial role in our nutrition. Genomic testing can reveal why certain nutrients or diets works for an individual and why it doesnt work for others. There are nutrigenomics services that are truly useful for anyone who wants to be proactive about their health.

She added, A nutrigenomics counsellor may be able to advise you on certain eating patterns that will or will not work well for you based on your individual genetic makeup. For example, because of genomic tendencies for fat metabolism, gene variants may indicate that your body would not benefit from a vegan diet or would not adapt well to a keto diet. A nutrigenomic test can identify your personal best sources of macronutrients and micronutrients. Choosing a diet based on your genetic tendencies can help you achieve your health objectives.

Elaborating upon the same, Dr Akansha Sahay, General Physician at Tattvan E-clinic, said, Nutrigenomics, a science that studies interaction of nutrition and genes is flourishing and changing lives. DNA test for diet and nutrition can give us information about foods that can be healthy for us and ones which can pose a risk of various health conditions. Choosing a diet based on your genetic tendencies can help you to achieve your desired health goals.

She listed the factors whose information can be provided by DNA testing:

1. Vitamin and mineral deficiencies - calcium, iron, vitamin A, vitamin B, and more.

2. Bone mineral density (BMD)

3. Body Mass Index (BMI)

4. Response of macronutrients like carbohydrates, protein, fats and fibers on your weight.

5. Salt intake and blood pressure sensitivity

What is a DNA-based diet?

Dr Akansha Sahay explained, These diets are based on nutrigenomics, the study of the relationship between nutrition and the human genome. Examining ones DNA can help determine which diet would be most appropriate for ones health. A genetic test is undertaken to determine the correlation between a persons genes and nutrition level for their overall health. This info is primarily used by experts to pinpoint the best diet for them. Nutrigenomics is a wonder by which we can even correct cardiovascular disease, obesity, type 1 diabetes and other lifestyle diseases,Your DNA can influence not only your food behaviour, but is also capable of altering the expression of various hormones and enzymes critical to metabolism. These determine your response to diet, predisposition to weight gain and metabolism.

She said, Nutrigenomics (also known as nutritional genomics) is broadly defined as the relationship between nutrients, diet and gene expression. Phenylketonuria is an example of single gene mutation. About the examples of nutrigenomics, she said, Phenylketonuria patients should avoid phenylalanine-rich food. Many Asian populations have the problem of deficiency of the aldehyde dehydrogenase enzyme, which is responsible for metabolism of ethanol.

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What is DNA-based diet? Here's how our genetic makeup is connected to nutrition - Hindustan Times

Summary: Researchers have identified a mechanism shared by mutations in the SHANK3 and ADNP genes. The genes have been associated with the development of ASD and schizophrenia.

Source: Tel Aviv University

Researchers at Tel Aviv University, led by Prof. Illana Gozes from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience, have unraveled a mechanism shared by mutations in the genes ADNP and SHANK3, which cause autism, schizophrenia, and other conditions.

The researchers also found that an experimental drug previously developed in Prof. Gozes lab is effective in lab models for these mutations and may be suitable for treating a range of rare syndromes that impair brain functions.

According to the researchers, the encouraging results may lead to effective treatments for a range of rare syndromes that impair brain functions and cause autism, schizophrenia, and neurodegenerative diseases like Alzheimers.

Participants in the study: Dr. Yanina Ivashko-Pachima, Maram Ganaiem, Inbar Ben-Horin-Hazak, Alexandra Lobyntseva, Naomi Bellaiche, Inbar Fischer, Gilad Levy, Dr. Shlomo Sragovich, Dr. Gidon Karmon, and Dr. Eliezer Giladi from the Sackler Faculty of Medicine and Sagol School of Neuroscience at TAU, Dr. Boaz Barak from the School of Psychological Sciences, Gershon H. Gordon Faculty of Social Sciences and the Sagol School of Neuroscience at TAU, and Dr. Shula Shazman from the Department of Mathematics and Computer Science at the Open University.

The paper was published in the scientific journalMolecular Psychiatry.

Prof. Gozes: Some cases of autism are caused by mutations in various genes. Today we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare).

In our lab we focus mainly on one of these, the ADNP syndrome, caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeleton of neurons in the brain.

In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 a gene associated with autism and schizophrenia. According to estimates, these two mutations are responsible for thousands of cases of autism around the world.

To start with, the researchers obtained cells from patients with ADNP syndrome. They discovered that when the ADNP protein is defective, neurons with faulty skeletons (microtubules) are formed, impairing brain functions. They also found, however, that ADNP mutations take different forms, some of which cause less damage.

