/ en Wed, 25 Feb 26 11:01:27 -0500 /news/scientists-sharpen-genetic-maps-help-pinpoint-dna-changes-influence-human-health-traits-and <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" class="datetime">February 25, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>By rapidly testing hundreds of thousands of DNA sequences, scientists have identified specific genetic variations that contribute to blood pressure, cholesterol, blood sugar, and more. </p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By The Jackson Laboratory </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" title="Wednesday, February 25, 2026 - 11:01" class="datetime">February 25, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=DgGIIguf 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=SHXPThIv 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/News_JAX_ext-main_022526_v2.png?itok=Jxss8ZYL 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb" alt="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" title="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Susanna Hamilton, Ó³»­´«Ã½ Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2941/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/2941/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/2941/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="background-color:#f3f3f3;font-family:Open Sans;margin-bottom:2em;padding:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Thousands of regions of the genome are associated with human traits and disease risk, but identifying the precise genetic variants underlying those associations is challenging.</li> <li>Using a technology called a massively parallel reporter assay, researchers tested more than 220,000 disease-associated genetic variants for their ability to influence gene expression in five cell types.</li> <li aria-level="1">More than 13,000 of these variants significantly influenced genes' expression, highlighting mechanisms contributing to health-related traits such as cholesterol levels, blood sugar, and blood pressure.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related stories</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=vWgkpcUk 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo" alt="" typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">A massive approach to finding what's "real" in genome-wide association data</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CRE-Main.jpg?h=6d684022&itok=saD9jaab 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh" alt="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " title="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Machine learning guides researchers to new synthetic genetic switches</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Scientists have identified how specific genetic changes function in cells to influence disease risk and other human health traits. By probing regions of DNA previously linked to disease, the work has created high resolution maps of DNA variant activity, helping pinpoint the exact changes that shape blood pressure, cholesterol levels, blood sugar, and other complex human traits.</p> <p>The study, published in <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6"><em>Nature</em></a> and led by researchers from The Jackson Laboratory (JAX), the Ó³»­´«Ã½, and Yale University, takes on a long-standing challenge in human genetics. Scientists have known for years that certain regions of the genome — often spanning tens of thousands to millions of DNA letters — are associated with diseases. But because these regions usually contain many variants that could potentially drive those associations, performing the necessary experiments to pinpoint which specific DNA changes truly matter has been difficult and time-consuming.</p> <p>The solution was scale. Using a method capable of testing thousands of such variants at once, the team tested more than 220,000 previously identified DNA changes in five different cell types. By doing so, they resolved about 20 percent of these regions across the genome, revealing new insights into what these variants do, which in turn can help improve risk prediction and guide the development of new therapies.</p> <p>"For nearly two decades, genetic studies have identified where in the genome we need to look for disease risk, but not which specific DNA changes are responsible," said Ryan Tewhey, a geneticist and an associate professor who led the team at JAX. "Our study helps close this gap by working at the scale needed to confidently pinpoint the specific DNA changes that matter across thousands of regions all at once, rather than one by one."</p> <p>Tewhey explained that previously making these connections was like searching for a single typo on one page of a massive book. This experimental approach is akin to speed reading, scanning thousands of pages at once and flagging the exact letters that change meaning, dramatically accelerating genetic discovery.</p> <p>"What excites me is that this is a bridge from association to biology," said Layla Siraj, first author of the study, which she spearheaded while in the Lander Lab at the Ó³»­´«Ã½, and now a resident in obstetrics and gynecology at Columbia University/New York Presbyterian. "By uncovering the patterns underlying how single-letter changes affect gene regulation, we can start mechanistically connecting genetic risk to the pathways therapies could target."</p> <p>In addition to Tewhey and Siraj, the study was co-led by Jacob Ulirsch, currently a group leader at Illumina. Key authors also include Steven Reilly, assistant professor at Yale School of Medicine; and <a href="/bios/hilary-finucane">Hilary Finucane</a>, associate member in the <a href="/medical-population-genetics">Program in Medical and Population Genetics</a> at the Ó³»­´«Ã½, an assistant professor at Harvard Medical School, and faculty in the Center for Genomic Medicine and Analytical and Translational Genetics Unit at Massachusetts General Hospital.