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While much of the human genome is identical across populations, it is estimated that as much as 0.4% of the genome can differ due to ancestry. This variation is primarily characterized by single nucleotide variants (SNVs), which are often unique to specific genetic populations. Knowledge of a patient's genetic ancestry can inform clinical decisions, from genetic testing and health screenings to medication dosages, based on ancestral disease predispositions. Nevertheless, the current reliance on self-reported ancestry can introduce subjectivity and exacerbate health disparities. While genomic sequencing data enables objective determination of a patient's genetic ancestry, existing approaches are limited to ancestry inference at the continental level.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>To address this challenge, and create an objective, measurable metric of genetic ancestry we present SNVstory, a method built upon three independent machine learning models for accurately inferring the sub-continental ancestry of individuals. We also introduce a novel method for simulating individual samples from aggregate allele frequencies from known populations. SNVstory includes a feature-importance scheme, unique among open-source ancestral tools, which allows the user to track the ancestral signal broadcast by a given gene or locus. We successfully evaluated SNVstory using a clinical exome sequencing dataset, comparing self-reported ethnicity and race to our inferred genetic ancestry, and demonstrate the capability of the algorithm to estimate ancestry from 36 different populations with high accuracy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>SNVstory represents a significant advance in methods to assign genetic ancestry, opening the door to ancestry-informed care. SNVstory, an open-source model, is packaged as a Docker container for enhanced reliability and interoperability. It can be accessed from <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/nch-igm\/snvstory\">https:\/\/github.com\/nch-igm\/snvstory<\/jats:ext-link>.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12859-024-05703-y","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T08:02:34Z","timestamp":1708416154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["SNVstory: inferring genetic ancestry from genome sequencing data"],"prefix":"10.1186","volume":"25","author":[{"given":"Audrey E.","family":"Bollas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Rajkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Defne","family":"Ceyhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B.","family":"Gaither","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine R.","family":"Mardis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"key":"5703_CR1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"A Auton","year":"2015","unstructured":"Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, et al. 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The participant\u2019s legal guardian\/next of kin provided written informed consent to participate in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"No competing interests: AEB, AR, DC, JBG, and PW. ERM: Qiagen N.V., supervisory board member, honorarium, and stock-based compensation. Singular Genomics Systems, Inc., board of directors, honorarium, and stock-based compensation.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"76"}}