Find our the lastest about what HudsonAlpha Institute for Biotechnology is researching. See how genomics is improving lives.
RESEARCH REPORT
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contents
From the Desk of Dr. Rick Myers ............................................................................................... 5
Foundational research . ................................................................ 6 Mapping the Regulatory Regions of the Human Genome . ..................................................... 8–11 Uncovering the Genetics of Plant Reproduction ................................................................. 12–13 Cracking the code of complexity in human DISEASE ........14 Diseases of the Brain ....................................................................................................... 16–17 Harnessing Genetic Data to Diagnose and Treat Neurodevelopmental Disease .................... 18–19 Discovering Targets for Better Quality-of-life Treatments ................................................... 20–21 Unraveling the Genetic Mysteries of Neurodegeneration ................................................... 22–25 Overcoming Challenges in Cancer Diagnosis and Therapy with Genomics .......................... 26–27 UNLOCKING NATURE’S POTENTIAL: GENOMICS IN CROP IMPROVEMENT . ................................................28 Crop Improvement Utilizing Genomics in Plants . ............................................................... 30–31 Empowering the Global Peanut Community ...................................................................... 32–33 A Greener Tomorrow: Perennial Grasses for Sustainable Bioproducts ................................ 34–37 Unraveling the Genetics of Saponin Biosynthesis ............................................................... 38–39 ILLUMINATING THE UNKNOWN: TOOLS FOR GENOMIC INSIGHTS ........................................................40 Advancing Genomic Research: The Power of High-Quality Reference Genome..................... 42–43 The Power of Pangenomes in Agricultural Breeding Programs....................................... 44–45 Tools for Investigating Transcription Factors..................................................................... 46–47 CULTIVATING THE FUTURE: TRAINING THE NEXT GENERATION OF GENOMIC LEADERS ..........48 Over a Decade of Training the Next Generation of Genomic Leaders .................................... 50–53 Student Scientists Help Select the First Peanut in Drought Trials ....................................... 54–55 Inspiring Students Through Hands-on Research ................................................................ 56–57 Profiles in Genomic Expertise ...................................................58 HudsonAlpha Faculty, Adjust Faculty and Scientific Advisory Board . ................................... 60–65 References, Funding and Contributors . .................................................................................. 68
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The Power of Thought
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FROM THE DESK OF CHIEF SCIENTIFIC OFFICER RICK MYERS, PHD T he power of genomics to improve human health and our understanding of the natural world continues to unfold. At HudsonAlpha, we remain at the forefront of this revolution, harnessing the latest advancements in genetic and genomic research to address some of the most pressing challenges of our time. The two years since our last report were filled with groundbreaking discover- ies, grant funding victories, celebrating trainee accomplishments, and much more. Our researchers authored more than 85 scientific papers and secured more than $10 million in grant funding in 2024. We also hosted two international conferences that brought hundreds of researchers from around the world together on HudsonAlpha’s campus. Six of our talented graduate students successfully defended their PhD dissertations, showcasing the exceptional training and research opportunities we provide. These emerging scientists are now making significant contributions to the field, thanks in part to the strong foundation they received at HudsonAlpha. 2023 marked a significant milestone as we celebrated our 15th anniversary. That year, we successfully hosted numerous public events to mark the occasion, and now the event series is a mainstay on our calendars. Throughout 2024, we hosted 9 public events with more than 4,280 attendees. These events help our community engage with our work, grow support for our research, and deepen our community’s appreciation for genomic science. We are also proud of the expansion and maturation of our training pipelines. Programs like AOMA internships and BRIDGES fellowships provide invaluable opportunities for students from untapped populations to gain hands-on research experience. By fostering a culture that promotes belonging and values the contributions of all of our members, we are cultivating the next generation of genomic scientists and making STEM a more equitable and accessible field. We expanded the reach of our doctoral training programs, with current students training in HudsonAlpha labs now enrolled at Alabama A&M, Auburn University, UAB, UAH, and the University of Georgia. As we look ahead, we remain committed to a future where genomics unlocks the secrets of human health and illuminates the wonders of nature. We are excited to share the latest find- ings from our research programs and to continue our work as a catalyst for innovation and discovery.
Richard M. Myers, PhD Chief Scientific Officer President Emeritus M. A. Loya Chair in Genomics Faculty Investigator
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POWERING DISCOVERY IN GENOMICS
•••
We must not forget that when radium was discovered, no one knew that it would prove useful in hospitals.
—MARIE CURIE, PHD
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MAPPING the regulatory OF THE HUMAN GENOME
T he human genome, once an un- decipherable code, is now more easily and completely understood than ever. After the completion of the first human genome sequence in 2003, researchers were left with the monumental task of figuring out what parts were functionally important. It became apparent that only about one percent of the human genome codes for proteins that play important roles in the cells throughout our bodies. The vast majority of our genome was thought to be non-coding. These often-overlooked portions of DNA emerged as key players in the field of genetics. Many of these non-coding regions act as in- tricate DNA switches, controlling when and where genes are turned on and off. This process, called gene regulation, is important in all normal func- tions of our bodies, including cell differentiation, response to environmental changes, development, and growth. Dysregulation of gene regulation can lead to disease. By understanding gene regulation and how it changes in response to the environment, during differentiation, and during development, re- searchers are unlocking new frontiers in medicine, with the potential to develop targeted therapies for a wide range of conditions.