Prof. Gozes, who is also Director of the Adams Super Center for Brain Studies at TAU, explains: We discovered that in some mutations, a section added to the protein protects it and reduces the damage by connecting to a control site of the neurons skeletal system. We know that this same control site is found on SHANK3 a much studied protein, with mutations that are associated with autism and schizophrenia.We concluded that the ability to bond with SHANK3 and other similar proteins provides some protection against the mutations damaging effects.

At the next stage of the study, the researchers found additional sites on the ADNP protein that can bond with SHANK3 and similar proteins. One of these sites is located on NAP, a section of ADNP which was developed into an experimental drug (Davunetide) by Prof. Gozes lab.

Moreover, the researchers demonstrated that extended treatment with Davunetide significantly improved the behavior of model animals with autism caused by SHANK3.

Prof. Gozes: In previous studies we showed that Davunetide is effective for treating ADNP syndrome models. The new study has led us to believe that it may also be effective in the case of Phelan McDermid syndrome, caused by a mutation in SHANK3, as well as other syndromes that cause autism through the same mechanism.

The experimental drug Davunetide was recognized by the FDA as an orphan and rare pediatric drug for future treatment of the developmental syndrome ADNP and is protected by patents through Ramot, the technology transfer company at Tel Aviv University and exclusively licensed to ATED Therapeutics Ltd.

ATED Therapeutics Ltd. (ATED)

ATED was formed around the work of Dr. Gozes by experienced business managers to develop Davunetide for clinical use. ATED is led by Dr. Jeff R. Swarz as CEO, Joe Chiarelli as CFO, an experienced clinical trial Chief Medical Officer, and Dr. Gozes as Chief Scientific Officer.

ATEDs broad focus is on diseases of the central nervous system (CNS). Our initial target is achronic, debilitatingform of autism called ADNP Syndrome (activity-dependent neuroprotective protein) that affects about 3,000-5,000 patients (ages 1-17) worldwide. The lead compound, Davunetide, is patented, safe, non-toxic, andhas been tested in over 300 adult patients. As there is no treatment for ADNP Syndrome, it has rare pediatric and orphan drug designation from the FDA.

Author: Noga ShaharSource: Tel Aviv UniversityContact: Noga Shahar Tel Aviv UniversityImage: The image is in the public domain

Original Research: Open access.SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism by Yanina Ivashko-Pachima et al. Molecular Psychiatry

Abstract

SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism

De novo heterozygous mutations in activity-dependent neuroprotective protein (ADNP) cause autistic ADNP syndrome. ADNP mutations impair microtubule (MT) function, essential for synaptic activity.

The ADNP MT-associating fragment NAPVSIPQ (called NAP) contains an MT end-binding protein interacting domain, SxIP (mimicking the active-peptide, SKIP). We hypothesized that not allADNPmutations are similarly deleterious and that the NAPV portion of NAPVSIPQ is biologically active.

Using the eukaryotic linear motif (ELM) resource, we identified a Src homology 3 (SH3) domain-ligand association site in NAP responsible for controlling signaling pathways regulating the cytoskeleton, namely NAPVSIP.

Altogether, we mapped multiple SH3-binding sites in ADNP. Comparisons of the effects of ADNP mutations p.Glu830synfs*83, p.Lys408Valfs*31, p.Ser404* on MT dynamics and Tau interactions (live-cell fluorescence-microscopy) suggested spared toxic function in p.Lys408Valfs*31, with a regained SH3-binding motif due to the frameshift insertion.

Site-directed-mutagenesis, abolishing the p.Lys408Valfs*31 SH3-binding motif, produced MT toxicity. NAP normalized MT activities in the face of all ADNP mutations, although, SKIP, missing the SH3-binding motif, showed reduced efficacy in terms of MT-Tau interactions, as compared with NAP.

Lastly, SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), a major autism gene product, interact with the cytoskeleton through an actin-binding motif to modify behavior.

Similarly, ELM analysis identified an actin-binding site on ADNP, suggesting direct SH3 and indirect SHANK3/ADNP associations. Actin co-immunoprecipitations from mouse brain extracts showed NAP-mediated normalization of Shank3-Adnp-actin interactions.

Furthermore, NAP treatment ameliorated aberrant behavior in mice homozygous for theShank3ASD-linked InsG3680 mutation, revealing a fundamental shared mechanism between ADNP and SHANK3.

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Mechanism Shared by Mutations in Different Genes Associated With Autism, Schizophrenia, and Other Conditions Discovered - Neuroscience News

image:Patagonian sheepdog view more

Credit: Rodrigo Muoz

The Patagonian sheepdog (PGOD) originated from the ancestral shepherds of the United Kingdom is nowadays the closest link to a now extinct population of shepherds from which modern herding breeds descend. This was shown by research recently published in the journal named PLOSGenetics.

