{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T14:22:29Z","timestamp":1769264549238,"version":"3.49.0"},"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["IOS-2038528"],"award-info":[{"award-number":["IOS-2038528"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In various organisms, sequencing of selectively bred lines at apparent selection limits has demonstrated that genetic variation can remain at many loci, implying that evolution at the genetic level may continue even if the population mean phenotype remains constant. We compared selection signatures at generations 22 and 61 of the \u201cHigh Runner\u201d mouse experiment, which includes 4 replicate lines bred for voluntary wheel-running behavior (HR) and 4 non-selected control (C) lines. Previously, we reported multiple regions of differentiation between the HR and C lines, based on whole-genome sequence data for 10 mice from each line at generation 61, which was &gt;31 generations after selection limits had been reached in all HR lines. Here, we analyzed pooled sequencing data from ~20 mice for each of the 8 lines at generation 22, around when HR lines were reaching limits. Differentiation analyses of allele frequencies at ~4.4 million SNP loci used the regularized T-test and detected 258 differentiated regions with FDR = 0.01. Comparable analyses involving pooling generation 61 individual mouse genotypes into allele frequencies by line produced only 11 such regions, with almost no overlap among the largest and most statistically significant peaks between the two generations. These results implicate a sort of \u201cgenetic churn\u201d that continues at loci relevant for running. Simulations indicate that loss of statistical power due to random genetic drift and sampling error are insufficient to explain the differences in selection signatures. The 13 differentiated regions at generation 22 with strict culling measures include 79 genes related to a wide variety of functions. Gene ontology identified pathways related to olfaction and vomeronasal pathways as being overrepresented, consistent with generation 61 analyses, despite those specific regions differing between generations. Genes <jats:italic>Dspp<\/jats:italic> and <jats:italic>Rbm24<\/jats:italic> are also identified as potentially explaining known bone and skeletal muscle differences, respectively, between the linetypes.<\/jats:p>","DOI":"10.1371\/journal.pone.0306397","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T18:14:12Z","timestamp":1722536052000},"page":"e0306397","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Large changes in detected selection signatures after a selection limit in mice bred for voluntary wheel-running behavior"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7062-7376","authenticated-orcid":true,"given":"David A.","family":"Hillis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liran","family":"Yadgary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George M.","family":"Weinstock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando Pardo-Manuel","family":"de Villena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Pomp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7916-3552","authenticated-orcid":true,"given":"Theodore","family":"Garland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"pone.0306397.ref001","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1073\/pnas.62.1.75","article-title":"Artificial and natural selection for two behavioral traits in Drosophila pseudoobscura","volume":"62","author":"T Dobzhansky","year":"1969","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0306397.ref002","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1017\/S0003356100022856","article-title":"Genetic variation in a line of mice selected to its limit for high body weight","volume":"19","author":"WK Al-Murrani","year":"1974","journal-title":"Anim Sci"},{"key":"pone.0306397.ref003","doi-asserted-by":"crossref","first-page":"3102","DOI":"10.1111\/evo.12200","article-title":"Limits to behavioral evolution: the quantative genetics of a complex trait under directional selection","volume":"67","author":"V Careau","year":"2013","journal-title":"Evolution"},{"key":"pone.0306397.ref004","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/hdy.2014.86","article-title":"Combining experimental evolution with next-generation sequencing: a powerful tool to study adaptation from standing genetic variation","volume":"114","author":"C Schl\u00f6tterer","year":"2015","journal-title":"Heredity"},{"key":"pone.0306397.ref005","article-title":"Bidirectional selection for body weight on standing genetic variation in a chicken model","author":"M Lillie","year":"2019","journal-title":"Genes|Genomes|Genetics"},{"key":"pone.0306397.ref006","volume-title":"Introduction to quantitative genetics","author":"DS Falconer","year":"1989","edition":"3"},{"key":"pone.0306397.ref007","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1111\/eva.13320","article-title":"How much energetic trade\u2010offs limit selection? 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