ENCODE’s legacy lies not only in its groundbreaking discoveries but also in its commitment to open data, fostering the strong
spirit of collaborative innovation we see today.
—Rick Myers, PHD
ENCODE group early days
THE ENCODE PROJECT: PIONEERING BREAKTHROUGHS IN GENE REGULATION
After the first human genome was sequenced, a new era of genetic discovery was unfolding. A major con- tributor to this endeavor was a team led by Faculty Investigator Rick Myers, PhD , who played a signifi- cant leadership role in the Human Genome Project. One of the most notable contributions of Myers’
cont. on p. 10
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regions
Chris Partridge, PhD, retrieving cells from cold storage to use in experiments.
ENCODE at a Glance n The Myers Lab joined ENCODE when it launched in 2003, first participating in the pilot project aimed at annotating one percent of the human genome and then joining the full genome effort in 2007.
n The lab moved to HudsonAlpha in 2008.
n The Consortium produced more than 15 terabytes of raw data.
n Through ENCODE, dozens of protocols for looking at the functionality of genetic regions were developed or adapted, several from the Myers group, including ChIP-seq, RNA sequencing, CETCH-seq, and DNA methylation.
n The Consortium discovered more than a million DNA switches and hundreds of transcription factors that bind them.
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and deposited in the ENCODE data repository has empowered thousands of researchers worldwide to make discoveries in human diseases, from cardio- vascular disease to bipolar disease. ENCODE also produced numerous protocols for genome-wide functional analysis that have become standards in the field. The project led to the identification of more than a million DNA switches and made significant head- way into understanding the 1,600 or so DNA-binding proteins called transcription factors, better under- standing how they turn genes on or off or determine the levels of gene expression in different cell types and at different times during development. Throughout the ENCODE Project, Myers and his lab, in collaboration with Dr. Eric Mendenhall at HudsonAlpha and Dr. Barbara Wold at Caltech, conducted the largest study of transcription factors expressed at normal levels to date. They generated hundreds of genome-wide datasets that measure transcription factor binding sites in the human genome, identified RNA transcripts in mouse and human cells, and identified DNA methylation sites throughout the human genome. By expanding the catalog of known transcription factors and their functions, Myers and his lab helped unlock new ave- nues for medical innovation, enabling researchers to navigate the complexities of human biology and identify potential therapeutic targets.
lab has been its pivotal role in the Encyclopedia of DNA Elements (ENCODE) Project . This ambitious international effort aimed to characterize all of the functional elements within the human genome, in- cluding both protein-coding genes and non-coding elements that regulate gene activity. It also sought to understand how these components interact in biological processes. The ENCODE Consortium, funded by the National Human Genome Research Institute (NHGRI) , spanned two decades and included more than 30 institutions and 500 scientists worldwide. It made monumental strides in advancing our knowledge of the human genome, maintaining the large-scale, open-access data release championed by the Human Genome Project. The wealth of pub- licly accessible data generated by the Consortium
BEYOND ENCODE: SEARCHING FOR BRAIN-SPECIFIC TRANSCRIPTION FACTORS
The ENCODE Project’s legacy will live on for de- cades as researchers utilize the vast amounts of data generated by the Consortium. For their part, Myers and his lab are just getting started. In late 2023, they published a comprehensive analysis of the binding of 680 human transcription factors and how they regulate gene expression patterns in HepG2 cells, a type of human liver cancer cell with extensive ENCODE data 1 . Transcription factors play a crucial role in gene regulation by binding to cis-regulatory elements (CREs), short stretches of DNA near the genes they regulate. ChIP-seq is a powerful technique that
BrainTF, a comprehensive resource that maps the binding sites of more than 100 transcription factors in human postmortem brain tissue.
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Tess Vessels, PhD, Marshae Scott, and Jacob Loupe, PhD, looking at transcription factor expression data.
reveals how proteins interact with DNA. By leveraging the vast amount of ENCODE ChIP-seq data, Myers and his team found that most known candidate CREs are bound by at least one of the 680 assayed DNA-associated proteins, suggesting that this research has identified a significant portion of the regulatory elements in the human genome. The study not only confirmed the binding of many known transcription factors to their target genes but also uncovered novel transcription fac- tors and regulatory relationships. These findings provide valuable insights into the complex net- work of gene regulation in human cells and may have significant implications for understanding human disease and developing targeted thera- pies. The work highlights the enduring impact of the ENCODE Project and sets the stage for future discoveries in the field of gene regulation. While large-scale datasets like ENCODE have provided valuable insights into gene regulation, their reliance on cancer-derived cell lines of- ten limits their ability to accurately capture the complexities of gene expression in diverse human tissues, particularly the brain. In early 2024, Myers and his lab made a significant contribu- tion to the field of neuroscience by publishing
BrainTF , a comprehensive resource that maps the binding sites of more than 100 transcription factors in human postmortem brain tissue 2 . The study represents the largest dataset to date on transcription factor binding in human neurolog- ical cells, offering unprecedented insights into the intricate regulatory mechanisms governing gene expression in the brain. This brain study identified many novel transcription factor binding sites not found in existing databases, highlighting the unique aspects of brain regulation. The valuable data generated from this study is publicly available. By providing open access to this comprehensive resource from difficult-to-obtain brain tissues, the researchers aim to empower the scientific community to delve deeper into the intricate mechanisms of brain function and dysfunction, ultimately accelerating the development of novel therapeutic strategies for psychiatric illness- es. Further experiments are being done in the Myers Lab to understand the regulation of genes that cause neurodegenerative diseases and include ways of possibly mitigating the effects of these mutant genes. ■
Read this Everyday DNA blog article to learn more.
