The results are published in Cell.<\/a><\/p>\nThis is your genome on FIRE<\/p>\n
The researchers used FIRE to reveal how changes in DNA sequence affect the regulation of health-critical parts of the genome.\u00a0<\/p>\n
Previous studies had found a genetic difference that was associated with risk of celiac disease, but no one knew if the difference actually affected how genes work or was just an innocent bystander\u2014an important distinction for developing genetic medicines.\u00a0<\/p>\n
The celiac-associated genetic difference sits in a gene \u201cswitch\u201d next to an immune gene that has also been linked to celiac disease, the researchers found. The DNA change disrupts a spot where gene-controlling proteins normally attach, and changing just that one DNA letter in lab experiments was enough to change how open the switch was. This suggests that, out of thousands of nearby genetic differences, this is likely the single one that changes gene regulation.<\/p>\n
Using FIRE, the team also identified tens of thousands of previously overlooked DNA regions that are likely to be important for gene regulation. These regions are more likely than other parts of the genome to contain DNA changes associated with human disease, which suggests that they have important, undiscovered functions for health.<\/p>\n
The limits of genetics<\/p>\n
FIRE also enabled researchers to search on an unprecedented scale for parts of DNA that are regulated differently between maternally and paternally inherited chromosomes. What they found was unexpected. In most cases, differences in gene regulation between the two copies of a DNA region could be linked to differences in the DNA itself. But in a large minority of cases, the two differentially regulated copies were genetically identical at that spot.<\/p>\n
\u201cI think the most surprising result of this work was finding the limits of how much our genetics can determine our gene regulation,\u201d Vollger says. \u201cAbout 40% of the time that we see a regulatory difference between the copies we inherited from mom and dad, there\u2019s no genetic difference between them at that spot.”<\/p>\n
How FIRE works<\/p>\n
FIRE starts with an existing technique that \u201chighlights\u201d physically accessible regions of DNA, then uses advanced sequencing to read long stretches of individual DNA molecules. Because each stretch is so long, the researchers can usually tell whether it came from the mother\u2019s or father\u2019s copy based on slight differences in the sequence. Highlighted regions can indicate active genes or parts of the DNA that are important for gene regulation\u2014but they can also mark less-important regions that just happen to be accessible to the \u201chighlighter\u201d at that moment.<\/p>\n
The new tool adds a machine learning-based analysis that can check every one of these highlighted regions and assess which ones are likely to be actually important for gene regulation. Researchers can do a similar assessment by hand for individual sites, but the tool scales it up to check billions of highlighted regions across the genome.<\/p>\n
\u201cMachine learning here is really copying something that we\u2019re able to see with our own eyes in the data. But it\u2019s doing it at a scale that we could never manage by eye.\u201d Mitchell R. Vollger, PhD Toward cures for genetic diseases<\/p>\n
Vollger hopes that, by linking changes in the genetic code to functional differences in gene regulation, FIRE will help find which genetic differences cause human disease\u2014a crucial early step toward developing therapies that edit DNA to treat or even cure hereditary diseases.<\/p>\n
\u201cThis might show us how we could edit the DNA switches that control a person\u2019s genes to help lower their risk for a common disease, or even cure them of a rare disease,\u201d Vollger says. \u201cIt\u2019s a small step toward turning the genetic variants we find into something doctors can act on.\u201d\u00a0<\/p>\n
\u00a0<\/p>\n
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These results are published in Cell as \u201cSomatic epimutations cap genetic determinism in the human diploid chromatin epigenome.\u201d<\/a><\/p>\nThis research was funded by the National Institutes of Health (1DP5OD029630, OT2OD002748), including the National Human Genome Research Institute (1U01HG013744), the National Institute on Drug Abuse (UM1DA058220, R01HG002385), the National Institute of Allergy and Infectious Diseases (1DP2AI183504, 1U01AI176320), the National Institute of General Medical Sciences (2T32GM007454-46, 1K99GM155552-01), the Brotman Baty Institute, Google.org, and the Crohn\u2019s and Colitis Foundation (1158945). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.<\/p>\n","protected":false},"excerpt":{"rendered":"\u00a0Key points: Changes to how our genes are turned on and off are critical to health but are…\n","protected":false},"author":2,"featured_media":883855,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[50],"tags":[200,371038,10741,79,154693],"class_list":["post-883854","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-genetics","tag-human-geneticshuman-genomegene-regulationepigeneticsgenetic-diseasemachine-learningartificial-intelligenceai","tag-newswise","tag-science","tag-university-of-utah-health"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/883854","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/comments?post=883854"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/883854\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media\/883855"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media?parent=883854"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/categories?post=883854"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/tags?post=883854"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}