Category Archives: Genetics

Genetics

CRISPR gene-editing therapies need more diverse DNA to realize their full potential – Vox.com

Medicine has entered a new era in which scientists have the tools to change human genetics directly, creating the potential to treat or even permanently cure diseases by editing a few strands of troublesome DNA. And CRISPR, the gene-editing technology whose creators won the Nobel Prize for Chemistry in 2020, is the face of this new normal.

CRISPRs novel harnessing of bacterial proteins to target disease-carrying genes has reshaped medical research over the past decade. While gene-editing itself has been around for more than 30 years, scientists can use CRISPR to edit genomes faster, cheaper, and more precisely than they could with previous gene-editing methods.

As a result, investigators have gained far more control over where a gene gets inserted and when it gets turned on. That in turn has opened the door to a new class of better gene therapies treatments that modify or replace peoples genes to stop a disease.

Last December, the US Food and Drug Administration approved the first-ever CRISPR-based therapy, designed to treat sickle cell disease. In February, the treatment, called Casgevy, gained approval from the European Commission as well. It joins the dozen or so pre-CRISPR gene therapies that are already available to patients. In early May, the first patients began to receive treatment

But theres a significant impediment to maximizing CRISPRs potential for developing novel therapies: the lack of diversity in genetics research.

For decades, gene therapy has been defined by both its enormous therapeutic potential, and by the limitations imposed by our imprecise knowledge of human genetics. Even as gene-editing methods, including CRISPR, have become more sophisticated over the years, the data in the genetic databases and biobanks that scientists use to find and develop new treatments are still riddled with biases that could exclude communities of color from enjoying the full benefits of innovations like CRISPR. Unless that gap is closed, CRISPRs promise wont be fully fulfilled.

Developing effective gene therapies depends on growing our knowledge of the human genome. Data on genes and their correlation with disease have already changed the way cancer researchers think about how to design drugs, and which patients to match with which drug.

Scientists have long known that certain genetic mutations that disrupt regular cell functions can cause cancer to develop, and they have tailored drugs to neutralize those mutations. Genetic sequencing technology has sped that progress, allowing researchers to analyze the genetics of tumor samples from cancer patients after theyve participated in clinical trials to understand why some individuals respond better than others to a drug.

In a clinical trial of the colorectal cancer drug cetuximab, investigators found retrospectively that tumors with a mutation in the KRAS gene (which helps govern cell growth) did not respond to treatment. As a result, clinicians are now asked to confirm that patients do not have the mutation in the KRAS gene before they prescribe that particular drug. New drugs have been developed to target those mutations in the KRAS gene.

Its a step-by-step process from the discovery of these disease-related genes to the crafting of drugs that neutralize them. With CRISPR now available to them, many researchers believe that they can speed this process up.

The technology is based on and named after a unique feature in the bacterial immune system that the organism uses to defend itself against viruses. CRISPR is found naturally in bacteria: Its short for Clustered Regularly Interspaced Short Palindromic Repeats, and it functions like a mugshot database for bacteria, containing snippets of genetic code from foreign viruses that have tried to invade in the past.

When new infections occur, the bacteria deploys RNA segments that scan for viral DNA that matches the mugshots. Special proteins are then dispatched to chop the virus up and neutralize it.

To develop CRISPR into a biotech platform, this protein-RNA complex was adapted from bacteria and inserted into human and animal cells, where it proved similarly effective at searching for and snipping strands of DNA.

Using CRISPR in humans requires a few adjustments. Scientists have to teach the system to search through human DNA, which means that it will need a different mugshot database than what the bacteria originally needed. Critical to harnessing this natural process is artificial RNA, known as a guide RNA. These guide RNAs are designed to match genes found in humans. In theory, these guide RNAs search for and find a specific DNA sequence associated with a specific disease. The special protein attached to the guide RNA then acts like molecular scissors to cut the problematic gene.

CRISPRs therapeutic potential was evident in the breakthrough sickle cell treatment approved by the FDA late last year. What made sickle cell such an attractive target is not just that it affects around 20 million people or more worldwide, but that it is caused by a mutation in a single gene, which makes it simpler to study than a disease caused by multiple mutations. Sickle cell is one of the most common disorders worldwide that is caused by a mutation in a single gene. It was also the first to be characterized at a genetic level, making it a promising candidate for gene therapy.

In sickle cell disease, a genetic mutation distorts the shape of a persons hemoglobin, which is the protein that helps red blood cells carry and deliver oxygen from the lungs to tissues throughout the body. For people with sickle cell disease, their red blood cells look like sickles instead of the normal discs. As a result, they can get caught in blood vessels, blocking blood flow and causing issues like pain, strokes, infections, and death.

Since the 1990s, clinicians have observed that sickle cell patients with higher levels of fetal hemoglobin tend to live longer. A series of genome-wide association studies from 2008 pointed to the BCL11A gene as a possible target for therapeutics. These association studies establish the relationships between specific genes and diseases, identifying candidates for CRISPR gene editing.

Casgevys new CRISPR-derived treatment targets a gene called BCL11A. Inactivating this gene stops the mutated form of hemoglobin from being made and increases the production of normal non-sickled fetal hemoglobin, which people usually stop making after birth.