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Plant reproduction
UNCOVERING GENETIC ANSWERS
Visiting researcher T.J. Singh preparing DNA samples from hemp plant leaves.
P lant breeding and global food production hinge on the delicate process of pollina- tion, wherein pollen from the male part of a flower is transferred to the female part, enabling fertilization and seed pro- duction. While it may seem simple, the intricacies of floral reproduction are far from straightforward. Plants can be either male or female (dioecious) or both (hermaphroditic). Some species can even change sex over their lifespan, adding a layer of complexity to this essential biological function. Understanding this complex process is crucial for modern agriculture. It is particularly important for species where one sex is more desirable than the other. For instance, female hops yield the prized cones used in brewing, male asparagus plants have a longer lifespan, and hermaphroditic papaya fruits offer superior flavor compared to female fruits.
By unraveling the genetics underlying plant sex determination, scientists can develop innovative breed- ing strategies to improve crop yields and quality.
UNDERSTANDING THE GENETIC MECHANISMS THAT DETERMINE PLANT SEX HudsonAlpha Faculty Investigator Alex Harkess, PhD , and his lab are at the forefront of this exciting research. They are diving into plant genomes to unravel the mysteries of sex determination and exploring how to harness this knowledge to improve agriculture. To date, sex-determination genes have been definitively identified in fewer than ten plant species, and Harkess made a significant contribution to their discovery in garden asparagus.
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proportion of female plants and significantly boost- ing the yield of fiber, oil, and protein. This ground- breaking research has the potential to revolutionize hemp cultivation, making it a more sustainable and profitable crop for farmers while providing consum- ers with high-quality, eco-friendly products.
Nicole Stark and Sarah Carey, PhD, analyzing sex chromosome characterization data.
TRACING SEX CHROMOSOME EVOLUTION TO UNDERSTAND PLANT REPRODUCTION
Male Amborella flower
Thanks to support from an NSF CAREER grant , Harkess and his lab are characterizing sex chro- mosomes and sex-determining genes across every order of flowering plants, the largest genomic sampling of dioecious plant species to date. To help them achieve that monumental goal, the lab devel- oped a pipeline called Cytogenetics-by-Sequencing (CBS) to more easily and inexpensively identify and characterize sex chromosomes in plants. So far, they have successfully used the CBS pipeline to dis- cover new sex chromosomes in nearly 30 dioecious plant and animal species. The immense amount of data produced during this study will serve as an invaluable resource for plant breeding. Harkess’s team plans to use the information to identify new genes that control sex in plants and engineer artificial sex chromosomes to genetically modify hermaphroditic crops. This could revolutionize agriculture by giving farmers unprec- edented control over plant sex determination, allow- ing them to cultivate only desired sexes, accelerate breeding programs, reduce unwanted pollination, and adapt plants to changing environments. Industrial hemp is a specific crop that will benefit from the Harkess lab’s work. This versatile crop has a rich history and has been used for centu- ries for a wide variety of purposes, including fiber, grain, and oil. Female hemp plants are particularly valuable due to their higher biomass production and exclusive ability to yield seeds rich in beneficial lipids and proteins. Through a USDA-NIFA-funded grant , Harkess and his lab, along with collaborators at New West Genetics, will interrogate the hemp sex chromosomes to identify the master sex determina- tion genes in hemp. Manipulating these genes could allow for precise control of plant sex, increasing the
Studying sex-determination genes can help us understand how plant reproduction has evolved over time. Flowering plants, which the Harkess lab studies extensively, have evolved dioecy independently hundreds of times, making them an ideal model for studying the evolution of plant reproductive systems. Amborella trichopoda , a fascinating dioecious plant, offers a glimpse into the early evolution of flowering plants. As the only living species in the sister lineage to all other flower- ing plants, it offers a valuable reference point for studying the evolution of sex determination. Comparing Amborella ’s genetics to other flowering plants can help researchers trace the evolution of dioecy and other reproductive strategies. In 2024, the Harkess lab published the most complete and accurate Amborella genome to date in Nature Plants 1 . Using advanced sequencing techniques, the team assembled highly contiguous genome sequences, including the Amborella Z and W sex chromosomes, which are historically difficult to assemble. The team determined that Amborella ’s sex chromosomes evolved after it split off from other living flowering plants. This allowed them to examine the early stages of sex chromosome evolution and identify potential sex-determining genes. Understanding the genetic mechanisms that led to dioecy in Amborella could help develop controllable sex determination systems in agri- cultural crops. This research provides a strong foundation for studying sex chromosome evolution in all flowering plants. ■
Read this Everyday DNA blog article to learn more.
