This Biotechnology Discoveries and Application Guidebook is crafted with policymakers in mind, highlighting recent findings, breakthroughs, and applications of innovative genomics technologies. The articles provide a small sampling of the thousands of global research advances over the past two years. There is information on genetics; clinical applications of genetics and genomics; cancer; bacteria, viruses, and other pathogens; and agriculture. Genomics is an important tool across the life science landscape, shaping conversations in agriculture, health, bioinformatics, ethics, science-related funding, regulation, and legislation. The purpose of the Guidebook is to provide content and context around these topics.
118th Congress Edition
2023
EXECUTIVE SUMMARY
Our nation’s bioscience industry is making scientific discoveries, generating quality jobs, producing positive economic impact, and helping people in this country and throughout the world. Much of this success can be traced to the Human Genome Project, which achieved the bold goal of sequencing an entire human genome. In the two decades since this groundbreaking achievement, advancements have transformed humanity’s ability to treat and diagnose pediatric diseases, cancer, and infectious disease, accelerate drug development, and improve agricultural practices to feed and fuel a growing population. Today, Americans in academia and industry are working on the most challenging problems in human health and agriculture. At HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, our scientists conduct discovery-based research alongside over 50 resident associate companies that move discoveries into real-world applications through products and services to help patients, educators, farmers, and the public. A 501(c)(3) non-profit institute, HudsonAlpha is home to leaders in childhood genetic disorders, cancer, neurodegenerative diseases, and plant genomics. These men and women are uncovering and applying cutting-edge research to impact the clinic, the farm, and a host of other industries. Often, this is happening through collaborations with scientists across the country. This Biotechnology Discoveries and Application Guidebook is crafted with policymakers in mind, highlighting recent findings, breakthroughs, and applications of innovative genomics technologies. The articles provide a small sampling of the thousands of global research advances over the past two years. There is information on genetics; clinical applications of genetics and genomics; cancer; bacteria, viruses, and other pathogens; and agriculture. Genomics is an important tool across the life science landscape, shaping conversations in agriculture, health, bioinformatics, ethics, science-related funding, regulation, and legislation. The purpose of the Guidebook is to provide content and context around these topics. On behalf of HudsonAlpha, I am excited to bring you these stories.
Please let me know if I can answer questions or be a resource in the future.
With very best regards,
J. Carter Wells Vice President for Economic Development HudsonAlpha Institute for Biotechnology cwells @ hudsonalpha.org
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CONGRESSIONAL GUIDEBOOK CONTENTS
About HudsonAlpha Institute for Biotechnology . ...............................4–5 Types of Genetic Tests .......................................................................... 6-7 New Findings GENETICS & GENOMICS IN THE CLINI C. ................................... 8-11 GENETICS & SOCIETY ................................................................ 12-13 CANCER GENETICS & GENOMICS . .......................................... 14-17 BACTERIA, VIRUSES & OTHER PATHOGENS ............................. 18-21 AGRICULTURE ........................................................................... 22-26
ONLINE BIOTECH BASICS
HudsonAlpha offers easy-to-understand explanations of foundational concepts at hudsonalpha.org/biotech-basics. Twenty-four key technologies or concepts are described in detail. Language and concepts are intentionally geared to a public audience. If you would like to listen to some of the recent findings in human health, agriculture and the business of biotech, tune into HudsonAlpha's podcast, Tiny Expeditons: hudsonalpha.org/tinyexpeditions
The Everyday DNA blog also contains even more stories about the impact that genetics and genomics has on society: hudsonalpha.org/everyday-dna
Image Credits Unless otherwise stated, images were purchased or provided by: Adobe® Stock, Unsplash, Biorender.com, nasa.gov, and the image library of HudsonAlpha Institute for Biotechnology.
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SCIENCE FOR LIFE
science for life ®
About HudsonAlpha The HudsonAlpha Institute for Biotechnology is a nonprofit institute dedicated to developing and applying scientific advances to health, agriculture, learning and commercialization. Opened in 2008, HudsonAlpha’s vision is to leverage the synergy between discovery, education, medicine and economic development in genomic sciences to improve the human condition around the globe.
The HudsonAlpha biotechnology campus consists of 152 acres nestled within Cummings Research Park, the nation’s second largest research park. The state-of-the-art facilities co-locate nonprofit scientific researchers with entrepreneurs and educators. HudsonAlpha is a national and international leader in genetics and genomics research and biotech education. It includes more than 50 diverse biotech companies on campus. HudsonAlpha is supported by grants from the U.S. federal government, the state of Alabama, private foundations, and the HudsonAlpha Foundation; revenue from HudsonAlpha services, and leases from resident associate companies; and philanthropic contributions.
Genomic Research
HudsonAlpha scientists are adding to the world’s body of knowledge about the basis of life, health, disease and biodiversity and seeking to enable:
● Earlier and/or less invasive diagnostics ● Better, more customized treatments for disease ● Improved food, fiber and energy sources
Current research focus areas are:
Foundational Research
Plant Science and Sustainable Agriculture Applying genomic knowledge to agriculture and bioenergy to create a more sustainable world
Genomic Health Leveraging the power of the human genome to diagnose, pre- dict and prevent disease as well as helping others incorporate genomics into practice
Research that improves the under- standing of biological phenomena. Includes studies of natural variation, principles of bioethics, and compu- tational biology and bioinformatics
Our researchers have been published in more than 1,000 scientific publications since the beginning of HudsonAlpha to help secure a global leadership position in genomic research.
