Here\u2019s what you\u2019ll learn when you read this story:<\/p>\n
For decades, scientists have theorized that two genetic defects have the potential to essentially \u201ccancel each other out,\u201d restoring normal protein function in the process.<\/p>\n
A new study confirms this long-held theory, discovering that 60 percent of defective genetic pairs impacting the production of the enzyme argininosuccinate lyase could actually restore healthy levels of protein function.<\/p>\n
This discovery was made possible by the rise of AI models that can accurately forecast how two genetic variants will interact, intended to help avoid the worst outcomes of rare genetic disorders.<\/p>\n
In 1964, Francis Crick\u2014the Nobel Laureate famous for his contribution to the discovery of the structure of DNA<\/a>\u2014and his Cambridge University colleague Leslie Orgel came up with an unintuitive hypothesis. Known as inter-allelic (or intragenetic) complementation, the idea was that two genetic<\/a> defects could sort of cancel each other out and create normal protein function.<\/p>\n \u201cDefects in two subunits mutually correct each other,\u201d Crick and Orgel wrote in Journal of Molecular Biology in 1964<\/a>. \u201cThus a defect in A [\u2026] might, after aggregation, lie next to a complementary defect, B, in the other so that, although the combinations (A+A) and (B+B) both prevent the enzyme<\/a> from working, in the combination (A+B) the two defects compensate for each other and active enzyme is formed.\u201d<\/p>\n Fast-forward more than 60 years, and scientists from George Mason University and the Pacific Northwest Research Institute (PNRI) have found compelling evidence that Crick and Orgel were onto something. The team focused on the enzyme argininosuccinate lyase (ASL), which helps remove toxic ammonia<\/a> from the body. A malfunction of this important system can lead to urea cycle disorders, which can result in lethargy, vomiting, seizures, or comas. Roughly one out of every 35,000 babies born in the U.S.<\/a> will have this disorder.<\/p>\n The team noticed that, after sifting through more than 3,600 combinations of functional impact, roughly 60 percent of pairs that were individually damaged could actually restore enzyme activity. The results of the study were published in the journal Proceedings of the National Academy of Sciences<\/a> (PNAS).<\/p>\n \u201cThis work shows that genetic variants don\u2019t act independently in many important cases,\u201d Michelle Tang, lead author of the study and a staff scientist at PNRI, said in a press statement<\/a>. \u201cFor a defined group of genes, the default assumptions we use to predict disease risk simply don\u2019t hold.\u201d<\/p>\n This entire study was only possible because of the advent of artificial intelligence<\/a>\u2014specifically, AI-based models that could accurately sift through data and forecast whether two genetic variants could work together to restore protein function. The authors worked with an AI lab at George Mason University that confirmed near-100-percent accuracy in predicting intragenetic complementation in both ASL and the enzyme fumarase (FH), suggesting that the model could work across the human genome. The authors estimate that 4 percent of genes in the human genome could have similar effects to those seen in ASL and FH.<\/p>\n \u201cWe\u2019ve shown that, in many cases, two damaging variants can work together to restore protein function,\u201d Aim\u00e9e Dudley, senior author of the study from PNRI, said in a press statement. \u201cThis kind of genetic interaction is not an isolated exception, but a widespread and under-appreciated way that variants can interact, especially in rare disease<\/a> contexts.\u201d<\/p>\n This could be a game-changer for clinical genomics, as physicians could now consider variant combinations of genomics<\/a> when trying to save the lives of those impacted by rare genetic diseases.<\/p>\n \u201cClinical genomics has been stuck in a rut for decades. We\u2019ve shown that you need to look at combinations of variants to fully understand their impact,\u201d Amarda Shehu, a co-author of the study and Chief AI Officer from George Mason University, said in another press statement<\/a>. \u201cOur AI model expands coverage from one gene to another, accelerating interpretation and bringing us closer to true precision medicine<\/a>.\u201d<\/p>\n You Might Also Like<\/p>\n","protected":false},"excerpt":{"rendered":"Here\u2019s what you\u2019ll learn when you read this story: For decades, scientists have theorized that two genetic defects…\n","protected":false},"author":2,"featured_media":429454,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[178958,49,178959,48,124192,178954,178957,17272,62742,178955,92572,92656,178956,66],"class_list":["post-429453","post","type-post","status-publish","format-standard","has-post-thumbnail","category-science","tag-argininosuccinate-lyase","tag-ca","tag-cambridge-university","tag-canada","tag-enzyme-activity","tag-francis-crick","tag-genetic-defects","tag-genetic-variants","tag-george-mason-university","tag-leslie-orgel","tag-pacific-northwest-research-institute","tag-pnri","tag-protein-function","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/429453","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/comments?post=429453"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/429453\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media\/429454"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media?parent=429453"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/categories?post=429453"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/tags?post=429453"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}