Out of the 45 patients who have received Casgevy since the start of the trials, 28 of the 29 eligible patients who have stayed on long enough to have their results analyzed reported that they have been free of severe pain crises. Once the treatment moves out of clinical settings, its exact effects can vary. And if the underlying data set doesnt reflect the diversity of the patient population, the gene therapies derived from them might not work the same for every person.

Sickle cell disease as the first benefactor of CRISPR therapy makes sense because its a relatively simple disorder that has been studied for a long time. The genetic mutation causing it was found in 1956. But ironically, the same population that could benefit most from Casgvey may miss out on the full benefits of future breakthrough treatments.

Scientists developing CRISPR treatments depend on whats known as a reference genome, which is meant to be a composite representation of a normal human genome that can be used to identify genes of interest to target for treating a disease.

However, most of the available reference genomes are representative of white Europeans. Thats a problem because not everybodys DNA is identical: Recent sequencing of African genomes shows that they have 10 percent more DNA than the standard reference genome available to researchers. Researchers have theorized that this is because most modern humans came out of Africa. As populations diverged and reconcentrated, genetic bottlenecks happened, which resulted in a loss of genetic variation compared to the original population.

Most genome-wide association studies are also biased in the same way: They have a lot of data from white people and not a lot from people of color.

So while those studies can help identify genes of importance that could lead to effective treatments for the population whose genes make up the majority of the reference data i.e., white people the same treatments may not work as well for other nonwhite populations.

Broadly, theres been an issue with human genetics research theres been a major under-representation of people of African ancestry, both in the US and elsewhere, said Sarah Tishkoff, professor of genetics and biology at the University of Pennsylvania. Without including these diverse populations, were missing out on that knowledge that could perhaps result in better therapeutics or better diagnostics.

Even in the case of the notorious breast cancer gene BRCA1, where a single gene mutation can have a serious clinical impact and is associated with an increased risk of developing cancer, underlying mutations within the gene tend to differ in people of different ancestries, Tishkoff said.

These differences, whether large or small, can matter. Although the vast majority of human genomes are the same, a small fraction of the letters making up our genes can differ from person to person and from population to population, with potentially significant medical implications. Sometimes during sequencing, genetic variations of unknown significance appear. These variants could be clinically important, but because of the lack of diversity in previous research populations, no one has studied them closely enough to understand their impact.

If all the research is being done in people of predominantly European ancestry, youre only going to find those variants, Tishkoff said.

Those limitations affect scientists up and down the developmental pipeline. For researchers using CRISPR technology in preclinical work, the lack of diversity in the genome databases can make it harder to identify the possible negative effect of such genetic variation on the treatments theyre developing.

Sean Misek, a postdoctoral researcher at the Broad Institute of MIT and Harvard, started developing a project with the goal of investigating the differences in the genetic patterns of tumors from patients of European descent compared to patients of African descent. CRISPR has become a versatile tool. Not only can it be used for treatments, but it can also be used for diagnostics and basic research. He and his colleagues intended to use CRISPR to screen for those differences because it can evaluate the effects of multiple genes at once, as opposed to the traditional method of testing one gene at a time.

We know individuals of different ancestry groups have different overall clinical responses to cancer treatments, Misek said. Individuals of recent African descent, for example, have worse outcomes than individuals of European descent, which is a problem that we were interested in trying to understand more.

What they encountered instead was a roadblock.

When Miseks team tried to design CRISPR guides, they found that their guides matched the genomes in the cells of people with European and East Asian ancestry, whose samples made up most of the reference genome, but not on cells from people of South Asian or African ancestry, who are far less represented in databases. In combination with other data biases in cancer research, the guide RNA mismatch has made it more difficult to investigate the tumor biology of non-European patients.

Genetic variations across ancestry groups not only affect whether CRISPR technology works at all, but they can also lead to unforeseen side effects when the tool makes cuts in places outside of the intended genetic target. Such side effects of off-target gene edits could theoretically include cancer.

A big part of developing CRISPR therapy is trying to figure out if there are off-targets. Where? And if they exist, do they matter? said Daniel Bauer, an attending physician at Dana-Farber/Boston Childrens Cancer and Blood Disorders Center.

To better predict potential off-target edits, Bauer collaborated with Luca Pinello, associate professor at Massachusetts General Hospital and Harvard Medical School, who had helped develop a tool called CRISPRme that makes projections based on personal and population-level variations in genetics. To test it, they examined the guide RNA being used for sickle cell disease treatment, and found an off-target edit almost exclusively present in cells donated by a patient of African ancestry.

It is currently unclear if this off-target edit detected by the CRISPRme tool has any negative consequences. When the FDA approved the sickle-cell therapy in December 2023, regulators required a post-marketing study to look into off-target effects. Any off-target edits affecting a persons blood should be easily detected in the blood cells, and drawing blood is easier to do than collecting cells from an internal organ, for example.

The genetic variant where the off-target effect occurred can be found in approximately every 1 in 10 people with African ancestry. The fact that we actually were able to find a donor who carried this variant was kind of luck, Bauer said. If the cells we were using were only of European ancestry, it wouldve been even harder to find.

Most of these [off-target] effects probably wont cause any problems, he said. But I think we also have these great technologies, so thats part of our responsibility to look as carefully as we can.