Human Health
Rare disease Undiagnosed childhood genetic disorders
Autoimmune diseases Including lupus, rheumatoid arthritis, and other complex autoimmune diseases.
Neurological and Psychiatric Disorders Including Alzheimer disease, Parkinson disease, ALS, Huntington disease, bipolar disorder, schizophrenia, autism and epilepsy
Cancer Multiple forms of cancer, including breast, ovarian, prostate, kidney, brain, colon and pancreatic
Immunogenomics Application of genomic technology to understand the immune system’s role in health and disease
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Educational Outreach
HudsonAlpha’s Educational Programs HudsonAlpha's Educational Outreach team inspires and trains the next generation of life science researchers and workforce while building a more genomically-literate soci- ety. The dynamic educators at HudsonAlpha reach students, educators, medical prac- titioners, and the community through hands-on classroom modules, in-depth school and workshop experiences along with digital learning opportunities. HudsonAlpha also provides educational opportunities for healthcare providers and learning tools for patients who are making medical decisions using their personal genomic information.
Educator Professional Learning HudsonAlpha has opportunities for teacher professional learning, ranging from single-day workshops to ongoing classroom support. These increase an educator’s comfort in discussing genetic concepts and terminology along with the associated ethical, social and legal issues. Clinical Applications HudsonAlpha empowers patients to be informed genomic healthcare consumers and members of society. Our genetic counselors provide patient education and support for clinical and research activities across the Institute. The genetic counseling team also provides education and training programs for healthcare providers and trainees to support the integration of genomics into routine and specialized medicine.
Classroom Kits and Digital Resources HudsonAlpha developed kits and activities to students in hands-on experiences that match state curriculum requirements related to DNA and genetics. Laboratory activities have also been crafted for students in grades 9-12. Activities highlight topics such as trait inheritance patterns, extracting DNA, exploring chromosome behavior in cells, diagnosing genetic disorders, and using bioinformatics databases. Many of these resources are commercially available to classrooms around the nation through a partnership with Carolina Biological (www.Carolina.com). Student Experiences Field trips, classroom visits by industry leaders, summer camp sessions, in-depth internship opportunities and college-level laboratory courses engage students in biotechnology-related fields, increase exposure to career options, provide mentoring opportunities and equip students with a toolbox of content-specific skills.
Biotech Enterprises
HudsonAlpha’s Economic Development team strength- ens and diversifies Alabama’s economy by fostering success in life sciences companies of all stages and sizes. Through entrepreneur- and recruitment-based economic development, HudsonAlpha’s 152-acre Biotech Campus is now home to more than 50 resident associate companies, from startups to global leaders with space for more. HudsonAlpha offers turnkey and build-to-suit laboratory and office space for lease in an energizing environment with superior shared amenities. Bioscience enterprises on campus benefit from access to HudsonAlpha scientists and custom- ized concierge strategic support through entrepreneur mentoring, investor forums, workforce and business assistance, marketing resources, and bioscience industry networking events.
Across HudsonAlpha’s research labs and the resident associate companies, 1,100 men and women are performing research to find genomic markers for diseases, providing diagnostic tests guiding cancer treatment, developing medical devices for infectious diseases, and offering products and services for all facets of the biosciences industry. For more information, go to to HudsonAlpha.org/Innovate.
Government support comes from: National Science Foundation Department of Energy Joint Genome Institute U.S. Department of Agriculture
Alabama Department of Education Alabama Department of Commerce Alabama Department of Economic Community Affairs (ADECA)
National Institutes of Health
National Human Genome Research Institute National Institute of Arthritis and Musculoskeletal and Skin Diseases National Heart, Lung and Brain Institute National Institute of Mental Health National Institute of Environmental Health Sciences
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TYPES OF GENETIC TESTING Genetic tests use various laboratory methods to examine your DNA. They range from studying a single letter of the DNA sequence to analyzing the entire genome.
The HudsonAlpha Clinical Services Lab, The Smith Family Clinic for Genomic Medicine and companies on the campus of HudsonAlpha, provide many of these tests.
Prenatal: There are two types of prenatal tests related to genetic conditions: screening and diagnostic. Prenatal screening tests
generally measure the concentration of specific proteins or hormones in the mother’s bloodstream to identify the risk of having a child with certain genetic disorders, such as Down syndrome. Recent noninvasive techniques are even able to collect and test pieces of fetal DNA that circulate in the mother’s blood. These approaches do not diagnose a disorder, but signal that further testing should be considered. Diagnostic tests directly analyze fetal DNA, often obtained through invasive procedures such as amniocentesis or chorionic villus sampling (CVS). Prenatal diagnostic tests may study the number
Wellness:
and structure of the chromosomes in fetal cells, or identify the sequence of a specific gene or region of the genome.