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CRACKING
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OF COMPLEXITY IN HUMAN DISEASE
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Genetics is a powerful tool for unlocking the mysteries of human health and disease.
— francis Collins, MD, PhD
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diseases
OF THE BRAIN
T he human brain is a complex, three-pound organ responsible for everything from our simplest reflexes to our most intricate thoughts. Made up of a network of billions of neurons, it processes sensory information, controls our movements, regulates vital functions, and enables us to learn, reason, and create.
THE GENETIC CAUSES BEHIND DISEASES OF THE BRAIN ARE QUITE COMPLEX, BUT GENOMICS IS A POWERFUL TOOL THAT ENABLES US TO FIND MISSING PIECES OF THE PUZZLE.
—rick myers, PHD
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In the human brain, some 86 billion neurons form 100 trillion connections to each other — powering our thoughts, actions and dreams.
Our brains are constantly working. Different regions of the brain specialize in specific tasks, such as the visual cortex for sight, the auditory cortex for hearing, and the prefrontal cortex for decision-making and planning. Our brains make us who we are. They define our personalities, shape our memories, and guide our decisions. Therefore, when things go wrong with the brain, the consequences can be devastating. Diseases of the brain can manifest in various forms, depending on the affected region and the underlying cause. In early development, if the brain does not form properly, developmental problems and neurodevelopmental disorders can occur. As we age, the abnormal destruction of brain cells can lead to neurodegenerative diseases.
At HudsonAlpha, we are committed to unraveling the mysteries of the brain from early development throughout life. By harnessing the power of genomics, we are delving deep into the genetic blueprint that underlies both the healthy and diseased brain. Our goal is to transform lives by accelerating the diagnosis and treatment of brain disorders. By understanding the genetic factors that contrib- ute to these conditions, we aim to eliminate the often-frustrating diagnostic odyssey, help develop more effective, targeted therapies, and create innovative tools for early detection. This could lead to significant improvements in the quality of life for millions of people affected by brain disorders. ■
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HARNESSING GENOMIC DATA TO BETTER DIAGNOSE AND TREAT RARE NEURODEVELOPMENTAL DISEASES E very year, millions of children are born with neurodevelopmental disorders that can affect their communication, learn- ing, behavior, and social interactions. These developmental delays can lead to lifelong challenges for both the child and their families. Compounding these challenges is the fact that many of these disorders are hard to diagnose, leaving children and their families searching for answers. HudsonAlpha Faculty Investigator Greg Cooper, PhD , and his lab are experts at using genome sequencing to revolutionize the diagnosis of rare neurodevelopmental disorders while also identifying new genetic contributors to these disorders.
Thanks to advances in genomic technology, it is now clear that many neurodevelopmental disorders are caused by changes in an individual’s genome that interfere with critical developmental processes. The Cooper and Kodani (p. 20) labs at HudsonAlpha focus their research on better understanding the genetic basis of neurodevelopmental disorders. Their goal is to help families receive a faster diagnosis, support from the moment of diagnosis, and the knowledge and tools they need to navigate their health journey with greater confidence. ENDING THE DIAGNOSTIC ODYSSEY ONE GENOME AT A TIME Geneticists have identified over 1,500 genes associated with neurodevelopmental disorders. Although this helps about one-third of patients with neurodevelopmental diseases receive a genetic diagnosis, many patients remain without an answer. There are likely still thousands of undiscovered ge- netic contributors to neurodevelopmental diseases.
Since 2013, Cooper and his lab have sequenced the genomes of nearly 2,000 children, providing over 40 percent with a genetic finding that may be relevant to their symptoms.
Pictured above: Susan Hiatt, PhD and Donald Latner, PhD, reviewing long-read sequencing data to find genetic variants that could be responsible for patient symptoms.
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Much of the work in the Cooper lab involves heavy computational analysis. Here, Greg Cooper, PhD, analyzes genome sequence data.
identified in sixteen individu- als (16%), eight of which had pathogenic or likely pathogenic variants.