These issues recur again and again as investigators hunt for novel treatments. Katalin Susztak, professor of medicine and genetics at the University of Pennsylvania, thinks one promising candidate for a future CRISPR therapy is a standout gene for kidney disease: APOL1.

Researchers identified the gene when they looked into kidney disease risk in African Americans. While genome-wide association studies turned up thousands of distinct genes increasing risk for people of European ancestry, in African Americans, this single gene was responsible for 3 to 5 times higher risk of kidney disease in patients, said Susztak.

The APOL1 variant is common among African Americans because it protects people from developing African sleeping sickness, which is spread by the Tsetse fly present across much of the continent. This is similar to the story of the sickle cell mutation, which can protect people from malaria.

The variant is maybe only 5,000 years old, so this variant has not arisen in Europe, Asia, or anywhere else. Just in West Africa, Susztak said. But because of the slave trades, West Africans were brought to the United States, so millions of people in the United States have this variant.

The variant also predisposes people to develop cardiovascular disease, high blood pressure, and COVID-related disease, which maybe explains why there was an increased incidence of deaths in African Americans during COVID than in Europeans, Susztak said. APOL1 is potentially a very interesting target [for CRISPR] because the disease association is strong.

A CRISPR treatment for kidney disease is currently being investigated, but using the tool comes with complications. Cutting the APOL1 gene would set off an immune response, Susztak noted, so they will have to somehow prevent undesirable side effects, or find a related, but editable gene, like they did with sickle cell.

An alternative RNA-based strategy utilizing CRISPR is also in the works. DNA needs to be transcribed into a messenger RNA sequence first before it can be turned into proteins. Instead of permanently altering the genome, RNA editing alters the sequence of RNAs, which can then change what proteins are produced. The effects are less permanent, however, lasting for a few months instead of forever which can be advantageous for treating temporary medical conditions.

And it may turn out that gene therapy is simply not the right approach to the problem. Sometimes, a more conventional approach still works best. Susztak said that a small molecule drug developed by Vertex which works similarly to most drugs except special classes like gene therapies or biologics to inhibit the function of the APOL1 protein has enjoyed positive results in early clinical trials.

Even with these limitations, more CRISPR treatments are coming down the pike.

As of early last year, more than 200 people have been treated with experimental CRISPR therapies for cancers, blood disorders, infections, and more. In the developmental pipeline is a CRISPR-based therapeutic from Intellia Therapeutics that treats transthyretin amyloidosis, a rare condition affecting the function of the heart tissues and nerves. The drug has performed well in early trials and is now recruiting participants for a Phase III study. Another CRISPR drug from Intellia for hereditary angioedema, a condition that causes severe swelling throughout the body, is slated to enter Phase III later this year.

As the CRISPR boom continues, some research groups are slowly improving the diversity of their genetic sources.

The All of Us program from the National Institutes of Health, which aims to find the biological, environmental, and lifestyle factors that contribute to health, has analyzed 245,000 genomes to date, over 40 percent of which came from participants who were not of European ancestry. They found new genetic markers for diabetes that have never been identified before.

Then theres the Human Pangenome project, which aims to create a reference genome that captures more global diversity. The first draft of its proposal was released last May. Another project called the PAGE study, funded by the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities, is working to include more ancestrally diverse populations in genome-wide association studies.

But at the current pace, experts predict that it will take years to reach parity in our genetic databases. And the scientific community must also build trust with the communities its trying to help. The US has a murky history with medical ethics, especially around race. Take the Tuskegee experiment that charted the progression of syphilis in Black American men while hiding the true purpose of the study from the participants and withholding their ability to seek treatment when it became available, or the controversy over Henrietta Lacks cervical cells, which were taken and used in research without her consent. Those are just two prominent historical abuses that have eroded trust between minority communities and the countrys medical system, Tishkoff said. That history has made it more difficult to collect samples from marginalized communities and add them to these critical data sets.

Where the research is being done, where the clinical trials are being held, as well as whos doing the research, can all have an impact on which patients participate. The Human Genetics & Genomics Workforce Survey Report published by the American Society of Human Genetics in 2022 found that 67 percent of the genomic workforce identified as white. Add in the financial burden of developing new treatments when using a reference genome, or a pre-made biobank from past efforts to collect and organize a large volume of biological samples, saves time and costs. In the race to bring CRISPR treatments to market, those shortcuts offered valuable efficiency to drug makers.

What this means is that the first-generation of CRISPR therapeutics might therefore be blunter instruments than they might otherwise be. However, if improvements can be made to make sure the source genomes reflect a wider range of people, Pinello believes that later generations of CRISPR will be more personalized and therefore more effective for more people.

Finding the genes and making drugs that work is, of course, momentous but ultimately, thats only half the battle. The other worry physicians like Susztak have is whether patients will be able to afford and access these innovative treatments.

There is still an overwhelming racial disparity in clinical trial enrollment. Studies have found that people of color are more likely to suffer from chronic illness and underuse medications like insulin compared to their white counterparts. Gene therapies easily rack up price tags in the millions, and insurance companies, including the Centers for Medicare and Medicaid Services, are still trying to figure out how to pay for them.