The research was based on the genomic characterization of the Patagonian sheepdog. For this, it was necessary to take samples of 159 Patagonian sheepdogs from the region of Aysn and Magallanes, in addition to some of them belonging to the Province of Chubut, Argentina. In this route of almost 13.000 kilometers, hair samples and 22 body measurements were extracted, in addition to collecting information on their pastoralist behavior, health status, reproductive status and nutrition, among other data.

For Natasha Barrios, a member of Universidad Austral de Chile and who led the study, this Patagonia dog, unknown in the world, is shown as the missing link between the old shepherds of the United Kingdom and the modern herding breeds. In that line, she said that today we have an idea of what these dogs were and looked like before the official set up of modern breeds. It has been incredibly silent and stealthy working in the extreme of South America for the last 140 years, making it a valuable genetic and cultural reservoir.

DNA sequencing from blood samples was performed by means of a whole-genome genotyping chip. This chip has approximately 170.000 potential markers of polymorphisms within the dog's genome. To identify these variants, the obtained data were compared with data of similar characteristics from 1,514 individuals belonging to 175 recognized dog breeds, considering within this group herding breeds of European origin.

Regarding the advantages of this type of approach, Guillermo Nourdin, Bioinformatics expert at the MELISA Institute, who was responsible for the management and analysis of genomic data, highlighted the global, integrative and massive look at genomic data in the research. In addition, this approach identified common traits that match populations of Patagonian sheepdog together with modern herding dog breeds that have a common ancestor of European origin, he stated.

Finally, Prof. Elard Koch, senior researcher and Chairman at the MELISA Institute, said that they were pleased with the participation of Guillermo Nourdin in this study of Patagonian sheepdogs: "Collaborating with our bioinformatics capabilities in research as relevant as this one, is encouraging for our researchers and a major goal for our institution" Koch remarked.

This research opens the door to the future exploration of different phenotype-genotype association analyzes, which would, for example, the exploration of genetic traits associated with their behavior, resistance and ability to work; additionally, to search for possible diseases prone to some modern herding breeds, where Patagonian sheepdog could be key to understanding how and why they have spread today.

###

This work was funded by: National Research and Development Agency, FONDECYT 1181592, Chile. (https://www.anid.cl) to MAG, National Agency for Research and Development, National Doctoral Scholarship 2018, Chile (www.anid.cl) to NB, National Agency for Research and Development, REDI 170062, Chile (www.anid.cl) to CGL, National Agency for Research and Development, PIA/BASAL FB0002, Chile (www.anid.cl) to CGL, The Intramural Program of the National Human Genome Research Institute of the National Institute of Health, Bethesda, Maryland, United States of America to EAO, DLD, HGP, ANH. The sponsors had no role in the design of the study, the collection and analysis of data, the decision to publish or the preparation of the manuscript.

Participating researchers:

Natasha Barrios, Institute of Pharmacology and Morphophysiology, Graduate School, School of Veterinary Sciences, Southern University of Chile; Cesar Gonzalez-Lagos, Department of Sciences, School of Liberal Arts, Adolfo Ibanez University, Santiago, Chile, and Center for Applied Ecology and Sustainability (CAPES), Santiago, Chile; Dayna L. Dreger, Heidi G. Parker, Andrew N. Hogan and Elaine A. Ostrander, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA; Guillermo Nourdin-Galindo, Biotechnology Division, MELISA Institute, Concepcion, Chile; Marcelo A. Gomez, Institute of Pharmacology and Morphophysiology, School of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.

Experimental study

Animals

Patagonian sheepdog: Genomic analyses trace the footprints of extinct UK herding dogs to South America

28-Apr-2022

Competing interests: The authors have declared that no competing interests exist.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Discovery of the link between the Patagonian sheepdog and the former shepherds from the UK - EurekAlert

NEW YORK A team from Stanford University and other centers in the US and China have demonstrated that polygenic risk scores (PRS) based on common variants can be bolstered by incorporating clues from rare variants linked to significant gene expression shifts, dubbed expression outliers.

"As individual PRS estimates are comprised of variants across hundreds to thousands of genes, we reasoned that the disease effects of outlier-associated rare variants might have the greatest impact in individuals with a relatively larger burden of outlier-associated rare variant effects mapping to disease-relevant genes," Stanford University researchers Craig Smail and Stephen Montgomery, first and senior authors on a studyappearingin the American Journal of Human Genetics on Wednesday, explained in an email.

Using genotyping data from UK Biobank participants, together with expression quantitative trait locus data from the GTEx project and a computational method known as CrossMap that takes rare variant-related gene expression changes into account, the researchers first flagged rare variants with outsized effects on gene expression.