Over the past decade, Cooper’s lab has kept up with advancing technology, adjusting their sequencing methods from exome sequencing to short-read genome sequencing to the newest technology, long-read genome sequencing. Long-read genome sequencing provides a far more comprehensive view of the genome, allowing scientists to identify many genetic variants that traditional sequenc- ing methods may miss. One type of variation that shows great promise in diagnosing rare diseases is structural variants. These include large deletions, duplications, inversions, translocations, and more complex events that can disrupt gene function, resulting in diseases. Dr. Cooper and his team feel confident that they will identify many variants with long-read genome sequencing that might be responsible for some individuals’ symptoms. In a study recently published in Genome Research , the Cooper lab performed long-read genome sequencing on 96 individuals who had received no diagnostic results from short-read sequencing 1 . New disease-relevant or potentially relevant genetic findings were
Because of the promising results from this study, Cooper and his lab, along with the HudsonAlpha Genome
Sequencing Center , were awarded a five-year, $2.9 million National Institutes of Health (NIH) grant to use long-read sequencing to re-sequence hundreds of genomes from individuals who previously had genome sequencing with no diagnostic results. In addition to potentially helping diagnose dozens of individuals, the study will allow computational biologists in the Cooper lab to continue updating and improving their analysis pipeline to identify more genetic variants in future individuals. ■
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Discovering targets FOR BETTER QUALITY-OF-LIFE TREATMENTS
H udsonAlpha’s newest Faculty opmental diseases. Kodani and his lab work closely with clinicians and patient groups to identify genetic causes of disease in cohorts of patients with similar conditions. Once a potential genetic contributor is identified, the team uses various experimental systems to val- idate its role in neurodevelopment, a complex pro- cess involving intricate interactions between various developmental signaling pathways that regulate the proliferation, differentiation, and migration of neural stem cells. They are particularly interested in the WNT and mTOR signaling pathways, which regulate neural progenitor cell proliferation in the developing brain. Disruptions in these pathways during development Investigator, Andrew Kodani, PhD , aims to use genetics to better understand healthy brain development and what goes wrong in neurodevel-
can lead to brain size and function abnormalities, as seen in conditions like autism spectrum disorder and microcephaly. The Kodani lab aims to better understand how genetic changes in neurodevelopmental disorders disrupt these signaling pathways and contribute to brain disease. By targeting these pathways, they hope to develop new therapies that can improve cognitive and social behavioral issues in individuals with neurodevelopmental disorders. Genetic and molecular information opens numerous doors for individuals and their families. It allows them to seek out resources, patient groups, and, most importantly, potential treatment options. The Kodani lab helps patients diagnosed with rare neurodevelopmental disorders by connecting them with appropriate physicians, hospitals running clinical trials, and support groups.
Members of the Kodani lab discussing an experiment. (L to R, Anamika Gupta, Matthew Kneusel, PhD, Lauren Kneeland, and Nafisa Nuzhat, PhD)
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Nafisa Nuzhat, PhD, and Matthew Kneusel, PhD, looking at Western blot results.
Receiving care from a specialist allows individuals to receive specific interventions to improve their quality of life. Non-pharmaceutical interventions like therapy help improve the quality of life for some patients, but often, patients benefit most from drug treatment. The Kodani lab uses genetic and molecular information to identify potential drug treatments (including clinical trials) for patients with rare diseases. Sometimes, that is as simple as identifying an existing drug that will help the patient. By screen- ing hundreds of thousands of drugs in publicly available drug libraries, Kodani and his lab try to find potential compounds that will help re-establish the signaling pathways that went awry in neuro- developmental diseases. Their ultimate goal is to repurpose FDA-approved drugs for use in patients with rare diseases. In other cases, the scientists get creative and look toward natural compounds or dietary changes that could modulate the broken pathway, thus improving the quality of life in indi- viduals with neurodevelopmental disorders. ■
I truly believe that every child deserves a happy childhood. I know we can’t fix every disorder, but we won’t let families continue to face uncertainty alone.
—ANDREW KODANI, PHD
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Unraveling the genetic MYSTERIES OF NEURODEGENERATION
Quinn Johnston is a former BioTrain intern who is now a research associate in the Cochran lab.
N eurodegenerative diseases, including Alzheimer’s disease and other demen- tias, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), pose a significant global health burden. These devastat- ing diseases are characterized by the progressive damage and loss of brain cells that lead to declines in cognitive function, movement, and other bodily functions over time. The exact causes of these diseases are unknown but are believed to be a combi- nation of genetic and environmental factors. Understanding the genetic basis of these diseases is crucial for several reasons. Identifying specific
genetic markers associated with different neurodegenerative diseases can lead to earlier and more accurate diagnoses. Genetic information also helps guide the development of targeted treatments. By understanding the specific molecular mechanisms underlying disease, researchers can also develop therapies that address the root cause of the disorder rather than just treating symptoms. While advances in genetic sequencing technologies have allowed researchers, including those at HudsonAlpha, to identify numerous genetic variations associated with these diseases, there’s still much to learn in the quest for earlier diagnostics and more effective treatments.
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UNDERSTANDING THE REGULATION OF KNOWN GENETIC CONTRIBUTORS TO DISEASE ONSET AND PROGRESSION
HudsonAlpha Faculty Investigators Nick Cochran, PhD , and Rick Myers, PhD , are at the forefront of genomic research in neurodegeneration. They aim to understand what causes progressive brain cell damage and how it can be prevented. A leading theory in neurodegeneration is that damage is largely due to the aberrant buildup of protein aggregates, like beta-amyloid and tau, within and around brain cells. The Cochran lab is working to understand tau at a deeper level in hopes of discovering what goes amiss and how to best prevent or reverse it. In healthy brains, tau protein plays a critical role in maintaining neuronal health. However, in neuro- degenerative diseases, tau undergoes pathologi- cal changes, forming protein tangles that disrupt cellular function and communication. This leads to neuronal degeneration and cognitive decline. Studies on MAPT and tau have been used to create biomarkers and design potential treatments. Cochran’s research extends beyond changes in the MAPT gene itself, focusing on regulatory elements that control whether the gene is expressed at the right time, in the right place, and in the right amount. In a study published in January 2024 in The American Journal of Human Genetics , Cochran and his team, as well as the Myers lab, used many genomic technologies to better understand MAPT expression and identify new regulatory regions that could one day be the target of therapeutics 1 . Through these exhaustive studies, the team identi- fied 97 candidate regulatory elements that control MAPT expression. In late-2024, Drs. Cochran and Myers, along with a collaborator at the University of California San Francisco, were awarded a 5-year, $3.5 million grant from the National Institutes of Health to further study MAPT . The collaborative team will use cutting-edge techniques to discover more controllers of MAPT expression, providing an
Rick Myers, PhD, and Nick Cochran, PhD, collaborating in the lab.
