In 1999, a group of scientists scoured the genomes of around 150 pairs of siblings in an attempt to find genes that are involved in autism. They came up empty. They reasoned that this was because the risk of autism is not governed by a small number of powerful genes, which their study would have uncovered. Instead, its likely affected by a large number of genes that each have a small effect. Perhaps, they wrote, there might be 15 such genes or more.
Two decades later, that figure seems absurdly and naively low. If you told a modern geneticist that a complex traitwhether a physical characteristic like height or weight, or the risk of a disease like cancer or schizophreniawas the work of just 15 genes, theyd probably laugh. Its now thought that such traits are the work of thousands of genetic variants, working in concert. The vast majority of them have only tiny effects, but together, they can dramatically shape our bodies and our health. Theyre weak individually, but powerful en masse.
But Evan Boyle, Yang Li, and Jonathan Pritchard from Stanford University think that this framework doesnt go far enough.
They note that researchers often assume that those thousands of weakly-acting genetic variants will all cluster together in relevant genes. For example, you might expect that height-associated variants will affect genes that control the growth of bones. Similarly, schizophrenia-associated variants might affect genes that are involved in the nervous system. Theres been this notion that for every gene thats involved in a trait, thered be a story connecting that gene to the trait, says Pritchard. And he thinks thats only partly true.
Yes, he says, there will be core genes that follow this pattern. They will affect traits in ways that make biological sense. But genes dont work in isolation. They influence each other in large networks, so that if a variant changes any one gene, it could change an entire gene network, says Boyle. He believes that these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.
The Stanford trio call this the omnigenic model. In the simplest terms, theyre saying that most genes matter for most things.
More specifically, it means that all the genes that are switched on in a particular type of cellsay, a neuron or a heart muscle cellare probably involved in almost every complex trait that involves those cells. So, for example, nearly every gene thats switched on in neurons would play some role in defining a persons intelligence, or risk of dementia, or propensity to learn. Some of these roles may be starring parts. Others might be mere cameos. But few genes would be left out of the production altogether.
This might explain why the search for genetic variants behind complex traits has been so arduous. For example, a giant study called er GIANT looked at the genomes of 250,000 people and identified 700 variants that affect our height. As predicted, each has a tiny effect, raising a persons stature by just a millimeter. And collectively, they explain just 16 percent of the variation in heights that you see in people of European ancestry. Thats not very much, especially when scientists estimate that some 80 percent of all human height variation can be explained by genetic factors. Wheres that missing fraction?
Pritchards team re-analyzed the GIANT data and calculated that there are probably more than 100,000 variants that affect our height, and most of these shift it by just a seventh of a millimeter. Theyre so minuscule in their effects that its hard to tell them apart from statistical noise, which is why geneticists typically ignore them. And yet, Pritchards team noted that many of these weak signals cropped up consistently across different studies, which suggests that they are real results. And since these variants are spread evenly across the entire genome, they implicate a substantial fraction of all genes, Pritchard says.
The team found more evidence for their omnigenic model by analyzing other large genetic studies of rheumatoid arthritis, schizophrenia, and Crohns disease. Many of the variants identified by these studies seem relevant to the disease in question. For example, some of the schizophrenia variants affect genes involved in the nervous system. But mostly, the variants affect genes that dont make for compelling stories, and that do pretty generic things. According to the omnigenic model, theyre only contributing to the risk of disease in incidental ways, by rippling across to the more relevant core genes. Its the only model I can come up with that make all the data fit, Pritchard says.
Pritchards a very perceptive investigator, who looks beyond what most people do, says Aravinda Chakravarti, a geneticist at John Hopkins Medicine. Do I believe this all correct? No, but its very compelling. Its a serious hypothesis that weve got to prove or disprove.
If Pritchard is right, it has big implications for genetics as a field. Geneticists are running ever-bigger and more expensive searches to identify the variants behind all kinds of traits and diseases, in the specific hope that their results will tell them something biologically interesting. They could show us more about how our bodies develop, for example, or point to new approaches for treating disease. But if Pritchard is right, then most variants will not provide such leads because they exert their influence in incidental ways.
Put it this way: The Atlantic is produced by all of us who work here, but our lives are also affected by all the people we encounterfriends, roommates, partners, taxi drivers, passers-by etc. If you listed everyone who influences what happens at The Atlantic, even in small ways, all of those peripheral people would show up on the list. But almost none of them would tell you much about how we do journalism. They're important, but also not actually that relevant. Pritchard thinks the same is true for our genes. And if thats the case, he says, its not clear to me that increasing your study size is going to help very much.