From nearly 1.8 million rare variants found in the UK Biobank set and in the gnomAD database, they flagged nearly 90,900 rare outlier variants that appeared to impact the expression of 15,871 genes, based on rare variant annotations gleaned from whole-genome and transcriptome sequences in version 8 of the GTEx.

From there, the team used its "independent outlier gene count" (IOGC) score to demonstrate that the expression outlier-related rare variants could improve the performance of body mass index (BMI) PRSs in more than 96,600 of the UK Biobank participants, distinguishing between individuals at higher or lower risk of so-called severe obesity or early bariatric surgery findings that were further validated using data for Million Veteran Program participants.

"We have demonstrated that a high burden of rare variants identified by their association with outlier gene expression can lead to substantial deviations in PRS-predicted phenotype," the authors wrote. "Furthermore, by integrating these rare variants into genetic risk prediction using the IOGC score, we demonstrated improvements in predicting risk for obesity beyond what was achievable with common variant-based PRSs."

In particular, the investigators found that predictions made using expression outlier-linked rare variants outperformed those possible by incorporating insights on protein-truncating rare variants into PRSs. Based on UK Biobank GWAS data spanning more than 1,900 traits or conditions, meanwhile, they saw signs that gene expression outlier-linked variants were somewhat enriched compared to rare variants that did not shift gene expression.

The findings so far suggest that "prediction for multiple complex diseases will benefit from integrating outlier-associated rare variants, including coronary heart disease, type 2 diabetes, and breast cancer," Smail and Montgomery wrote, noting that preliminary work points to improved predictive accuracy in at least two populations, hinting that a similar strategy may boost efforts to apply PRSs in non-European cohorts.

The investigators cautioned that the current approach is reliant on rare variant annotation insights from a relatively small set of GTEx representatives so far, and may be further improved by tapping into growing RNA sequence datasets and resulting variant-gene expression annotations. Likewise, whole-genome sequences from the UK Biobank project are expected to reveal far more rare variants missed with more limited sequence data used in the current analysis.

Consequently, Smail and Montgomery called the current work "a baseline for phenotypic prediction of complex diseases by integrating outlier-associated rare variants."

"Future extensions to our model will include more rare variants as we continue to sequence both transcriptomes and genomes in populations, will look at tissue-specific outlier effects, and incorporate longer-range gene expression impacts such as outlier-associated rare variants in enhancer regions," they noted.

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Polygenic Risk Score Performance Improved With Expression-Related Rare Variant Insights - GenomeWeb

This kind of first-degree offspring is extraordinary, only having been cited in royal families of the past headed by god-kings such as the Egyptian pharaohs seeking to maintain a pure dynastic bloodline. (It is known, for instance, that Akhenaten married his eldest daughter, Meritaten, and much later, Ptolemy II married his sister, Arsinoe II hence his nickname, "Philadelphus" or "sibling loving.") It has been suggested that this Neolithic elite may have claimed to possess divine powers to ensure the continuity of agricultural cycles by keeping the Sun's movements going.

The findings support the notion that these Neolithic communities were socially stratified and that the massive stone structures were used to bury transgenerational patrilineal members of these clans. Perhaps equally interesting is the fact that in one case relatives were separated by up to 12 generations, pointing to an unusual stability through time of both the funerary tradition and the stratified society where they lived.

We have seen several case studies of past inequality correlating funerary archaeology with genetics that might no longer apply today, where legal regulations (and also the exponential increase of cremations) represent a certain degree of standardisation in funeral practices. Nevertheless, an opposite trend could shape thefuture of the archaeology of death: the trend toward personalised coffins, unconventional funerary memorials, and special grave goods. One way or another, mortuary archaeology will always be an important subfield of this discipline, and one that will need to rely on the hard sciences such as genetics and forensics.

Perhaps one encouraging conclusion is that despite what we have seen on the archaeology of past inequality, societies have been able to evolve and change their social stratifications. One example is Iceland the country has become one of the most egalitarian societies in the world. In 2018, Iceland passed a law that all companies employing more than 25 people will have four years to ensure gender-equal payment because, according to the head of the Equality Unit at Iceland's Welfare Ministry, "equality won't come about by itself, from the bottom up alone".

* This is an edited version of an article thatoriginally appearedinThe MIT Press Reader, and is republished with permission.

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Carles Lalueza-Foxis Research Professor and Director of the Paleogenomics Lab at the Institute of Evolutionary Biology (CSIC-Universitat Pompeu Fabra) in Barcelona. He participated in the Neanderthal Genome Project and led the first retrieval of the genome of an 8,000-year-old European hunter-gatherer. He is the author of Inequality: A Genetic History, from which this article is adapted (this is an edited version of the original MIT Reader piece).

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Why some ancient societies were more unequal than others - BBC