Because its the pharmaceutical industry, if they dont turn around profit, if they cannot test the drug, or if people are unwilling to take it, then this inequity is going to be worsened, said Susztak. We are essentially going to be creating something that makes things worse even though we are trying to help.

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CRISPR gene-editing therapies need more diverse DNA to realize their full potential - Vox.com

Genetics

An epigenome editing toolkit to dissect the mechanisms of gene regulation – EurekAlert

image:

Creative depiction of the epigenetic editing toolkit: each building represents the epigenetic state of a single gene (dark windows are silenced genes, lit up windows are active genes). The crane illustrates the epigenetic editing system which enables de novo deposition of chromatin marks on any genomic location.

Credit: Marzia Munaf

Understanding how genes are regulated at the molecular level is a central challenge in modern biology. This complex mechanism is mainly driven by the interaction between proteins called transcription factors, DNA regulatory regions, and epigenetic modifications chemical alterations that change chromatin structure. The set of epigenetic modifications of a cells genome is referred to as the epigenome.

In a study just published in Nature Genetics, scientists from the Hackett Group at EMBL Rome have developed a modular epigenome editing platform a system to program epigenetic modifications at any location in the genome. The system allows scientists to study the impact of each chromatin modification on transcription, the mechanism by which genes are copied into mRNA to drive protein synthesis.

Chromatin modifications are thought to contribute to the regulation of key biological processes such as development, response to environmental signals, and disease.

To understand the effects of specific chromatin marks on gene regulation, previous studies have mapped their distribution in the genomes of healthy and diseased cell types. By combining this data with gene expression analysis and the known effects of perturbing specific genes, scientists have ascribed functions to such chromatin marks.

However, the causal relationship between chromatin marks and gene regulation has proved difficult to determine. The challenge lies in dissecting the individual contributions of the many complex factors involved in such regulation chromatin marks, transcription factors, and regulatory DNA sequences.

Scientists from the Hackett Group developed a modular epigenome editing system to precisely program nine biologically important chromatin marks at any desired region in the genome. The system is based on CRISPR a widely used genome editing technology that allows researchers to make alterations in specific DNA locations with high precision and accuracy.

Such precise perturbations enabled them to carefully dissect cause-and-consequence relationships between chromatin marks and their biological effects. The scientists also designed and employed a reporter system, which allowed them to measure changes in gene expression at single-cell level and to understand how changes in the DNA sequence influence the impact of each chromatin mark. Their results reveal the causal roles of a range of important chromatin marks in gene regulation.

For example, the researchers found a new role for H3K4me3, a chromatin mark that was previously believed to be a result of transcription. They observed that H3K4me3 can actually increase transcription by itself if artificially added to specific DNA locations. This was an extremely exciting and unexpected result that went against all our expectations, said Cristina Policarpi, postdoc in the Hackett Group and leading scientist of the study. Our data point towards a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.

Hackett and colleagues are currently exploring avenues to leverage this technology through a promising start-up venture. The next step will be to confirm and expand these conclusions by targeting genes across different cell types and at scale. How chromatin marks influence transcription across the diversity of genes and downstream mechanisms, also remains to be clarified.

Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome, said Jamie Hackett, Group Leader at EMBL Rome. The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.

ystematic Epigenome Editing Captures the Context-dependent Instructive Function of Chromatin Modifications

9-May-2024

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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An epigenome editing toolkit to dissect the mechanisms of gene regulation - EurekAlert

Genetics

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Introgression and disruption of migration routes have shaped the genetic integrity of wildebeest populations - Nature.com

Genetics

Is Left-Handedness Tied to Your Genetics? Possibly, New Study Suggests – Technology Networks

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Its a question that has spurred many hypotheses over the years. The general consensus in modern science is that right- or left-brain hemisphere dominance dictates our handedness.

Studies of human fetuses have shown that right-lateralized predominance of arm movements can occur as early as 10 weeks into gestation in right-handed individuals. The fact that this right- or left-sided preference is apparent so early on in human development suggests that genetically regulated mechanisms could be at play.

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To further probe how genetics might contribute to handedness, scientists at the Max Planck Institute (MPI) for Psycholinguistics turned to the UK Biobank, a large-scale biomedical database that contains genetic data from thousands of individuals in the UK. Their research is published in Nature Communications.

Continue reading below...

Led by Dr. Clyde Francks, senior investigator in the language and genetics department at MPI, the scientists analyzed and compared exome data from 313,271 right-handed people and 38,043 left-handed people.

The collection of exons protein-coding DNA sequences in the genome is known as the exome.

A specific genetic variant was found to be much more common in left-handed people than right.

The beta-tubulin gene TUBB4B shows exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers than right-handers, the authors said.

TUBB genes encode proteins found in microtubules, which help to control the structure and movement of cells. Microtubules are prominent parts of the cytoskeleton the framework of protein filaments internal to cells that contributes to a wide range of processes including cellular growth, division, migration, shape and axis formation, axon outgrowth and intracellular transport, the researchers explained.

How microtubules affect variation in human handedness is not currently known. Previous research suggests a role in cellular chirality during brain development, which might impact the formation of the brains leftright axis.