Diving into the regulation of genes will lead to a more holistic picture of how variation in our genomes
leads to disease risk, allowing us to better understand and target problemS involved in these diseases.
— Nick Cochran, PHD
cont. on p. 24
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neurodegenerative disease
Brianne Rogers, PhD, looking at cell culture plates with lab members Erin Barinaga, Becky Hauser, PhD, and Jared Taylor
IDENTIFYING BIOMARKERS OF NEURODEGENERATION Because neurodegeneration is a progressive process, cell damage in the brain occurs years, sometimes decades, before symptom onset. To truly reduce the global burden of neurodegen- erative disease, scientists and physicians must be able to identify early changes in the brain that indicate potential neurodegeneration. By identifying early genetic changes associated with these diseases, scientists can develop noninva- sive tests to diagnose them before much damage has occurred. Blood-based biomarkers are a promising method to identify neurodegenerative disease pathol- ogy early. A few blood-based biomarkers are currently in use for diagnosing Alzheimer’s disease but there is a growing need for more. Dr. Myers and his lab are involved in several research studies seeking to find blood-based biomarkers for various neurodegenerative diseases. For several years, they’ve led a study in
innovative path for achieving tau reduction in the human brain. Using what they’ve learned in studying MAPT , Cochran and his lab are expanding their research into the regulation of other neurodegenerative disease genes. Brianne Rogers, PhD , a Postdoctoral Fellow in the Cochran lab, is leading research funded through the American Parkinson’s Disease Association to study the gene SNCA , which encodes the protein alpha-synuclein that forms damaging Lewy bodies in the brains of Parkinson’s disease patients. Through an Alzheimer’s Association -funded grant, Cochran and his team are also studying the regulation of APP , the gene that provides instructions for amyloid protein that is involved in Alzheimer’s disease. By studying how APP is turned on or off, they hope to better understand the role it plays in Alzheimer’s disease risk and shed light on ways to regulate the gene through potential therapeutics.
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collaboration with Crestwood Medical Center’s ALS Care Clinic in Huntsville, Alabama. Blood samples from ALS patients are analyzed alongside sam- ples from individuals without ALS to identify and validate unique nucleic acids in the blood of ALS patients that could be used as predictive biomark- ers. The team has found some exciting preliminary results that they’re working to validate in the upcoming year. In 2024, researchers in the Myers lab launched a study in conjunction with the Smith Family Clinic for Genomic Medicine to identify biomarkers linked to Parkinson’s disease. Patients diagnosed with Parkinson’s disease, as well as unaffected family or friends, enroll at the clinic to donate blood samples for the study. As of late 2024, more than
100 samples have already been collected. Once the team has a representative number of samples, they’ll start analyzing them for potential biomark- ers. In addition to diagnosing disease earlier, bio- markers are also extremely helpful in monitoring disease progression and patient response to treat- ments. During clinical trials, pharmaceutical com- panies rely on biomarkers to help identify patients who are most likely to benefit from a specific drug, measure how well a drug is working by assessing changes in specific biological markers related to the disease, and help predict clinical outcomes. ■
To learn more, listen to
Dr. Cochran discussing an experiment with BRIDGES fellow Aminatou Diallo.
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Sara Cooper, PhD, Emily Gordon, PhD, and BRIDGES fellow Eliza Croom looking at cancer cells through a microscope.
C ancer is a class of devastating diseases that affect millions worldwide. While many factors contribute to the development of cancer, at its core, it is caused by grow and multiply unchecked. While the field recognizes several dozen inheritable genetic changes that predispose individuals to cancer, not all genetic changes that lead to cancer are inherited. Many are acquired throughout our life- time due to random mutations, environmental expo- sures, or other factors. Understanding the full spectrum of the genetic basis of cancer is crucial for developing more effective diagnostic methods, more personalized treatments, and better preventative measures. genetic changes that give cancer cells a survival advantage, allowing them to
SEARCHING FOR NEW GENETIC CAUSES OF CANCER HudsonAlpha Faculty Investigator Sara Cooper, PhD , and her lab are at the forefront of this genetic exploration. The field of cancer genetics has made major strides over the past few decades in identifying common genetic changes that predispose individu- als to cancer. While these gene variants have been game-changers for many individuals in their cancer journey, numerous others with cancer diagnoses do not have these common genetic changes. Dr. Cooper and her lab aim to identify more genetic changes associated with different types of cancer. Through a collaboration with Clearview Cancer Institute in Huntsville, Alabama, Cooper’s lab is studying the genomes of individuals with a strong family history of
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cancer, seeking to uncover new genetic causes of the disease. Through a pilot project, Cooper’s lab analyzed the genomes of ten individuals with a strong family (and personal) history of cancer but negative results from standard genetic testing. They used whole-genome sequencing to look at all of the DNA in a person’s genome rather than just a few regions already known to be involved in cancer. Using this approach, Cooper’s team aimed to identify rare variants that could explain the high incidence of cancer in these families. Initially, the researchers focused on rare coding variants in known cancer risk genes. Their initial analysis led them to ask whether other regions of the genetic landscape should be further considered. They shifted their attention to non- coding regulatory sequences and splicing variants, which can also play a role in gene expression and function.