The alternative, he says, is to map the networks of genes that operate within different cells. Once we know those, well be better placed to understand the results from the forthcoming mega-studies. It is a really hard problem, says Boyle. Historically, even understanding the role of one gene in one disease has been considered a major success. Now we have to somehow understand how combinations of seemingly hundreds or thousands of genes work together in very complicated ways. Its beyond our current ability.
There are, however, projects that are trying to do exactly that. Im very excited about trying to understand whether these network ideas are correct, says Pritchard. I think its telling us something profound about how our cells work.
See the original post here:
What If (Almost) Every Gene Affects (Almost) Everything? - The Atlantic
- BENITEC BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) - Marketscreener.com - February 13th, 2023 [February 13th, 2023]
- CENTOGENE to Participate in Upcoming Conferences in February in the Lead Up to Rare Disease Day - Marketscreener.com - February 7th, 2023 [February 7th, 2023]
- Gene | Definition, Structure, Expression, & Facts | Britannica - January 27th, 2023 [January 27th, 2023]
- New gene therapy delivers treatment directly to brain - January 27th, 2023 [January 27th, 2023]
- Indian Pharma Congress: Gene-cell therapy, preventive medicine future of health care, says expert - Economic Times - January 25th, 2023 [January 25th, 2023]
- A blood test that identifies people at higher risk of miscarriage? Thats the goal of this award-winning Rutgers med student. - The Philadelphia... - January 19th, 2023 [January 19th, 2023]
- Gene Therapy: Genes As Medicine | Pfizer - January 6th, 2023 [January 6th, 2023]
- How Genomics will ensure a risk-free and beneficial treatment for good health and well-being - The Financial Express - December 28th, 2022 [December 28th, 2022]
- Regenerative Medicine Advanced Therapy Designation | FDA - December 18th, 2022 [December 18th, 2022]
- 3576 - Gene ResultCXCL8 C-X-C motif chemokine ligand 8 [ (human)] - November 23rd, 2022 [November 23rd, 2022]
- Study identifies new gene that drives colon cancer - EurekAlert - October 17th, 2022 [October 17th, 2022]
- Updated Stroke Gene Panels: Rapid evolution of knowledge on monogenic causes of stroke | European Journal of Human Genetics - Nature.com - October 17th, 2022 [October 17th, 2022]
- The challenges of translating CRISPR to the clinic - Labiotech.eu - October 17th, 2022 [October 17th, 2022]
- Editas Medicine Presents Preclinical Data on EDIT-103 for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa at the European Society of Gene... - October 17th, 2022 [October 17th, 2022]
- 'We have to find a way': FDA seeks solutions to aid bespoke gene therapy - BioPharma Dive - October 17th, 2022 [October 17th, 2022]
- Mathematical model could bring us closer to effective stem cell therapies - Michigan Medicine - October 17th, 2022 [October 17th, 2022]
- Approval, Commercialization Highlighted at Cell & Gene Meeting on the Mesa - Genetic Engineering & Biotechnology News - October 17th, 2022 [October 17th, 2022]
- CANbridge-UMass Chan Medical School Gene Therapy Research in Oral Presentation at the European Society of Gene and Cell Therapy (ESGCT) 29th Annual... - October 17th, 2022 [October 17th, 2022]
- Depression Treatment: How Genetic Testing Can Help Find the Right Medication - Dunya News - October 17th, 2022 [October 17th, 2022]
- The Risk-Reward Proposition for CGT Clinical Trials - Applied Clinical Trials Online - October 17th, 2022 [October 17th, 2022]
- Precision Medicine Could Get Even More Precise With Allarity Therapeutics Next-Generation Diagnostics - Benzinga - October 17th, 2022 [October 17th, 2022]
- Decibel Therapeutics Receives FDA Clearance of IND Application for DB-OTO, a Gene Therapy Product Candidate Designed to Provide Hearing to Individuals... - October 17th, 2022 [October 17th, 2022]
- Time for your medicine: unlocking the power of our body clocks - The Guardian - October 17th, 2022 [October 17th, 2022]
- Replay establishes distinguished Scientific Advisory Board of genomic medicine and cell therapy experts - Yahoo Finance - October 17th, 2022 [October 17th, 2022]