Genetic testing to identify lifestyle and wellness-related traits is an emerging field. These tests provide information on topics ranging from earwax type and personality style to nicotine dependence and muscle performance. Since many of these traits are influenced by multiple genetic and environmental factors, the accuracy and utility of these tests is unclear.
Pediatric: Between two and three percent of all children have a physical birth defect or clinical disorder. These may be seen at birth, or become evident
during childhood. All infants born in the United States undergo newborn screening to identify disorders that can affect a child’s long-term health. Using a few drops of blood from a baby’s heel, clinical laboratories test for at least 29 diseases, most of which are genetic in nature. Children who have symptoms of a genetic disorder or do not meet developmental milestones may undergo diagnostic genetic testing to identify or rule out a specific condition. This may be a targeted test for a specific mutation, a test of a single gene or a handful of genes known to be associated with the child’s symptoms, or a genome-wide analysis to more broadly search for answers.
Adult:
Genetic testing in adults generally falls into one of three categories:
Diagnostic testing seeks to identify disease-causing mutations to explain a patient’s existing set of symptoms. Predictive/Presymptomatic testing detects mutations for disorders that often appear later in life. These tests are usually ordered for individuals who have a family history of a disease but have no signs of that disease at the time of testing. Carrier testing identifies people who carry a single copy of a mutation that - when present in two copies – causes disease. The individual is healthy but could pass along the mutation to a child. Couples may decide to have carrier testing to determine their risk of having a child with certain genetic conditions.
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Pharmacogenomic: Some genes are responsible for how the body processes medications. Pharmacogenomic testing looks for changes in those genes and seeks to correlate that information to a person’s response to medications. It seeks to predict the most effective drug at the right dose, as well as identify those drugs that may cause harmful side effects. For example, warfarin is a drug that helps prevent blood clots, strokes and heart attacks. Individuals who have specific genetic variants require lower doses for therapy. Similar variants are associated with medications for depression and chemotherapy. While these types of tests are currently used for only a few health issues, they will become increasingly important in the years ahead. At the moment, no single pharmacogenomics test can predict an individual’s response to all medications. In addition, no such tests are available for most over the counter medications.
How does a human genome get sequenced?
Your genome is your unique sequence of DNA, 3 billion letters long. It’s found in almost every cell in your body. DNA
A denine T hymine C ytosine G uanine
Bases
Sugar phosphate backbone
The letters A , T , C and G represent the chemical elements, or bases, of DNA.
Ancestry:
a sequencing machine . 1
DNA is extracted from a sample and loaded on to
Because certain patterns of DNA variation are more commonly found among individuals of specific backgrounds, DNA analysis can shed light on where an individual’s ancestors likely came from. The more of these patterns that two people share, the more closely related they are. Genetic ancestry testing usually examines DNA variation on the Y chromosome (to study the male line), the mitochondria (for details about the female line) or single letter changes throughout the genome (to estimate the overall ethnic background). This type
2 The machine determines the sequence of short pieces of DNA,150 letters long. These are called reads . 3 The ‘reads’ from the sequencing machine are matched to a reference sequence. This is called mapping .
of testing does not reveal any medical or health-related information and while it may provide geographic origins for distant ancestors, it cannot provide the names of those ancestors.
Cancer:
Genetic testing may be useful as a predictive test for individuals with a family history of certain types of cancers (such as breast, ovarian and colorectal). A positive test result indicates the person has inherited a genetic mutation that significantly increases his or her lifetime risk of developing cancer. These individuals may have more frequent cancer screenings or chose to undergo surgery to reduce the cancer risk. In some cases, this type of genetic testing for inherited mutations may also be appropriate when cancer has already been detected. In addition, genetic testing of the tumor cells may be requested to determine which cancer-causing mutations have been acquired by the tumor. This knowledge may aid in diagnosis and shape a physician’s choice of therapy to treat the cancer.
4 Analysis
Within the 3 billion letters in your genome are 20,000 genes. These make up about 2% of the sequence. The position of most of our genes is known, and is marked on the reference sequence . Every person has millions of differences (called variants ) from the reference sequence. Most of these difference are harmless – they are the reason we are different from each other. Some differences could be causing a disease. Bioinformatics specialists use a variety of tools and techniques to filter these differences down from millions to just a handful that could be harmful. If it is not clear which difference is causing disease, researchers anaylze the genome further.
Identity Testing: DNA profiling identifies an individual’s unique pattern of DNA variation and is often used in parentage testing and criminal investigations.
A parent shares 50% of his or her genetic variation with a child. A paternity or maternity test compares the DNA patterns between the child and alleged parents to look for evidence of genetic sharing. Forensic DNA testing can link a perpetrator or victim to a crime scene as well as exonerate individuals convicted of crimes they did not commit. There are limitations to this type of testing, including the
inability to distinguish between identical twins and the challenge of assessing samples with degraded or low amounts of DNA.