The analysis of this data is still ongoing, but the team hopes to find new genetic contributors to early hereditary cancers that can help individuals gain a more complete picture of their cancer risk. GENETIC MECHANISMS OF CHEMOTHERAPY RESISTANCE Being diagnosed with cancer is often just the beginning of a long journey for many individuals. Receiving the right treatment for your cancer can be difficult, with many patients undergoing com- binations of different drugs or switching from one therapy to another. Still, others face the challeng- ing obstacle of their cancer becoming resistant to a treatment that was previously working well for them. This phenomenon, called chemotherapy resistance, is a growing problem in treating cancer and leads to higher mortality in some cancers. Dr. Cooper’s lab wants to understand the mechanisms behind chemotherapy resistance in certain types of cancer, especially those with a high incidence of resistance, like pancreatic and ovarian cancers. To help identify the genetic basis of che- motherapy resistance, the lab uses the gene-editing tool CRISPR to identify genes that contribute to resistance to common chemotherapy drugs. They’ve had success with this method in pancreatic cancer. In a study published in BMC Cancer , Cooper’s lab identified a genetic variant in the ANGPTL4 gene that is associated with chemo- therapy resistance 1 . Overexpression of the gene was found to protect cancer cells from chemotherapy. Cooper’s lab is now applying the same tech- nology to ovarian cancer cells. They have already identified several genes involved in chemotherapy resistance, many of which are related to cell prolif- eration and cell-cell interactions. The next step in this research is to explore the complex interplay between tumor cells and the immune system. By understanding how these interactions contribute to cancer progression and treatment response, researchers can develop more targeted and effective therapies. Ultimately, Dr. Cooper’s research goal is to use genetic information to predict patient response to different treatments, develop personalized treat- ments, and improve patient outcomes. ■
The more we can uncover about genetic changes that contribute to cancer, the more personalized diagnostics and treatments we can develop, increasing the chances of successful treatments.
—sara cooper, PHD
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Graduate students Zach Meharg (l) and Laramie Akozbek (r) pollinating peanut plants with Renan Souza, PhD.
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GENOMICS IN CROP IMPROVEMENT
Science and agriculture go hand in hand in shaping a better future.
—norman borlaug, PHD american agronomist and Nobel Peace prize winner
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CROP improvement UTILIZING GENOMICS IN PLANTS H umans have long relied on agriculture to sustain life. About 10,000 years ago, people living in the region known as the Fertile Crescent began adapting wild plants for human use, a process known as domestication. These early farmers selected plants with desirable traits, such as larger fruit or disease resistance, and cultivated them.
Over generations, humans transformed these wild plants into crops that can be reliably grown and har- vested at large scale, providing a stable food source for human populations. However, as our population grows and climate change alters our environment, the demand for efficient, resilient, and sustainable agriculture has never been greater. The differences that distinguish one plant from another are encoded in the plant’s DNA. By understand- ing the genetic makeup of plants, scientists can identify specific genes that control traits like yield, disease resistance, drought tolerance, and nutritional content. This knowledge allows them to develop new crop va- rieties that are more productive and better adapted to changing conditions. At the HudsonAlpha Institute for Biotechnology, our plant scientists and geneticists are experts at plant genome sequencing and analysis. Using this genomic information, they seek to help address critical challenges in agriculture, such as climate change and food security. Our research teams collaborate with farmers and plant breeders globally to translate these genomic discoveries into practical applications, ultimately improving agricultural sustainability and ensuring a reliable food supply for the future. ■
hops
peanuts
Learn what is growing in HudsonAlpha’s Kathy L. Chan Greenhouse
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berries
Top: Morgan Brown studying perennial grasses for use in bioenergy and bioproducts. Laramie Aközbek (l) preparing plant DNA for sequencing.
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EMPOWERING
THE GLOBAL PEANUT COMMUNITY
P eanuts are a nutritional and economic lifeline for over a billion people world- wide, particularly in regions of Africa, Asia, and South America. This global commodity generates billions of dollars annually, supporting diverse livelihoods from multinational corporations to small family farms. Peanuts are an excellent source of plant- based protein, healthy fats, and essential vitamins and minerals, all of which promote healthy development, especially for children and pregnant women. While peanuts are a nutritional and economic powerhouse, they face growing threats from pests, diseases, and climate change. For a smallholder farmer, losing an entire peanut harvest to disease is cata- strophic, often leading to severe financial hardship and food insecurity for their family and community. With increasing threats to the peanut enterprise, the need for innovative solutions has never been greater. HudsonAlpha Faculty Investigator Josh Clevenger, PhD , and his lab are directly addressing some of the most pressing challenges facing peanut growers. By identifying genetic markers for traits like disease resistance and higher yields, their work is helping to develop new peanut varieties that are better equipped to withstand changing environmental condi- tions and pests. But they’re not stopping there; they’re revolutionizing the global peanut industry and ensur- ing breeders across all levels of operation have equal access to the genomic tools essential for success. The agricultural field is witnessing a genomic renaissance, with growing amounts of genomic information available to help scientists and breeders understand the inner workings of commodity crops. In 2012, the International Peanut Genome Initiative was formed to produce a genome of cultivated peanuts and create genomic tools to accelerate the develop- ment of improved peanut cultivars. Dr. Clevenger was involved in several research projects under the Peanut Genome Initiative.