- Scientists Reappraise the Role of Zombie Cells That Anti-aging Medicine Has Sought to Eliminate - Neuroscience News - October 17th, 2022 [October 17th, 2022]
- Forge Biologics Announces Updated Positive Clinical Data in RESKUE, a Novel Phase 1/2 Gene Therapy Trial for Patients with Krabbe Disease - Business... - October 17th, 2022 [October 17th, 2022]
- Gene Expression Signatures Are Analyzed for Biomarkers of Response in HCC - Targeted Oncology - October 17th, 2022 [October 17th, 2022]
- NHS England World-first national genetic testing service to deliver rapid life-saving checks for babies and kids - NHS England - October 17th, 2022 [October 17th, 2022]
- The proteinprotein relationship that could mend a broken heart - RegMedNet - October 17th, 2022 [October 17th, 2022]
- Study finds microprotein correlated to Alzheimers risk - Daily Trojan Online - October 11th, 2022 [October 11th, 2022]
- Passage Bio Announces Appointment of William Chou, M.D. as Chief Executive Officer - Yahoo Finance - October 11th, 2022 [October 11th, 2022]
- Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness - Newswise - October 11th, 2022 [October 11th, 2022]
- Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom - UNC Health and UNC School of Medicine - October 11th, 2022 [October 11th, 2022]
- The Pros and Cons of Lentiviral and Adeno-Associated Viral Vectors - The Medicine Maker - October 11th, 2022 [October 11th, 2022]
- Insights & Outcomes: Foreign DNA, quantum potholes and relapsing fever - Yale News - October 11th, 2022 [October 11th, 2022]
- Expediting IND applications with drug master files - BioPharma Dive - October 11th, 2022 [October 11th, 2022]
- UNC School of Medicine Awarded $3 Million to Lead Study to Reduce PTSD Frequency, Severity | Newsroom - UNC Health and UNC School of Medicine - October 11th, 2022 [October 11th, 2022]
- Lineage to Present at Alliance for Regenerative Medicine 2022 Cell & Gene Meeting on the Mesa - businesswire.com - October 8th, 2022 [October 8th, 2022]
- The Next Crispr Gene Editing IPO Could Be Near - Henry Herald - October 8th, 2022 [October 8th, 2022]
- 10-year CRISPR anniversary: How gene editing revolutionized medicine, and what lies ahead - Genetic Literacy Project - October 8th, 2022 [October 8th, 2022]
- Blood from a baby at birth can be gene sequenced to prevent diseases - USA TODAY - October 8th, 2022 [October 8th, 2022]
- What doctors wish patients knew about breast-cancer prevention - American Medical Association - October 8th, 2022 [October 8th, 2022]
- Growth in Cell and Gene Therapy Market - Pharmaceutical Technology Magazine - October 8th, 2022 [October 8th, 2022]
- Gene Editing Service Market 2022 : Top Players to Reflect Impressive Growth Rate till 2029: Caribou Biosciences, CRISPR Therapeutics, Merck KGaA,... - October 8th, 2022 [October 8th, 2022]
- Tip Sheet: $78 million to support new precision oncology institute, update on experimental gene therapy for herpes and the launch of Fred Hutch's new... - October 8th, 2022 [October 8th, 2022]
- Cell and Gene Therapy: Rewriting the Future of Medicine - Technology Networks - October 2nd, 2022 [October 2nd, 2022]
- Growth in Cell and Gene Therapy Market - BioPharm International - October 2nd, 2022 [October 2nd, 2022]
- CRISPR Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX130 for the Treatment of Cutaneous T-Cell... - October 2nd, 2022 [October 2nd, 2022]
- BioMarin Resubmits Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Severe Hemophilia A to the FDA - PR... - October 2nd, 2022 [October 2nd, 2022]
- Fighting Breast and Ovarian Cancer With a Lupus Antibody - Yale School of Medicine - October 2nd, 2022 [October 2nd, 2022]
- This gene therapy company is testing new tech to 'switch off' diabetes and obesity with a pill - Euronews - October 2nd, 2022 [October 2nd, 2022]
- Tenaya Therapeutics to Participate in Inaugural Hypertrophic Cardiomyopathy Medical Societys 2022 Scientific Sessions - Yahoo Finance - October 2nd, 2022 [October 2nd, 2022]
- Risk of Alzheimer's dementia may be predicted with help of new tool Washington University School of Medicine in St. Louis - Washington University... - October 2nd, 2022 [October 2nd, 2022]
- Tiny Sea Creature's Genes Shed Light on Evolution of Immunity - UPMC - October 2nd, 2022 [October 2nd, 2022]
