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Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson\u2013Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre\u2010 and post\u2010expansion and sequenced at high depth (1656\u00d7 mean coverage), over a cumulative 290\u00a0kb target region, including the exons of 44 aging\u2010related genes. Allele frequencies of 58 somatic mutations differed between the pre\u2010 and post\u2010cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, <jats:italic>CDKN2A<\/jats:italic> c.53C&gt;T (T18M) and <jats:italic>ERCC8<\/jats:italic> c.*772T&gt;A, were identified in cells from a patient with XPA. The allele frequency of the <jats:italic>CDKN2A<\/jats:italic> mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, <jats:italic>BRCA2<\/jats:italic> c.6222C&gt;T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells.\u00a0Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.<\/jats:p>","DOI":"10.1111\/acel.13010","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T04:54:23Z","timestamp":1565067263000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-1156","authenticated-orcid":false,"given":"Narisu","family":"Narisu","sequence":"first","affiliation":[{"name":"National Human Genome Research Institute National 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Research Institute National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Z\u00f6llner","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan Ann Arbor MI USA"},{"name":"Department of Psychiatry University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6603-1833","authenticated-orcid":false,"given":"Michael R.","family":"Erdos","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1023-7410","authenticated-orcid":false,"given":"Francis S.","family":"Collins","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3233-2862","authenticated-orcid":false,"given":"Maria","family":"Eriksson","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health Bethesda MD USA"},{"name":"Department of Biosciences and Nutrition, Center for Innovative Medicine Karolinska Institutet Huddinge 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