</p> <h2>Building a foundation for better disease risk prediction</h2> <p>Most DNA changes linked to common diseases like heart disease and type 2 diabetes occur not within genes themselves — which only constitute about 2 percent of the genome — but in the vast stretches of non-coding DNA, where regulatory elements exist that control when, where and how strongly our genes are expressed. Genetic studies conducted over the last two decades have identified millions of such non-coding disease-related variants throughout the genome. The challenge has been identifying which of the many single-letter changes in these regulatory DNA regions affect gene activity, fine-tuning protein production and in turn shaping disease risk.</p> <p>To meet this challenge, the researchers used a technology called a massively parallel reporter assay, which allowed them to test the effects of more than 220,000 single-letter DNA variants at the same time across different cell types, including brain, liver, and blood cells. Each stretch of DNA was paired with a molecular tag, or reporter, that they could directly measure to see whether a variant increased, decreased, or had no effect on gene activity — an important step in understanding how regulatory DNA changes may affect health.</p> <p>The results revealed over 13,000 single-letter variants that influence how strongly a gene is expressed. While most act independently, the team found that about 11 percent behaved differently than expected when combined with a nearby variant. This surprising result suggests some genetic risk of disease depends on specific combinations of variants whose whole is greater than the sum of its parts.</p> <p>These insights revealed potential links to human health. In some cases, pairs of variants were associated with gene activity linked to lower levels of LDL, or "bad" cholesterol. Other combinations appear to affect a gene associated with blood pressure. The team also identified two variants near the <em>ESS2</em> gene — associated with developmental disorders — whose combined effect on gene expression was greater than would be expected from either variant alone.</p> <h2>Improving equity in genetics-driven advances</h2> <p>In another example, the researchers pinpointed a single variant associated with long-term blood sugar control discovered in people of European ancestry. Based on its molecular behavior, they predicted that similar but previously understudied variants, found predominantly in people of African ancestry, would show a similar association. Follow-up analysis confirmed that prediction, underscoring the importance of understanding genetic mechanisms across diverse populations.</p> <p>While the study identified which DNA variants regulate specific protein-coding genes in the brain, liver, and blood cells, additional experiments will be needed to determine how those variants ultimately influence traits and disease risk. Given the body’s many tissues and thousands of distinct cell types, switching genes on or off in a single cell type is only one piece of a much larger puzzle in determining health outcomes. In addition, millions of genetic variants remain untested. Even so, the researchers say the findings can already begin strengthening how scientists study genetic variation and how they influence health traits.</p> <p>"These findings do more than explain known disease associations. They provide training data to build predictive models of the effects of variants we haven’t yet studied or that remain undiscovered," Tewhey said.</p> <p>Tewhey, Reilly, and their colleagues recently created such a model with this data. Published in <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><em>Nature</em></a> in 2024, they used this model to design synthetic DNA sequences that could selectively turn genes on in distinct tissue types one at a time. It also builds on work Tewhey and Ulirsch <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data">published in 2016</a> while colleagues at Ó³»­´«Ã½. Together, these advances point toward a future where genetic risk can be more accurately predicted and where therapies can be designed to act only in the tissues where they are needed most.</p> <p><em>Adapted from </em><a target="_blank" href="https://www.jax.org/news-and-insights/2026/february/scientists-sharpen-genetic-maps-to-help-pinpoint-dna-changes-that-influence-human-health-traits-and-disease-risk"><em>a press release written by The Jackson Laboratory</em></a><em>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported by Howard Hughes Medical Institute, the US National Human Genome Research Institute, the National Institute of General Medical Sciences, and the Novo Nordisk Foundation. </p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Siraj L, et al. <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6">Functional dissection of complex trait variants at single-nucleotide resolution.</a> <em>Nature</em>. Online February 25, 2026. DOI: 10.1038/s41586-026-10121-6.