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SCIENCE FOR LIFE
GENETICS & GENOMICS IN THE CLINIC
The power of genome sequencing lies in its ability to interrogate a person’s entire DNA makeup in a single test. For cases where a definitive diagnosis is not made, future re-analysis of the genome data may lead to new diagnoses that cannot be made with current knowledge. This study provides evidence that genome sequencing can be imple- mented as a first-step test in the genetic workup of critically ill newborns to reduce the time these patients and their families spend in a diagnostic odyssey. Genome sequencing will be increasingly ordered and interpreted by healthcare providers that do not have formal genetics training. As a part of the SouthSeq study, NICU physicians were trained and equipped with educational resources to help them discuss genome sequencing results with their patients. This training made providers feel more confident in understanding genome sequencing and using results to guide patient care. Studies like SouthSeq help provide the evidence needed for genome sequencing to become a part of routine medical care. n
Genome sequencing in critically ill newborns
Genome sequencing is a powerful tool for diagnosing genetic conditions. With a genetic diagnosis, doctors and patients can make better decisions about medical management leading to better patient outcomes. In a recent study, scientists used genome sequencing to diagnose critically ill infants in NICUs across the southeastern U.S. An emphasis was placed on recruiting underrepresented patient populations, including racial/ethnic minorities and those living in rural and medically underserved areas. Of the more than 600 newborns enrolled in this study, almost 30% received a definite diagnosis of a genetic condition. Disease-causing genetic changes were identified in 105 different genes. Another 14% of cases had an uncertain genetic change that is currently poorly understood.
HudsonAlpha’s Genetic Counseling team and the research laboratories of Greg Barsh MD, PhD and Greg Cooper PhD contributed to this work in programs such as SouthSeq and CSER. The HudsonAlpha Clinical Services Lab also helps sequence newborn's DNA.
REFERENCES: Bowling, K. M., et al. Genome sequencing as a first-line diagnostic test for hospitalized infants. Genetics in Medicine (2021) 24:4, 851-861. DOI: 10.1016/j.gim.2021.11.020 East, K. M., et al. Education and Training of Non-Genetics Providers on the Return of Genome Sequencing Results in a NICU Setting. Journal of Personalized Medicine (2022) 5:12(3), 405. DOI: 10.3390/jpm12030405
Migraine genetic risk factors More than a billion people across the globe suffer from migraine headaches, with 15-20% of people experiencing migraine at some point during their lifetime. Migraine is a severe, pulsating headache that can occur either with or without aura — a term used to describe additional neurological symptoms such as visual changes that occur before the onset of a migraine. The cause of migraine is not fully understood, but it is believed to involve mechanisms in the brain and blood vessels in the head. A person’s risk for developing migraine is complex and influenced by many different factors, some of which are genetic. An international consortium of leading migraine specialists performed the largest genomic study on migraine to date. A genome-wide association study (GWAS) with data from 873,000 patients, 102,000 of whom have migraine, identified regions of the genome associated with the risk of migraine. More than 120 regions of the genome associated with migraine risk were identified, including 86 previously unknown.
The large dataset size allowed for comparisons between migraine with and without aura. It turns out that there are genetic risk factors specific to each type of migraine and genetic
risk factors that are shared. Two of the
genomic regions identified contain genes targeted by recently developed migraine medications. Other genomic regions may provide clues for additional gene targets and speed up the search for new treatments. This study highlights the value of large datasets when identifying genetic risk factors for complex, multifactorial conditions like migraine. n REFERENCE: Hautakangas, H., et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet (2022) 54, 152–160. DOI: 10.1038/s41588-021-00990-0
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Immune cell fingerprint Historically, health care has been approached from a one size fits all mentality. Treatments are developed based on the anticipated response
Successful treatment for sickle cell anemia Gene therapy holds promise for treating a wide range of diseases, but historically it has seen more failures than successes. However, within the last decade the field has begun stacking up some impressive wins. Recently, sever- al patients with a blood disorder called sickle cell disease have found relief from their excruciating symptoms thanks to a clinical trial using CRISPR-based gene therapy. Sickle cell disease is an inherited blood disorder caused by mutations that affect the production or struc- ture of hemoglobin, the protein that carries oxygen in red blood cells. The defective hemoglobin turns red blood cells into deformed, sickle shaped cells that get stuck inside blood vessels and clog up blood flow. This causes excruciating attacks of pain, organ damage, and often premature death. Early clinical trials for CRISPR-based gene therapy are showing promise for individuals with sickle cell disease. CRISPR is used to edit stem cells and allow them to pro- duce a slightly different type of hemoglobin called fetal hemoglobin which is normally inactivated after birth. Bone marrow stem cells are removed from the affected individuals and the gene that turns off fetal hemoglobin production is disabled using CRISPR. The edited cells are transfused back to the patient and the now active fetal hemoglobin can carry oxygen throughout the body. One year after her treatment, the first U.S. patient to receive the gene therapy has not had any severe pain attacks and has not required any emergency room treat- ments, hospitalizations, or blood transfusions. Nearly every red blood cell in her body produces some level of fetal hemoglobin and about 46% of her total hemoglobin is fetal. The company that produces the gene therapy also reported favorable results on seven additional sickle cell patients and fifteen patients with a related condition called beta thalassemia. Although these treatments are still in early trials, the results look promising and could one day bring relief to other individuals suffering from these types of blood-based genetic diseases. n REFERENCES: www.npr.org/sections/health- shots/2020/06/23/877543610/a-year-in-1st-patient-to-get-gene- editing-for-sickle-cell-disease-is-thriving. And “Vertex and CRISPR Therapeutics Present New Data in 22 Patients With Greater Than 3 Months Follow-Up Post-Treatment With Investigational CRISPR/Cas9 Gene-Editing Therapy, CTX001™ at European Hematology Associa- tion Annual Meeting” 11 June, 2021. www.businesswire.com/news/ home/20210611005069/en/Vertex-and-CRISPR-Therapeutics-Present- New-Data-in-22-Patients-With-Greater-Than-3-Months-Follow-Up- Post-Treatment-With-Investigational-CRISPRCas9-Gene-Editing-Ther- apy-CTX001%E2%84%A2-at-European-Hematology-Association-Annu- al-Meeting. Accessed 31 August 2021. Press Release.