Brain magnetic resonance imaging (MRI) data was only available for 13 of the UK Biobank TUBB4B variant carriers (left- and right-handers together), which is too small a sample for reliable association mapping with respect to brain structural or functional asymmetries, Francks and team said. Neither of the left-handed frameshift variant carriers had MRI data.

Some studies have identified TUBB genes as the underlying cause of incredibly rare neurological disorders. Intriguingly, mutations in TUBB2B can cause asymmetrical polymicrogyria (many and small folds) of the cerebral cortex, the researchers said. Mutations in TUBB3 can cause asymmetrical cortical dysplasia and unilateral hypohidrosis (reduced sweating on one side of the body, thought to be linked to disrupted function of the cortex, brain stem and spine). It may therefore be informative to collect brain MRI data from TUBB4B variant carriers in future studies, they add.

Reference: Schijven D, Soheili-Nezhad S, Fisher SE, Francks C. Exome-wide analysis implicates rare protein-altering variants in human handedness. Nat Comms. 2024;15(1):2632. doi: 10.1038/s41467-024-46277-w

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Is Left-Handedness Tied to Your Genetics? Possibly, New Study Suggests - Technology Networks

Genetics

A pan-genome of 69 Arabidopsis thaliana accessions reveals a conserved genome structure throughout the global … – Nature.com

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Genetics

Clemson researchers pave the way for precision medicine with AI – Clemson News

April 12, 2024April 12, 2024

Two people are prescribed the same drug to treat similar ailments. One patient quickly recovers, while the other realizes no real benefit from the course of treatment.

Why the same drug does not always produce the same result for different patients is part of what Clemson University researchers are trying to discoverin the realm of precision medicine.

Zhana Duren, an assistant professor in the Department of Genetics and Biochemistry, is delving into the genetic makeup of people to unlock the answer to this and other questions. He has co-authored a paper on the topic withpostdoctoral fellow Qiuyue Yuan. Both Duren and Yuan are at theClemson University Center for Human Genetics in Greenwood, South Carolina.

The researchers are using a novel approach by applying two relatively new tools big data and artificial intelligence to better understand the workings of gene-regulatory networks (GRNs), which are like roadmaps that show how genes, proteins and other substances interact uniquely from person to person.

GRNs map the complex interactions between genes, regulatory elements and proteins, holding the key to understanding how genetic variations influence phenotype like drug response, Duren explained. Each individual possesses a unique GRN shaped by their specific genotype, explaining why the same drug can elicit different responses in different people.

To interpret individual genetic variants within the context of unique GRNs, we aim to answer critical questions, (such as) how and why do genetic variants influence individual phenotypes through intricate GRN interactions, Duren said. By elucidating these mechanisms, we pave the way for predicting drug response based on personal genetics, enabling the development of more-targeted therapies and minimizing ineffective treatments.

The problem facing the researchers, according to Duren, is that most genetic variants linked to diseases are hidden in areas of our DNA that dont directly code for proteins. This makes it tricky to understand how they impact our health.

To help solve the riddle, Duren and Yuan turned to AI and big data analytics. Theydeveloped LINGER Lifelong Neural Network for Gene Regulation a novel deep learning-based method to infer GRNs from other cellular-level data.

With the help of the new tools, Duren and Yuan made discoveries that promise to more accurately predict how GRNs work.

There are many methods developed for gene regulatory network inference in the past two decades, Duren noted. However, our systematic benchmarking based on experimental data shows that the accuracies of these existing methods are about 17% to 29% higher than the random predictor. The new method increases it to 125% higher than the random predictor, showing four- to seven-fold relative increase.

Since this is a significant improvement in fundamental research, it will have the potential to lead discovery in broad biomedical research fields, he added.

The gains the two reported did not come without a variety of challenges. Chief among those was data sparsity.

Because it is single-cell data, the number of observations we get at each cell is so limited, Duren said. The gene regulatory network is such a complex problem that it requires large amounts of data to learn. But the available independent data we have data from many single cells, but they are not independent is not enough for this task.

The research has potential applications in a number of fields, according to Duren, including molecular biology, developmental biology and medical health research. Duren also noted the researchs potential for adding to the understanding of drug addiction, which could make it possible to develop more effective treatments.

Currently, we are applying this method in the field of drug addiction, he noted. I have three collaborations working on that; one is applying this to cocaine addiction.

The teams research was made possible in part through two National Institutes of Health grants for $2.2 million, which were awarded in 2023 and 2024, respectively.

The paper, Inferring gene regulatory networks from single-cell multiome data usingAtlas-Scale External Data, was published by the peer-reviewed top journal Nature Biotechnology.

Or email us at news@clemson.edu

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Clemson researchers pave the way for precision medicine with AI - Clemson News

Genetics

ACMG Foundation for Genetic and Genomic Medicine Elects Four Highly Accomplished Medical Genetics … – PR Newswire

BETHESDA, Md., April 11, 2024 /PRNewswire/ --The ACMG Foundation for Genetic and Genomic Medicine (ACMGF) announced today that Marilyn C. Jones, MD, FACMG; Harry Ostrer, MD, FACMG; Lisa G. Shaffer, PhD, FACMG and Katie Johansen Taber, PhD were elected to the Board of Directors of the ACMGF. The ACMG Foundation is a national nonprofit foundation dedicated to facilitating the integration of genetics and genomics into medical practice. The board members are active participants, serving as advocates for the ACMG Foundation and for advancing its policies and programs.