- Who will get the call from Stockholm? It's time for STAT's 2022 Nobel Prize predictions - STAT - October 2nd, 2022 [October 2nd, 2022]
- Excision BioTherapeutics Awarded California Institute for Regenerative Medicine (CIRM) Grant to Support Ongoing Phase 1/2 Trial Evaluating EBT-101 as... - October 2nd, 2022 [October 2nd, 2022]
- NeuroVoices: Emma Ciafaloni, MD, on the Vast Expansion of Innovative Approaches to Duchenne Muscular Dystrophy - Neurology Live - October 2nd, 2022 [October 2nd, 2022]
- COVID mRNA Jabs and Testing Kicked Off This Industry of Drug Development: Here's What You Need to Know - The Epoch Times - October 2nd, 2022 [October 2nd, 2022]
- Kidney resident macrophages have distinct subpopulations and occupy distinct microenvironments - University of Alabama at Birmingham - October 2nd, 2022 [October 2nd, 2022]
- Nobel Prize for medicine: the full list of winners - The National - October 2nd, 2022 [October 2nd, 2022]
- The surprising link between circadian disruption and cancer may have to do with temperature - EurekAlert - October 2nd, 2022 [October 2nd, 2022]
- The global live cell imaging market is expected to grow at a CAGR of 8.44% during 2022-2027 - Yahoo Finance - October 2nd, 2022 [October 2nd, 2022]
- Chroma Medicine Announces Formation of Scientific Advisory Board of Global Experts in Gene Editing and Cell and Gene Therapy - PR Newswire - September 20th, 2022 [September 20th, 2022]
- Ring Therapeutics Announces Issuance of U.S. Patent for its Anellovector Compositions - Yahoo Finance - September 20th, 2022 [September 20th, 2022]
- Cholesterol gene mutation: Why would a healthy 27-year-old have severe heart problems? - 69News WFMZ-TV - September 20th, 2022 [September 20th, 2022]
- Gene Therapy for Severe Hemophilia B Could Be More Cost Effective Than Current Treatments - Managed Healthcare Executive - September 20th, 2022 [September 20th, 2022]
- AVROBIO Receives Rare Pediatric Disease Designation from U.S. Food and Drug Administration (FDA) for First Gene Therapy in Development for Cystinosis... - September 20th, 2022 [September 20th, 2022]
- The Biggest CGT Breakthroughs Through the Eyes of Our 2022 Power List - The Medicine Maker - September 20th, 2022 [September 20th, 2022]
- Leading Virus Researcher to Chair UVA's Department of Microbiology, Immunology and Cancer Biology - UVA Health Newsroom - September 20th, 2022 [September 20th, 2022]
- Work remains on Tay-Sachs and other Ashkenazi genetic disorders J. - The Jewish News of Northern California - September 20th, 2022 [September 20th, 2022]
- Study Shows Genetic Link to Moving to the Beat of Music - Newswise - September 20th, 2022 [September 20th, 2022]
- Viewpoint: In the post Roe v Wade world, what changes should a biology textbook writer make to address the medical repercussions of Dobbs? - Genetic... - September 20th, 2022 [September 20th, 2022]
- Alnylam Receives Approval in Europe for AMVUTTRA (vutrisiran) for the Treatment of Hereditary Transthyretin-mediated (hATTR) Amyloidosis in Adult... - September 20th, 2022 [September 20th, 2022]
- CSL flexes gene therapy muscle with latest drug - Sydney Morning Herald - September 20th, 2022 [September 20th, 2022]
- The MIT Press releases new book on the science of the heart from cardiac expert Dr. Sian Harding - EurekAlert - September 20th, 2022 [September 20th, 2022]
- Global Pharmaceutical Contract Manufacturing Market is projected to reach a market value of US$329.7 Billion in 2032: Visiongain Reports Ltd - Yahoo... - September 20th, 2022 [September 20th, 2022]
- Alzheon Reports Industry-Leading Biomarker, Brain Preservation and Clinical Effects Following 12 Months of Treatment in Phase 2 Trial of Oral ALZ-801... - September 20th, 2022 [September 20th, 2022]
- Do You Have Lung Cancer With An EGFR Mutation? If So, The Drug Tagrisso Might Be Right For You Based On New Results From A 'Practice Changing' Trial -... - September 20th, 2022 [September 20th, 2022]
- Getting rid of unwanted transformed cells: Possible new directions in cancer therapy - EurekAlert - September 20th, 2022 [September 20th, 2022]
- Sven Kili on reconvening with the ISCT - The Medicine Maker - September 14th, 2022 [September 14th, 2022]