{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:16:11Z","timestamp":1778624171955,"version":"3.51.4"},"reference-count":74,"publisher":"The Royal Society","issue":"1710","license":[{"start":{"date-parts":[[2016,12,19]],"date-time":"2016-12-19T00:00:00Z","timestamp":1482105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"funder":[{"name":"The Intramural Research Program of the National Cancer Institute, National Institutes of Health, supports this research."}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Phil. Trans. R. Soc. B"],"published-print":{"date-parts":[[2016,12,19]]},"abstract":"<jats:p>\n                    Genetic aberrations of several unlinked loci cause human congenital split hand\/foot malformation (SHFM) development. Mutations of the\n                    <jats:italic>DLX5<\/jats:italic>\n                    (\n                    <jats:italic>distal-less<\/jats:italic>\n                    ) transcription factor-encoding gene in chromosome 7 cause SHFM through haploinsufficiency, but the vast majority of cases result from heterozygous chromosomal aberrations of the region without mutating the\n                    <jats:italic>DLX5<\/jats:italic>\n                    gene. To resolve this paradox, we invoke a chromosomal epigenetic mechanism for limb development. It is composed of a monochromatid gene expression phenomenon that we discovered in two fission yeasts with the selective chromosome copy segregation phenomenon that we discovered in mouse cells. Accordingly, one daughter cell inherits both expressed\n                    <jats:italic>DLX5<\/jats:italic>\n                    copies while the other daughter inherits both epigenetically silenced ones from a single deterministic cell of the developing limb. Thus, differentiated daughter cells after further proliferation will correspondingly produce proximal\/distal-limb tissues. Published results of a Chr. 7 translocation with a centromere-proximal breakpoint situated over 41 million bases away from the\n                    <jats:italic>DLX<\/jats:italic>\n                    locus, centromeric and\n                    <jats:italic>DLX5<\/jats:italic>\n                    -region inversions have satisfied key genetic and developmental biology predictions of the mechanism. Further genetic tests of the mechanism are proposed. We propose that the DNA double helical structure itself causes the development of sister cells' gene regulation asymmetry. We also argue against the conventionally invoked morphogen model of development.\n                  <\/jats:p>\n                  <jats:p>This article is part of the themed issue \u2018Provocative questions in left\u2013right asymmetry\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2015.0415","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T20:54:07Z","timestamp":1478552047000},"page":"20150415","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Split hand\/foot malformation genetics supports the chromosome 7 copy segregation mechanism for human limb development"],"prefix":"10.1098","volume":"371","author":[{"given":"Amar J. 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