of an ‘average’ patient, yet expected to benefit an entire diverse population. Unfortunately for many patients, this strategy doesn’t work, with drugs either not working for them or causing disrupting side effects. A new resource could help researchers understand why some treatments work well in some patients but not others. A multi-national team of researchers used single-cell RNA sequenc- ing to create a library of more than 1 million immune cells collected from hundreds of healthy individuals from Australia. Looking at single cells allows researchers to detect subtle changes in individual cells. The study identified genes and immune cell types linked to specific autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and Crohn’s disease. An individual’s unique genetic immune profile could be used to design and deliver treatments tailored to their immune system. In fact, the findings have led to clinical trials in Sydney to predict which treatments will work for individual Crohn’s disease patients. The researchers made the full dataset publicly available so that other researchers could use it for new drug development and repurposing current drug treatments for autoim- mune diseases. n
REFERENCE: Yazar, S., et al. Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease. Science (2022) 376 (6589) DOI: 10.1126/science.abf3041
Kidney disease disparities Many types of severe kidney disease occur more frequently among individu- als of African ancestry. In 2010, scientists discovered that the major contrib- utor to this disparity is genetic change in one particular gene, APOL1 , which arose thousands of years ago in populations living in sub-Saharan Africa. APOL1 variants protect against parasitic African sleeping sickness but also increase a person’s risk of developing severe kidney diseases. A recent paper summarized the current understanding of APOL1 risk variants and how kidney disease presents in the clinic. A person can have either zero, one, or two APOL1 gene changes. Having two changes, one on each copy of the gene, significantly increases risk. Having two changes one on each copy of the gene significantly increases risk. However, not all indi- viduals with two APOL1 changes develop kidney disease. This suggests that other genetic and environmental factors affect risk, and a person’s APOL1 status is not a perfect predictor of risk. Identifying an APOL1 gene change can help identify the cause of a patient’s kidney disease. However, currently, there are no targeted therapies or modifications to treatment options based on a patient’s APOL1 gene status. In the context of kidney transplants, multiple studies show that donor kidneys with high-risk APOL1 gene changes fail at a higher rate than those without high-risk changes. Many transplant centers have begun testing possible kidney donors for APOL1 gene changes. More research must be done utilizing large and diverse datasets to fully understand how APOL1 gene changes lead to kidney disease and leverage this information to develop APOL1 targeted therapeutics. n
REFERENCE: Friedman, D. J. and M. R. Pollack. APOL1 Nephropathy: From genetics to clinical applications. CJASN (2021) 16: 294–303. DOI: 10.2215/CJN.15161219
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SCIENCE FOR LIFE
GENETICS & GENOMICS IN THE CLINIC
predicts the structure of human proteins
Proteins fold their string of amino acids into specific three-dimen- sional structures to carry out their biological function. Knowing that three-dimensional structure allows scientists to understand how the protein works, identify what goes wrong when it’s been altered and design medications to boost or silence its activity. Unfortunately, predicting protein structure is hard work and can take months of computer-based simulations and modeling. Less than ⅓ of all human proteins (collectively known as the proteome) have a known structure. DeepMind, a sister company to Google, is an artificial intelli- gence laboratory based in the UK. They developed AlphaFold2, a machine-learning platform that predicts protein structures with a very high degree of accuracy. The platform uses a repetitive system of model refinement, applied millions of times to improve predictions based on prior experiences. With a relatively high level of confi- dence, AlphaFold2 predicted structures for nearly the entire human proteome, as well as the proteome of 20 model organisms such as mouse, fruit fly and E. coli . DeepMind has predicted more than 350,000 protein structure and plans to submit up to 130 million more by the end of 2021, nearly half of all known proteins. Protein predictions are freely available and academic research teams can use AlphaFold2 at no charge. Even though these predictions must still be experimentally verified, the sudden availability of so many protein structures will likely transform many aspects of biology and human health. n REFERENCES: Tunyasuvunakool K. et al. Highly accurate protein structure prediction for the human proteome. Nature (2021) 596:590-596. DOI: 10.1038/s41586- 021-03828-1. And AlphaFold protein structure database: https://alphafold.ebi.ac.uk/ Online resource helps healthcare workers treat genetic diseases With the advent of whole genome sequencing and other genom- ic testing, the cause for many genetic disorders are being rapidly discovered. One geneticist acknowledged this and set out to create a resource that serves as a convenient, readily available starting point for health care providers looking for treatment information for genetic disorders. The resource, called Rx-Genes (Rx-genes.com), provides information about current treatments and treatments that are in clinical trials for genetic disorders. The website and corresponding mobile app currently contain more than 630 disease entries that include references to disease information and treatment guidance, a brief summary of treatments, the inheritance pattern, disease frequency, nonmolecular confirmato- ry testing, and a link to experimental treatments. Existing entries are continuously updated, and new entries are added as new treatments appear in the literature. Rx-Genes is a promising tool that helps healthcare providers more easily and efficiently access the newest information about genetic disorders. n REFERENCE: Bick D. et al., An online compendium of treatable genetic disorders. Am J Med Genet . (2021) 187C:48-54. DOI: 10.1002/ajmg.c.31874. Rx-genes.com