OUR work is not just about science; it is about improving people’s lives. —josh clevenger, PHD
The first draft of the peanut genome was released in 2014, providing a valuable resource for peanut scientists. In 2019, a more comprehensive and accu- rate sequencing of the cultivated peanut genome was achieved, providing deeper insights into the crop’s ge- netic makeup. These reference genomes gave scientists the tools they needed to start looking at genetic con- tributors to important traits like greater yield, disease resistance, improved nutrition, improved processing traits, and better flavor. To find these genetic contributors, scientists must dig into the genomes of peanuts with and without valu- able traits, which requires advanced analysis methods. The Clevenger lab developed a suite of computational tools called KHUFU ® that helps them quickly and
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GLOBAL PEANUT GENOMICS
ALABAMA WIREGRASS: REGIONAL PEANUT
WESTERN AFRICA: PEANUT FOLIAR DISEASES
ARGENTINA: SMUT RESISTANCE
EASTERN AFRICA: GROUNDNUT ROSETTE DISEASE
accurately find genetic contributors to traits of interest. Using Khufu, the team has helped dozens of breeding programs across the globe implement genomic solutions into their programs. In a new project funded by USDA-ARS with support from U.S. Senator Katie Britt, Dr. Clevenger and his team are offering genotyping services to peanut scientists and breeders who want to use genomics to solve global peanut prob- lems and create better peanuts. Individuals can apply for genotyping grants through the Peanut Research Foundation , which is leading the selection of genotyping projects. The samples will come to the Clevenger lab, where they’ll use their cutting-edge genotyping software to find genomic answers to the breeders’ problems, which can range from invasive pests to diseases to drought. Already, the Clevenger lab has identified a region of the peanut genome that confers resistance to a devastating disease called peanut smut, which is prevalent in Argentina and could spread to other countries. The team is also working with the Groundnut Improvement Network of Africa (GINA) to help breeders across Africa combat specific problems in their region. Many households across Africa grow peanuts to feed their families and earn a living.
Not all threats to peanuts are uniform across the continent. Diseases like groundnut rosette virus threaten operations in East Africa, while foliar dis- eases are more prevalent in West Africa. GINA aims to build a core set of genetic diversity of African peanuts so that breeders across the continent can start integrating genomic tools into their breeding programs and react more quickly to emerging threats. By empowering breeders from operations of all sizes, the team is helping create a sustainable peanut industry that can survive environmental, disease, and pest threats for decades to come. Clevenger and his lab are leveraging the peanut genome and the tools they created to make an impact on generations of peanut producers, shell- ers, and manufacturers across the US and on the continents of Africa, South America, and Australia. As we have seen, genomic tools have immense potential to transform the peanut indus- try. By continuing to invest in research, fostering collaboration, and supporting the development of new technologies, we can ensure a sustainable future for this vital crop and the millions of people who rely on it. ■
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a greener tomorrow
P etroleum, a finite fossil fuel, has powered modern society for centuries. However, its extraction and consumption have contributed significantly to climate change and pollution. These pressing global challenges demand innovative solutions. As we seek to transition to a more sustainable future, perennial grasses emerge as a promising avenue for a greener tomorrow. These hardy plants, capable of thriving in diverse environments, offer a wealth of potential benefits. By harnessing their photosynthetic efficiency and rapid growth, we can produce a wide range of bioproducts, from renewable fuels to sustainable materials. Furthermore, their deep root systems can sequester significant amounts of carbon dioxide, helping to mitigate climate change. While domesticated species like sugarcane and maize are already used for various bioproducts, undomesticated species like miscanthus and switchgrass hold even greater potential because of their wider genetic diversity and resilience. By tapping into the genetic potential of undomesticated perennial grasses, researchers and farmers can develop more sustainable and productive agricultural systems. GENETICS TO IMPROVE PERENNIAL GRASSES FOR BIOPRODUCTS Researchers are turning to genetics to develop these species into competitive crops for use in sustainable products. By understanding their genetic makeup, researchers can identify and manipulate specific genes to improve key traits, such as biomass yield, drought tolerance, disease resistance, nutrient use efficiency, and cell wall composition.
Genomic research provides invaluable insights into plant genomes, facilitating the development of plant-based alternatives to fossil fuels, waste reduction strategies, and economically viable, environmen- tally sustainable systems.
—Kankshita Swaminathan, PHD
HudsonAlpha Faculty Investigator Kankshita Swaminathan, PhD , and her lab are at the forefront of this research. By combining genomics, gene editing tools like CRISPR-Cas9, and advanced phenotyping techniques, they are conducting in-depth analyses of genes and key traits in miscanthus, switchgrass, and sorghum. This integrated approach promises to significantly accelerate the development of sustainable bioenergy crops and the creation of new, high-yielding cultivars within a reasonable timeframe.
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