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/medical-and-population-genetics" hreflang="en">Medical and Population Genetics Program</a></div> <div class="field__item"><a href="/broad-tags/genome-regulation" hreflang="en">Genome regulation</a></div> </div> </div> </div> </div> </div> Wed, 25 Feb 2026 16:01:27 +0000 tulrich@broadinstitute.org 5560191 at /news/whyiscience-qa-systems-biologist-uses-ai-understand-how-genome-controls-cell-fate <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" class="datetime">February 25, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>By rapidly testing hundreds of thousands of DNA sequences, scientists have identified specific genetic variations that contribute to blood pressure, cholesterol, blood sugar, and more. </p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By The Jackson Laboratory </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" title="Wednesday, February 25, 2026 - 11:01" class="datetime">February 25, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=DgGIIguf 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=SHXPThIv 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/News_JAX_ext-main_022526_v2.png?itok=Jxss8ZYL 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb" alt="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" title="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Susanna Hamilton, Ó³»­´«Ã½ Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2941/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/2941/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/2941/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="background-color:#f3f3f3;font-family:Open Sans;margin-bottom:2em;padding:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Thousands of regions of the genome are associated with human traits and disease risk, but identifying the precise genetic variants underlying those associations is challenging.</li> <li>Using a technology called a massively parallel reporter assay, researchers tested more than 220,000 disease-associated genetic variants for their ability to influence gene expression in five cell types.</li> <li aria-level="1">More than 13,000 of these variants significantly influenced genes' expression, highlighting mechanisms contributing to health-related traits such as cholesterol levels, blood sugar, and blood pressure.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related stories</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=vWgkpcUk 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo" alt="" typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">A massive approach to finding what's "real" in genome-wide association data</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CRE-Main.jpg?h=6d684022&itok=saD9jaab 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh" alt="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " title="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Machine learning guides researchers to new synthetic genetic switches</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Scientists have identified how specific genetic changes function in cells to influence disease risk and other human health traits. By probing regions of DNA previously linked to disease, the work has created high resolution maps of DNA variant activity, helping pinpoint the exact changes that shape blood pressure, cholesterol levels, blood sugar, and other complex human traits.</p> <p>The study, published in <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6"><em>Nature</em></a> and led by researchers from The Jackson Laboratory (JAX), the Ó³»­´«Ã½, and Yale University, takes on a long-standing challenge in human genetics. Scientists have known for years that certain regions of the genome — often spanning tens of thousands to millions of DNA letters — are associated with diseases. But because these regions usually contain many variants that could potentially drive those associations, performing the necessary experiments to pinpoint which specific DNA changes truly matter has been difficult and time-consuming.</p> <p>The solution was scale. Using a method capable of testing thousands of such variants at once, the team tested more than 220,000 previously identified DNA changes in five different cell types. By doing so, they resolved about 20 percent of these regions across the genome, revealing new insights into what these variants do, which in turn can help improve risk prediction and guide the development of new therapies.</p> <p>"For nearly two decades, genetic studies have identified where in the genome we need to look for disease risk, but not which specific DNA changes are responsible," said Ryan Tewhey, a geneticist and an associate professor who led the team at JAX. "Our study helps close this gap by working at the scale needed to confidently pinpoint the specific DNA changes that matter across thousands of regions all at once, rather than one by one."</p> <p>Tewhey explained that previously making these connections was like searching for a single typo on one page of a massive book. This experimental approach is akin to speed reading, scanning thousands of pages at once and flagging the exact letters that change meaning, dramatically accelerating genetic discovery.</p> <p>"What excites me is that this is a bridge from association to biology," said Layla Siraj, first author of the study, which she spearheaded while in the Lander Lab at the Ó³»­´«Ã½, and now a resident in obstetrics and gynecology at Columbia University/New York Presbyterian. "By uncovering the patterns underlying how single-letter changes affect gene regulation, we can start mechanistically connecting genetic risk to the pathways therapies could target."</p> <p>In addition to Tewhey and Siraj, the study was co-led by Jacob Ulirsch, currently a group leader at Illumina. Key authors also include Steven Reilly, assistant professor at Yale School of Medicine; and <a href="/bios/hilary-finucane">Hilary Finucane</a>, associate member in the <a href="/medical-population-genetics">Program in Medical and Population Genetics</a> at the Ó³»­´«Ã½, an assistant professor at Harvard Medical School, and faculty in the Center for Genomic Medicine and Analytical and Translational Genetics Unit at Massachusetts General Hospital.