ACMG Foundation President Nancy J. Mendelsohn, MD, FACMG said, "We are pleased to welcome these four new members to the ACMG Foundation Board of Directors. Individually and combined they bring a new perspective along with their individual deep expertise. We are grateful for their enthusiasm and willingness to serve our genetics and genomics community."

Marilyn C. Jones, MD, FACMG

A Past President of the ACMG (2007-2009), Dr. Marilyn C. Jones is the Clinical Services Chief of the Genetics and Dysmorphology Division at Rady Children's Hospital in San Diego and a Distinguished Professor of Clinical Pediatrics at the UC San Diego School of Medicine.She has served as the Medical Director of the Helen Bernardy Center for Medically Fragile Children for more than 40 years. With expertise in providing detailed patient phenotyping to aid gene discovery, Dr. Jones's career has focused on identifying underlying causation among patients with cleft and craniofacial disorders. In 2020 she received the David Bixler Distinguished Scientist in Craniofacial Research Award from the Society for Craniofacial Genetics and Developmental Biology, as well as the David W. Smith Award for Excellence in Genetics and Birth Defects Education from the American Academy of Pediatrics.

"I am honored for the opportunity to serve the ACMG again through participation in the Foundation Board of Directors. The Foundation provides many of the resources that help the College move forward its agenda to help both the public and its members," said Dr. Jones.

Harry Ostrer, MD, FACMG

Dr. Harry Ostrer is Professor of Pathology and Pediatrics at Albert Einstein College of Medicine. From 1990-2011, he was the Director of the Human Genetics Program at New York University Langone Medical Center. His academic focus is in studying the genetic basis for common and rare disorders and developing new functional genomic technologies. Dr. Ostrer is also a long-time investigator of the genetics of the Jewish people and Hispanic and Latino people. In 2007, he organized the Jewish HapMap Project, an international effort to understand origins, migration and disease predispositions by mapping and sequencing the genomes of Jewish people. At his start-up company, Morgan and Mendel Genomics, Dr. Ostrer advises about translating the findings of novel functional genomic discoveries into tests that can be used to identify people's risks for having cancer or for predicting cancer's response to therapy.

"My professional career has been entwined with creating opportunities for others in medical genetics by training them, sometimes through training programs that I created. But part of passing the mantle of achieving 'better health through genetics' for everyone is to support even larger and scalable opportunities," said Dr. Ostrer. "I am delighted to have the means to do so by joining old and new friends on the Board of Directors of the American College of Medical Genetics Foundation, whose philanthropic mission is to fund new programs and research."

Lisa G. Shaffer, PhD, FACMG

Dr. Lisa G. Shaffer is founder and the former CEO of Genetic Veterinary Sciences, Inc. (DBA Paw Print Genetics), a canine, feline and avian genetic testing company serving breeders, veterinarians and owners. The company was acquired in 2021. Prior to that enterprise, she was co-founder, President and CEO of Signature Genomic Laboratories, the first diagnostic laboratory to offer clinical microarray testing for children with developmental disabilities. The recipient of numerous accolades for her entrepreneurship and business savvy, Dr. Shaffer was previously a tenured Professor of Molecular and Human Genetics at Baylor College of Medicine (1991-2002) and in the School of Molecular Biosciences at Washington State University (2002-2008). Dr. Shaffer has authored more than 340 peer-reviewed medical papers and four books.

"I am very excited to be rejoiningthe ACMG Foundation Board of Directors and look forward to supporting the mission of the ACMG and helping to raise awareness of medical genetics and promote its achievements. Medical genetics touches every aspect of human health, and this is an exciting time to be a part of the Foundation," said Dr. Shaffer.

Katie Johansen Taber, PhD

As the Vice President of Clinical Product Research & Partnerships at Myriad Genetics, Dr. Katie Johansen Taber's focus is on developing evidence and advancing initiatives to improve access to genetic testing in the areas of women's health, oncology and mental health.She leads a team responsible for clinical evidence strategy, real-world evidence development, clinical trial conduct and scientific publications. Prior to her current position, Dr. Johansen Taber was Senior Director of Clinical Development at the company's Women's Health business unit. Before joining Myriad Genetics, she served at the American Medical Association (2006-2017), where her work centered on educating healthcare professionals about the clinical implementation of genomics and precision medicine, and on identifying and managing precision medicine policy issues. Dr. Johansen Taber has held numerous positions on advisory committees and boards, including a current appointment on the National Academy of Sciences, Engineering and Medicine Roundtable on Genomics and Precision Health.

"I'm thrilled to be elected to the ACMG Foundation Board of Directors and I look forward to working together to improve access to genetic testing," said Dr. Johansen Taber. "The Foundation's focus on evidence-based guidelines development, education and advocacy are important initiatives in realizing the ability to provide genetics-informed care to all patients who need it."

ACMGF Also Announces New Board Position and Thanks Outgoing Board Members

In addition,Brynn Levy, MSc. (Med), PhD, FACMG, who joined the ACMG Foundation Board of Directors in 2019, was named to the newly created officer position of President-Elect.