Long-read sequencing identifies “missed” disease-causing variants
Many neurodevelopmental diseases are genetic in nature. Despite advances in genome sequencing technology, specific diagnoses for these disorders remain elusive. This is likely because certain disease-causing genetic variants are challenging to detect with typical sequencing approaches. Traditionally, genome sequencing is performed by gen- erating millions of “short” sequences, called reads, generally around 150 base pairs long. These short-reads are pieced back together like a puzzle using a human reference genome as a template. However, it is hard to accurately map certain types of short reads, especially regions containing highly repetitive stretches of DNA. These portions of the genome often go unanalyzed. One approach to overcome this limitation is to use a sequencing platform that produces longer reads. “Long- read” sequencers generate sequences up to 1,000 times longer than short-read systems. Fewer, bigger puzzle pieces means fewer gaps in the assembled sequence. Greater ge- nome coverage lets researchers and clinicians more accurately detect DNA variants. Recently, scientists used long-read sequencing to rean- alyze the genomes of six families with children suspected of having a genetic neurodevelopmental disorder. The families had previously been sequenced using short-read technology, but no disease-causing genetic variant had been identified. Long-read sequencing found multiple genetic variants in each family that had previously been missed. Among these newly detected variants, disease-causing DNA changes were identified in two of the six children. If these findings are extended to larger populations, long-read sequencing may supplement or even replace short-read analysis pipelines, improving the rare disease genetic discovery rates. n REFERENCE: Hiatt S.M. et al. Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders. HGC Advances (2021) 2:100023. DOI: 10.1016/j.xhgg.2021.100023.
The laboratories of HudsonAlpha faculty researchers Jane Grimwood PhD, Jeremy Schmutz and Greg Cooper PhD contributed to this work.
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Elective genetic testing of seemingly healthy individuals
Hereditary cancer genetic testing Hereditary cancers account for five to ten percent of all cancer diagnoses. Currently, genetic testing for hereditary cancer is recommended for individuals with a strong personal or family history of cancer, and not recommended in patients with a low-risk cancer history. Since 2015, the Information is Power Initiative has offered free and reduced cost hereditary cancer genetic testing to the individuals in North Alabama. The program is specifically targeted toward low-risk individuals who would not traditionally qualify for hereditary cancer genetic testing. When individuals sign up for the testing online, they are encouraged to watch a three-minute educational video with key genetic counseling messages. Then before accessing their results they must watch a three-minute educational video specific to their type of result (negative or positive). The Information is Power team performed a study to determine how participants felt about the testing procedure and educational material. Results from the participant survey found the pre-test and post-test educational video met most participants’ educational needs in a hereditary cancer population screening program. Educational videos could be used as a way to increase the scalability of genetic counseling. Elective genome sequencing Clinical genome sequencing tests offer a much deeper look into a person’s DNA by looking at their entire genetic code, not just a subset of variants like in genotyping tests. People may elect to have their genome sequenced to gain a better understanding of current medical problems, gain information about future disease risk to guide preventative healthcare decisions, fill in gaps in family history, or provide information to relatives and future generations. The Smith Family Clinic for Genomic Medicine, LLC, located on the campus of the HudsonAlpha Institute for Biotechnology is one of several centers around the United States that offers elective genome sequencing. By studying 52 participants in the elective ge- nome sequencing program, researchers showed that 11.5 percent of participants had variants that may explain one or more aspects of their medical history, 19 percent had variants that altered the risk of developing certain diseases in the future, and 85 percent were carriers of a recessive or X-linked disorder. Through the separate pharmacogenomic panel the team found that 100 percent of the participants had pharmacogenetic variants that affected current and/or future medications. Although there is still much progress to be made in elective genetic testing, these studies highlight how elective genetic testing allows individuals to realize the promise of personalized medicine. n REFERENCES: Bowling K.M. et al. Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls. Genetics in Medicine (2021) 23:280-288. DOI: 10.1038/s41436-020-00976-z. Cochran M. et al. A study of elective genome sequencing and pharmacogenetic testing in an unselected population. Mol Genet Genomic Med (2021) 00:e1766. DOI: 10.1002/ mgg3.1766. Davis B.H. et al. Evaluation of population-level pharmacogenetic actionability in Alabama. Clin Transl Sci (2021) 00:1-12. DOI: 10.1111/cts.13097. East K.M. et al. A state-based approach to genomics for rare disease and population screening. Genetics in Medicine (2021) 23:777-781. DOI: 10/1038/s41436-020-01034-4. Greve V. et al. Experiences and attitudes of hereditary cancer screening patients in a consumer directed testing model. Patient Education and Counseling 104:473-479. DOI: 10.1016/j.pec.2020.10.014. HudsonAlpha’s Genetic Counseling team and the research laboratories of Greg Barsh MD PhD, Greg Cooper PhD, Sara Cooper PhD, Thomas May PhD, and Richard Myers PhD contributed to these research and clinical studies.