</p> <h2>Building a foundation for better disease risk prediction</h2> <p>Most DNA changes linked to common diseases like heart disease and type 2 diabetes occur not within genes themselves — which only constitute about 2 percent of the genome — but in the vast stretches of non-coding DNA, where regulatory elements exist that control when, where and how strongly our genes are expressed. Genetic studies conducted over the last two decades have identified millions of such non-coding disease-related variants throughout the genome. The challenge has been identifying which of the many single-letter changes in these regulatory DNA regions affect gene activity, fine-tuning protein production and in turn shaping disease risk.</p> <p>To meet this challenge, the researchers used a technology called a massively parallel reporter assay, which allowed them to test the effects of more than 220,000 single-letter DNA variants at the same time across different cell types, including brain, liver, and blood cells. Each stretch of DNA was paired with a molecular tag, or reporter, that they could directly measure to see whether a variant increased, decreased, or had no effect on gene activity — an important step in understanding how regulatory DNA changes may affect health.</p> <p>The results revealed over 13,000 single-letter variants that influence how strongly a gene is expressed. While most act independently, the team found that about 11 percent behaved differently than expected when combined with a nearby variant. This surprising result suggests some genetic risk of disease depends on specific combinations of variants whose whole is greater than the sum of its parts.</p> <p>These insights revealed potential links to human health. In some cases, pairs of variants were associated with gene activity linked to lower levels of LDL, or "bad" cholesterol. Other combinations appear to affect a gene associated with blood pressure. The team also identified two variants near the <em>ESS2</em> gene — associated with developmental disorders — whose combined effect on gene expression was greater than would be expected from either variant alone.</p> <h2>Improving equity in genetics-driven advances</h2> <p>In another example, the researchers pinpointed a single variant associated with long-term blood sugar control discovered in people of European ancestry. Based on its molecular behavior, they predicted that similar but previously understudied variants, found predominantly in people of African ancestry, would show a similar association. Follow-up analysis confirmed that prediction, underscoring the importance of understanding genetic mechanisms across diverse populations.</p> <p>While the study identified which DNA variants regulate specific protein-coding genes in the brain, liver, and blood cells, additional experiments will be needed to determine how those variants ultimately influence traits and disease risk. Given the body’s many tissues and thousands of distinct cell types, switching genes on or off in a single cell type is only one piece of a much larger puzzle in determining health outcomes. In addition, millions of genetic variants remain untested. Even so, the researchers say the findings can already begin strengthening how scientists study genetic variation and how they influence health traits.</p> <p>"These findings do more than explain known disease associations. They provide training data to build predictive models of the effects of variants we haven’t yet studied or that remain undiscovered," Tewhey said.</p> <p>Tewhey, Reilly, and their colleagues recently created such a model with this data. Published in <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><em>Nature</em></a> in 2024, they used this model to design synthetic DNA sequences that could selectively turn genes on in distinct tissue types one at a time. It also builds on work Tewhey and Ulirsch <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data">published in 2016</a> while colleagues at Ó³»­´«Ã½. Together, these advances point toward a future where genetic risk can be more accurately predicted and where therapies can be designed to act only in the tissues where they are needed most.</p> <p><em>Adapted from </em><a target="_blank" href="https://www.jax.org/news-and-insights/2026/february/scientists-sharpen-genetic-maps-to-help-pinpoint-dna-changes-that-influence-human-health-traits-and-disease-risk"><em>a press release written by The Jackson Laboratory</em></a><em>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported by Howard Hughes Medical Institute, the US National Human Genome Research Institute, the National Institute of General Medical Sciences, and the Novo Nordisk Foundation. </p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Siraj L, et al. <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6">Functional dissection of complex trait variants at single-nucleotide resolution.</a> <em>Nature</em>. Online February 25, 2026. DOI: 10.1038/s41586-026-10121-6.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/medical-and-population-genetics" hreflang="en">Medical and Population Genetics Program</a></div> <div class="field__item"><a href="/broad-tags/genome-regulation" hreflang="en">Genome regulation</a></div> </div> </div> </div> </div> </div> Mon, 12 May 2025 13:00:00 +0000 adicorat 5558501 at /news/machine-learning-guides-researchers-new-synthetic-genetic-switches <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" class="datetime">February 25, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists sharpen genetic maps to help pinpoint DNA changes that influence human health traits and disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>By rapidly testing hundreds of thousands of DNA sequences, scientists have identified specific genetic variations that contribute to blood pressure, cholesterol, blood sugar, and more. </p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By The Jackson Laboratory </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-02-25T11:01:27-05:00" title="Wednesday, February 25, 2026 - 11:01" class="datetime">February 25, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/News_JAX_ext-main_022526_v2.png?itok=KmXPwuT7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=DgGIIguf 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/News_JAX_ext-main_022526_v2.png?itok=SHXPThIv 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/News_JAX_ext-main_022526_v2.png?itok=Jxss8ZYL 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/News_JAX_ext-main_022526_v2.png?itok=_n2XQPDb" alt="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" title="Illustrations of five kinds of cells on a dark blue background, each surrounded by a circle representing a plasmid carrying a genetic variant" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Susanna Hamilton, Ó³»­´«Ã½ Communications </div> <div class="media-caption__description"> </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2941/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/2941/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/2941/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="background-color:#f3f3f3;font-family:Open Sans;margin-bottom:2em;padding:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Thousands of regions of the genome are associated with human traits and disease risk, but identifying the precise genetic variants underlying those associations is challenging.</li> <li>Using a technology called a massively parallel reporter assay, researchers tested more than 220,000 disease-associated genetic variants for their ability to influence gene expression in five cell types.</li> <li aria-level="1">More than 13,000 of these variants significantly influenced genes' expression, highlighting mechanisms contributing to health-related traits such as cholesterol levels, blood sugar, and blood pressure.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related stories</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=zb7wS9Iz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=ef9j8BfC 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=vWgkpcUk 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/blog/images/2016/MPRA_TesselatedPeaFlower_SigridKnemeyer_325x337_72dpi.jpg?itok=U93JLRDo" alt="" typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">A massive approach to finding what's "real" in genome-wide association data</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CRE-Main.jpg?h=6d684022&itok=A2MjM6LO 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CRE-Main.jpg?h=6d684022&itok=zIPWatU- 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CRE-Main.jpg?h=6d684022&itok=saD9jaab 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CRE-Main.jpg?h=6d684022&itok=hss8LKDh" alt="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " title="An illustration of four circular diagrams representing plasmids, each with colored segments indicating different pieces of regulatory DNA. " typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Machine learning guides researchers to new synthetic genetic switches</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Scientists have identified how specific genetic changes function in cells to influence disease risk and other human health traits. By probing regions of DNA previously linked to disease, the work has created high resolution maps of DNA variant activity, helping pinpoint the exact changes that shape blood pressure, cholesterol levels, blood sugar, and other complex human traits.</p> <p>The study, published in <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6"><em>Nature</em></a> and led by researchers from The Jackson Laboratory (JAX), the Ó³»­´«Ã½, and Yale University, takes on a long-standing challenge in human genetics. Scientists have known for years that certain regions of the genome — often spanning tens of thousands to millions of DNA letters — are associated with diseases. But because these regions usually contain many variants that could potentially drive those associations, performing the necessary experiments to pinpoint which specific DNA changes truly matter has been difficult and time-consuming.</p> <p>The solution was scale. Using a method capable of testing thousands of such variants at once, the team tested more than 220,000 previously identified DNA changes in five different cell types. By doing so, they resolved about 20 percent of these regions across the genome, revealing new insights into what these variants do, which in turn can help improve risk prediction and guide the development of new therapies.</p> <p>"For nearly two decades, genetic studies have identified where in the genome we need to look for disease risk, but not which specific DNA changes are responsible," said Ryan Tewhey, a geneticist and an associate professor who led the team at JAX. "Our study helps close this gap by working at the scale needed to confidently pinpoint the specific DNA changes that matter across thousands of regions all at once, rather than one by one."</p> <p>Tewhey explained that previously making these connections was like searching for a single typo on one page of a massive book. This experimental approach is akin to speed reading, scanning thousands of pages at once and flagging the exact letters that change meaning, dramatically accelerating genetic discovery.</p> <p>"What excites me is that this is a bridge from association to biology," said Layla Siraj, first author of the study, which she spearheaded while in the Lander Lab at the Ó³»­´«Ã½, and now a resident in obstetrics and gynecology at Columbia University/New York Presbyterian. "By uncovering the patterns underlying how single-letter changes affect gene regulation, we can start mechanistically connecting genetic risk to the pathways therapies could target."