The ACMG Foundation also thanked the following board members who recently completed their terms of service: Nasha Fitter, MBA; Evan Jones, MBA and, in particular, David A.H. Whiteman, MD, FAAP, FACMG, who joined the Foundation Board of Directors in 2014 and served admirably as its Vice President since 2017.

A complete roster of the ACMG Foundation Board can be found at http://www.acmgfoundation.org.

About the ACMG Foundation for Genetic and Genomic Medicine

The ACMG Foundation for Genetic and Genomic Medicine, a 501(c)(3) nonprofit organization, is a community of supporters and contributors who understand the importance of medical genetics and genomics in healthcare. Established in 1992, the ACMG Foundation supports the American College of Medical Genetics and Genomics (ACMG) mission to "translate genes into health." Through its work, the ACMG Foundation fosters charitable giving, promotes training opportunities to attract future medical geneticists and genetic counselors to the field, shares information about medical genetics and genomics, and sponsors important research. To learn more and support the ACMG Foundation mission to create "Better Health through Genetics" visit acmgfoundation.org.

Contact: Kathy Moran, MBA [emailprotected]

SOURCE ACMG Foundation for Genetic and Genomic Medicine

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ACMG Foundation for Genetic and Genomic Medicine Elects Four Highly Accomplished Medical Genetics ... - PR Newswire

Genetics

Katie Gallagher MS ’15, CGC Named Director of the Joan H. Marks Graduate Program in Human Genetics at Sarah … – Sarah Lawrence College

The Joan H. Marks Graduate Program in Human Genetics at Sarah Lawrence Collegethe oldest and largest graduate program of its kindhas named alumna Katie Gallagher, CGC as its new director.

Katie intimately understands the missions and strengths of both the program and the College and the intricate web of relationships that help the program thrive, said Dean of Graduate & Professional Studies Kim Ferguson. She has demonstrated a relentless drive to make a meaningful impact on the world of genetics, and I am excited to see her bring that drive to her new role as director.

A 2015 graduate of the program, Gallagher has served in a number of roles, including clinical supervisor, course instructor, and, most recently, assistant director, since joining the Human Genetics program staff in 2016. An accomplished certified genetic counselor and educator with proven success in settings of innovation and rapid evolution, Gallagher has experience in clinical pediatric genetics, laboratory genetics services, and genomics research.

I take pride in shaping the future of genetic counselors and recognize the colossal reputation our program has, said Gallagher. I see the program as forward-thinking and a beacon of innovation, capable of guiding the profession towards positive change, and Im excited to be part of that work.

One particular area of focus as Gallagher takes the reins is a commitment to promoting diversity, equity, inclusion, and belonging within the program and in the genetic counseling profession. I fervently believe that diversity is not just an aspiration but an essential driver of progress in our field, she said.

Gallagher succeeds Claire Davis, EdD, MS, CGC, who has been the director of the Human Genetics program since 2018. Davis is moving on to a new role as co-director of the Master of Science in Genome Health Analysis program, a partnership between NYU and Sarah Lawrence College. She is also the Director of Curriculum for Sarah Lawrences Institute for Genomics Education, Workforce, and Leadership and will remain on the Human Genetics program faculty.

Gallagher will begin her tenure as director on May 1, 2024.

Founded in 1926, Sarah Lawrence is a prestigious, coeducational liberal arts college that consistently ranks among the leading liberal arts colleges in the country. Sarah Lawrence is known for its pioneering approach to education, rich history of impassioned intellectual and civic engagement, and vibrant, successful alumni. In close proximity to the unparalleled offerings of New York City, the historic campus is home to an intellectually curious and diverse community.

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Genetics

The genomic architecture of inherited DNA variants – Baylor College of Medicine | BCM

Image courtesy of the National Human Genome Research Institute

You have your mothers eyes and your fathers smile, but genetics is much more than just whats on the surface. In a study that spans more than a decade, researchers at Baylor College of Medicine have looked at generations of families in a specific population to reveal the role newly inherited DNA variants play on recessive disease traits, and in the process, they have created a population specific database revealing unique DNA information unseen in larger cohorts.

The findings, now published inGenetics in Medicine OPEN, revealed a correlation between occurrences of complex genetic disorders in those families with increased levels of consanguinity when compared to unaffected populations. Consanguinity is when both parents contribute similar genetic markers to an offspring, such as by sharing a common ancestor, and the genetic information from both the genome inherited from the father and that from the mother are identical.

We observed that the areas on the chromosome known as ROH, regions of homozygosity, were longer in those individuals in which there was a higher degree of parental consanguinity when compared to those with less, saidDr. Zeynep Coban-Akdemir, postdoctoral associate in molecular and human genetics at Baylor and currently assistant professor at UTHealth School of Public Health as well as co-lead author on the study. We can see what is happening when consanguinity is at play and also when new genetic variations are introduced into the family unit of the clan or tribe representing more distant ancestors.

Dr. Xiaofei Song, a former Baylor graduate student now working as an assistant professor at Moffitt Cancer Center, said, We further applied a statistical method to systematically assess the impact of these genetic variations on disease. Our results indicate that the newly introduced genetic variations can better explain the clinical features observed in our patients. Song also is co-lead author on the study.

