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In mammals, the nature, development and evolution of maternal-fetal interactions likely influence diseases of pregnancy. Here we show genes that evolved expression at the maternal-fetal interface in Eutherian mammals play essential roles in the evolution of pregnancy and are associated with immunological disorders and preterm birth. Among these genes is\n                    <jats:italic>HAND2<\/jats:italic>\n                    , a transcription factor that suppresses estrogen signaling, a Eutherian innovation allowing blastocyst implantation. We found dynamic\n                    <jats:italic>HAND2<\/jats:italic>\n                    expression in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to a low at term. HAND2 regulates a distinct set of genes in endometrial stromal fibroblasts including\n                    <jats:italic>IL15<\/jats:italic>\n                    , a cytokine also exhibiting dynamic expression throughout the menstrual cycle and gestation, promoting migration of natural killer cells and extravillous cytotrophoblasts. We demonstrate that\n                    <jats:italic>HAND2<\/jats:italic>\n                    promoter loops to an enhancer containing SNPs implicated in birth weight and gestation length regulation. Collectively, these data connect\n                    <jats:italic>HAND2<\/jats:italic>\n                    expression at the maternal-fetal interface with evolution of implantation and gestational regulation, and preterm birth.\n                  <\/jats:p>","DOI":"10.7554\/elife.61257","type":"journal-article","created":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T08:00:32Z","timestamp":1612166432000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.61257","source":"Crossref","is-referenced-by-count":52,"title":["Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7037-8389","authenticated-orcid":true,"given":"Mirna","family":"Marini\u0107","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Chicago, Chicago, United 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