The human genome holds vital information about each individual’s health. By studying the sequence of an individual’s DNA, health care providers can determine the cause of existing disease, predict potential risk for future disease, and determine if certain medications are safer or more effective for an individual. Genetic testing is used to identify changes in DNA sequences. While genetic testing has been successful in helping diagnose disease in individuals with undiagnosed conditions, less is known about the efficiency of elective genetic testing for healthy individu- als hoping to learn more about their genome. In response to rising demand of elective genetic testing, several initiatives were launched to investigate the accuracy of these tests, as well as best practices to implement them. Population-based genetic screening The Alabama Genomic Health Initiative (AGHI), launched in 2017, is one of the nation’s first statewide efforts to harness the power of genomic analysis to prevent and treat conditions having a genetic cause. The goal of AGHI is to determine the utility of genetic screen- ing in disease prevention, management, and treatment. In the population screening program, AGHI provides genomic testing, interpretation, and counseling free of charge to Alabama residents who are seemingly healthy (meaning they do not have a significant personal or family history suggestive of a genetic con- dition). Participants in the population screening group received a genotyping test, which looks at a preselected group of gene variants that are known to increase a person’s likelihood of disease. As of October 2020, the team had screened 5,369 Alabamians representing all 67 Alabama counties. Eighty-one positive genotyping results among 80 individuals (1.5%) were identified in the population cohort. These results include risk-increasing variants for hereditary cancer, cardiomyopathy, malignant hyperthermia, and hypercholes- terolemia. Pharmacogenetic screening
Within the AGHI popula- tion screening program, participants were also offered the opportunity to learn how their DNA might affect the medi- cations they take or may take in the future (called pharmacogenomics). DNA
variants in many different genes have been associated with how the human body responds to over one hundred drugs. Such pharmacog- enomic information can help doctors predict whether certain medica- tions or doses will be effective for their patient, or if they are likely to have an adverse reaction to that drug. The AGHI team found that 98.6 percent of participants have a gene variant that influences response to one or more medications. The researchers also found that the prevalence of such gene variants differed significantly by race. For example, about 50 percent of par- ticipants studied had a variant in a gene associated with decreased therapeutic response to beta blockers. For black participants, that rate was 62.5 percent, while it was 47.4 percent for white participants.
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A bone repair gene The protein Sonic Hedgehog, and its encoding gene, SHH , have an essential role in embryonic skeletal formation and brain development. SHH , and the hedgehog pathway, were named for functional studies in fruit flies in the early 1980s. Fruit fly embryos with nonfunctional SHH have bristles that clump into a single patch. The patch of bristles gives the embryo a spiny appearance that resembles a hedgehog. In humans, SHH is responsible for patterning in the central nervous system, such as vertebrae development. Changes in SHH can result in severe brain, skull, and facial defects. New research connects SHH to a critical early function in the repair of major bone injuries. In mice, researchers found increased SHH expression for a brief period following a major bone injury. SHH levels returned to normal after forming a callus, the initial network that connects across a bone break. Engineered mice, unable to GENETICS & GENOMICS IN SOCIETY
produce the Sonic Hedgehog protein, could not form this scaffold and were unable to heal the broken bones. Re- searchers hope this work will lead to new treatments for traf- fic accidents, combat wounds, and cancer-related bone loss. n REFERENCE: Serowoky, M.A., et al. A murine model of large-scale bone regeneration reveals a selective requirement for Sonic Hedgehog. npj Regen Med (2022) 7, 30. DOI: 10.1038/s41536-022-00225-8
Molecular pathway for sneezing Sneezing is a basic respiratory reflex that rids the airway of irritants and pathogens. Many sneezes are caused by allergens like dust or dander entering the nose or throat. Chronic allergy sufferers find some relief from allergy medica- tion, but there is a
Filling in the human genome gaps The Human Genome Project, completed in 2003, produced the first human reference genome. This spawned dramatic advances in sequencing technology and enhanced the understanding of genetic variation. Using the best technologies available then, the reference genome was only about 92% complete. March of 2022 marked the publication of a new and more complete human reference genome that includes complex and highly repetitive regions of DNA that had been notoriously challenging to interpret.