</p> <p>In addition to Tewhey and Siraj, the study was co-led by Jacob Ulirsch, currently a group leader at Illumina. Key authors also include Steven Reilly, assistant professor at Yale School of Medicine; and <a href="/bios/hilary-finucane">Hilary Finucane</a>, associate member in the <a href="/medical-population-genetics">Program in Medical and Population Genetics</a> at the Ó³»­´«Ã½, an assistant professor at Harvard Medical School, and faculty in the Center for Genomic Medicine and Analytical and Translational Genetics Unit at Massachusetts General Hospital.</p> <h2>Building a foundation for better disease risk prediction</h2> <p>Most DNA changes linked to common diseases like heart disease and type 2 diabetes occur not within genes themselves — which only constitute about 2 percent of the genome — but in the vast stretches of non-coding DNA, where regulatory elements exist that control when, where and how strongly our genes are expressed. Genetic studies conducted over the last two decades have identified millions of such non-coding disease-related variants throughout the genome. The challenge has been identifying which of the many single-letter changes in these regulatory DNA regions affect gene activity, fine-tuning protein production and in turn shaping disease risk.</p> <p>To meet this challenge, the researchers used a technology called a massively parallel reporter assay, which allowed them to test the effects of more than 220,000 single-letter DNA variants at the same time across different cell types, including brain, liver, and blood cells. Each stretch of DNA was paired with a molecular tag, or reporter, that they could directly measure to see whether a variant increased, decreased, or had no effect on gene activity — an important step in understanding how regulatory DNA changes may affect health.</p> <p>The results revealed over 13,000 single-letter variants that influence how strongly a gene is expressed. While most act independently, the team found that about 11 percent behaved differently than expected when combined with a nearby variant. This surprising result suggests some genetic risk of disease depends on specific combinations of variants whose whole is greater than the sum of its parts.</p> <p>These insights revealed potential links to human health. In some cases, pairs of variants were associated with gene activity linked to lower levels of LDL, or "bad" cholesterol. Other combinations appear to affect a gene associated with blood pressure. The team also identified two variants near the <em>ESS2</em> gene — associated with developmental disorders — whose combined effect on gene expression was greater than would be expected from either variant alone.</p> <h2>Improving equity in genetics-driven advances</h2> <p>In another example, the researchers pinpointed a single variant associated with long-term blood sugar control discovered in people of European ancestry. Based on its molecular behavior, they predicted that similar but previously understudied variants, found predominantly in people of African ancestry, would show a similar association. Follow-up analysis confirmed that prediction, underscoring the importance of understanding genetic mechanisms across diverse populations.</p> <p>While the study identified which DNA variants regulate specific protein-coding genes in the brain, liver, and blood cells, additional experiments will be needed to determine how those variants ultimately influence traits and disease risk. Given the body’s many tissues and thousands of distinct cell types, switching genes on or off in a single cell type is only one piece of a much larger puzzle in determining health outcomes. In addition, millions of genetic variants remain untested. Even so, the researchers say the findings can already begin strengthening how scientists study genetic variation and how they influence health traits.</p> <p>"These findings do more than explain known disease associations. They provide training data to build predictive models of the effects of variants we haven’t yet studied or that remain undiscovered," Tewhey said.</p> <p>Tewhey, Reilly, and their colleagues recently created such a model with this data. Published in <a href="/news/machine-learning-guides-researchers-new-synthetic-genetic-switches"><em>Nature</em></a> in 2024, they used this model to design synthetic DNA sequences that could selectively turn genes on in distinct tissue types one at a time. It also builds on work Tewhey and Ulirsch <a href="/blog/massive-approach-finding-whats-real-genome-wide-association-data">published in 2016</a> while colleagues at Ó³»­´«Ã½. Together, these advances point toward a future where genetic risk can be more accurately predicted and where therapies can be designed to act only in the tissues where they are needed most.</p> <p><em>Adapted from </em><a target="_blank" href="https://www.jax.org/news-and-insights/2026/february/scientists-sharpen-genetic-maps-to-help-pinpoint-dna-changes-that-influence-human-health-traits-and-disease-risk"><em>a press release written by The Jackson Laboratory</em></a><em>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported by Howard Hughes Medical Institute, the US National Human Genome Research Institute, the National Institute of General Medical Sciences, and the Novo Nordisk Foundation. </p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Siraj L, et al. <a target="_blank" href="https://www.nature.com/articles/s41586-026-10121-6">Functional dissection of complex trait variants at single-nucleotide resolution.</a> <em>Nature</em>. Online February 25, 2026. DOI: 10.1038/s41586-026-10121-6.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/medical-and-population-genetics" hreflang="en">Medical and Population Genetics Program</a></div> <div class="field__item"><a href="/broad-tags/genome-regulation" hreflang="en">Genome regulation</a></div> </div> </div> </div> </div> </div> Wed, 23 Oct 2024 15:05:19 +0000 tulrich@broadinstitute.org 5557621 at