The published study contributes to the field of both rare disease and population genomics. From a trainee perspective, the article provides a valuable resource for comprehending fundamental concepts of human genetics and applying diverse computational methods to elucidate these concepts, said Ph.D candidate Tugce Bozkurt-Yozgatli, with the Acibadem University in Istanbul, Turkey.

Coban-Akdemir, who worked in the Lupski Lab at Baylor where the research was conducted, says this is an important part of the findings because it reveals how genes act within different populations and clans to contribute to different recessive genetic disorders.

The population studied was a cohort of individuals originating from Turkey that is known to have different variations in genetic markers when compared to other populations from greater Europe. Researchers created and analyzed a database of variants derived from exome sequencing, a genomics assay providing a glimpse into genetic variation genomewide, of 773 unrelated volunteers who were affected with various suspected rare Mendelian disease traits, which are diseases caused by a mutation in a single gene and clearly passed down from one generation to the next in accordance with Gregor Mendel expectations. They were compared to another database created by the same researchers of 643 unaffected relatives.

Roughly half of the genetic variants in this Turkish group are not present in greater European control populations that are found in shared databases commonly used by genetic researchers.

This group of Turkish individuals and families gives us insight into genetics that the average population doesnt provide. What we found in this Turkish population is very unique. Not only is this group underrepresented in larger databases, but it shows us that they have an enriched genetic variation that is only seen within this population when compared to European populations, Coban-Akdemir said.

Dr. Davut Pehlivan, assistant professor of pediatrics neurology at Baylor, said on a single individual there are around 40 million Watson-Crick base pair variations within our DNA.

The Human Genome Project opened the doors for researchers to investigate entire genomic DNA complement using next-generation sequencing technology. However, more struggles appeared with these advancements. For example, it is hard to pinpoint which variant is causing disease among 40 million variations of our DNA. Studying healthy populations helps us to eliminate many of these common variations from consideration. Thus, we studied both patients and their healthy relatives in the Turkish population, Pehlivan said. There are a lot of changes in the genome, and we dont fully understand the meaning of all of those details, but the data from this population study will help all investigators around the world who are trying to interpret the results of other variants in the human genome DNA.

Pehlivan described gathering the information and families wanting to participate in genomics research beginning in 2010, traveling long distances to rural areas where the patients were mostly located, a human interest story itself, to make sure the database and clinical information would show an accurate representation for these families.

We discovered more than 200 genes that contributed to the existing body of disease gene associations. This will help us get closer to understanding, in this population and in others, what is causing these diseases and the human biological perturbation underlying a broad scope of diseases. Our studies will open new avenues of research in human biology and genome biology and eventually help to potentially bring nucleic acid treatments, something used to develop the COVID vaccine, to the patients and families Pehlivan said.

This team of researchers is not just helping the population that they studied, but their findings also can be applied to many populations. We all are very different individuals on this planet, yet our genes act very similarly, and we all share a common humanity. So, understanding how genetic disorders work helps us to support affected families across the globe, saidDr. James R. Lupski, the Cullen Foundation Endowed Chair in Genetics and Genomics at Baylor.

In the past, Coban-Akdemir and Dr. Claudia M.B Carvalho, previously with Baylor and currently in her own laboratory at the Pacific Northwest Research Institute (PNRI) in Seattle who also contributed to this study, have worked on studying variants of genes to identify causes of diseases through production of truncated or altered proteins that take on a new or different function. Their work also focused on databases of populations with and without genetic disease. Their current work reflects the importance of diversity and inclusion as work continues to reveal causes of genetic diseases.

This work was supported in part by the U.S. National Human Genome Research Institute /National Heart Lung and Blood Institute grant number UM1HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG), the U.S. National Human Genome Research Institute U01HG011758 to the Baylor College of Medicine for the Genomics Research to Elucidate the Genetics of Rare Disease consortium (BCM-GREGoR), the National Institute of Neurological Disorders and Stroke Q22 (NINDS) R35NS105078, and the National Human Genome Research Institute U54-HG003273. J.E.P. was supported by NHGRI K08 HG008986.

Other authors who contributed to the study include: Francisco C. Ceballos, Ender Karaca, Yavuz Bayram, Tadahiro Mitani, Tomasz Gambin, Tugce Bozkurt-Yozgatli, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Lewis, Pengfei Liu, Eric Boerwinkle, Ada Hamosh, Richard A. Gibbs, V. Reid Sutton, Nara Sobreira, Claudia M.B. Carvalho, Chad A. Shaw, Jennifer E. Posey, David Valle. They are affiliated with the Department of Molecular and Human Genetics, Baylor College of Medicine; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute; Instituto de Salud Carlos III, National Center of Microbiology, Madrid, Spain; Section of Neurology, Department of Pediatrics, Baylor College of Medicine; Sanford Medical Genetics Laboratory, Sanford Imagenetics; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Childrens Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania; Institute of Computer Science, Warsaw University of Technology; Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; Human Genome Sequencing Center, Baylor College of Medicine; Department of Pediatrics, Baylor College of Medicine; Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine; Texas Childrens Hospital; Pacific Northwest Research Institute; Baylor Genetics. To view list, along with author contributions, conflicts of interest and ethics declarations, clickhere.

By Graciela Gutierrez

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The genomic architecture of inherited DNA variants - Baylor College of Medicine | BCM