need for other interventions to curtail sneezing. However, until recently, little was known about the molecular process of sneezing to help create new therapeutics. Scientists discovered a neural pathway that seems to lead to sneezing in mice using a new experimental model of sneezing. In the lab, researchers exposed mice to aerosolized histamine (an allergen) and capsaicin (a chemical that gives spicy peppers their burn), both known to cause humans to sneeze. They monitored the mice for audible signs of sneez- ing and also measured muscle movements in the mice. Both histamine and capsaicin caused sneezing in the mice. To determine the neural pathway that induces sneezing, the team turned their attention to a type of sensory neuron in the mouse nose that expresses a receptor called Trpv1. The neurons release a signaling molecule that binds other neurons in the brainstem. These neurons send electrical signals to more neurons that eventually drive the initiation and propaga- tion of a sneeze. Understanding the mechanism of sneezing opens the door to finding therapies that can help control sneezing. More effective treatments for sneezing could help reduce the spread of infectious diseases. n
The Telomere to Telomere (T2T) consortium comprises researchers from multiple universities, the National Human Genome Research Institute (NHGRI), and the National Institutes of Health (NIH). The group used advances in long-read sequencing technology to produce the first ‘gapless’ genome. Long-read sequencing provides the advantage of producing 10,000 base pair reads instead of the much shorter 150 base pair reads generated by earlier short-read technology. The T2T genome has already revealed 151 megabase pairs of new DNA sequences and more than 2 million new human DNA vari- ants, 622 of those in medically relevant genes. The newly discovered sequences are primarily in telomeres located at the ends of chromo- somes or within centromeres, where replicated chromosomes are attached before cell division. Using long-read sequencing technology enabled a better understanding of chromosome architecture and the identification of previously invisible DNA variants. n More details can be found in the Shareable Science blog post: Filling in the gaps of the human genome.
More details can be found in the Shareable Science blog post: Achoo! Sneezing mice reveal molecular pathway that initiates sneezes
REFERENCE: Li., F., et al. Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem. Cell (2021) 184:14, 3762-3773. DOI: 10.1016/j.cell.2021.05.017
REFERENCE: Nurk, S., et al. The complete sequence of a human genome. Science (2022) 376:6588 44-53. DOI: 10.1126/science.abj6987
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Decoding complex traits Have you ever wondered why your sibling or best friend is taller than you? The size of certain parts of their DNA may be to blame. DNA encodes proteins which are the building blocks of life. Changes in DNA can affect the protein product, making it work differently or not work at all. New research revealed that DNA changes called variable num- bers of tandem repeats (VNTRs) are linked to several human traits. VNTRs are sequences of DNA that are seven or more base pairs long and are repeated a varying number of times in each individual. Researchers found that differences in the number of repeats across individuals might explain variation in traits like height. The study scrutinized 118 VNTRs in protein-coding regions in more than 400,000 UK Biobank participants. Five distinct VNTRs seemed to be causative of certain traits. One finding strongly associ-
ated a VNTR in a gene called ACAN with height. Specifically, they iden- tified a 3.4-centimeter difference in the heights of individuals with 22 and 29 repeats in this region. Although the study only focused on a small number of VNTRs, hundreds of thousands of these repeats are in the human genome. This study opens the door to addi- tional research that may provide further evidence for determining polygenic risk scores that would provide insight into disease risk. n
Human gene editing guidelines developed
Although human genome editing has the potential to im- prove human health and medicine, it also raises important ethical and social issues. In 2018, after a Chinese scientist announced that he had genetically modified embryos that became twin babies, the World Health Organization (WHO) established an expert advisory committee tasked with devel- oping international standards for human genome editing. In July 2021, WHO released two reports outlining global recommendations for regulating human genome editing, with an emphasis on ensuring ethical and equitable use of the technology. The reports present a framework to help people who regulate human genome editing, providing suggestions on how such regulations could be implemented and enforced. Within the reports, the committee also outlines nine key recommendations related to the ethics of human genome editing, including the establishment of an international regis- try of gene-editing experiments and ways for whistleblowers to report illegal and/or unethical research. It also provides several hypothetical scenarios that the proposed strategies may help prevent, such as conducting gene editing trials in low-income countries to develop therapies that would ulti- mately be too costly for all but the wealthiest ones to buy. Throughout the reports, the WHO reiterates its existing opposition to using genome editing on germline cells (sperm and egg cells) until researchers have a better understanding of the implications it could hold. Overall, the recommenda- tions in the report form an important first step in the uniform regulation of human genome editing. n REFERENCES: www.who.int/news/item/12-07-2021-who-issues-new- recommendations-on-human-genome-editing-for-the-advancement-of- public-health WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. Human Genome Editing: recommendations. Geneva: World Health Organization; 2021. ISBN: 978-92-4-003038-1.
REFERENCE: Mukamel, R. E., et al. Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science (2021) 373:6562 1499-1505. DOI: 10.1126/science.abg8289
The American Society of Human Genetics recently released a report detailing how human genetics and genomics research impacts the U.S. economy, society, and healthcare. In the United States, this field supports 850,000 jobs and generates $15.5 billion in tax revenue every year….that’s a higher dollar amount than the gross domestic profit of one-third of the countries in the world. The annual federal investment of more than $3 billion in human genetics and genomics has a return on investment of nearly five times that amount. n Genetics and genomics impacts U.S. economy with jobs and revenue
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