{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:06:02Z","timestamp":1789160762885,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,9]]},"group-title":"Genomics","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["DAF2021-239932"],"award-info":[{"award-number":["DAF2021-239932"]}],"id":[{"id":"https:\/\/ror.org\/02qenvm24","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DAF2020-217686"],"award-info":[{"award-number":["DAF2020-217686"]}],"id":[{"id":"https:\/\/ror.org\/02qenvm24","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35GM142983"],"award-info":[{"award-number":["R35GM142983"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute of Child Health and Human Development","award":["R01HD068524"],"award-info":[{"award-number":["R01HD068524"]}]},{"name":"Christopher Hess Research Fund"},{"name":"March of Dimes Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Human pregnancy unfolds in a unique mosaic tissue context. Embryonic\/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker\n                  <jats:italic>NID2<\/jats:italic>\n                  , which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific\n                  <jats:italic>NID2<\/jats:italic>\n                  promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower\n                  <jats:italic>NID2<\/jats:italic>\n                  expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal\u2013fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.\n                <\/jats:p>","DOI":"10.64898\/2026.09.04.749511","type":"posted-content","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:10:18Z","timestamp":1788959418000},"source":"Crossref","is-referenced-by-count":0,"title":["Spatial Logic and Evolutionary Innovation in Human Placentation"],"prefix":"10.64898","author":[{"given":"Zhida","family":"Luo","sequence":"first","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA"},{"name":"Center for Reproductive Science, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"The Institute for Human Genetics, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA"},{"name":"Center for Reproductive Science, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"The Institute for Human Genetics, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Center for Reproductive Science, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Deparments of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuhin Kumar","family":"Guha","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purnima","family":"Narasimhan Iyer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina Lao","family":"Mason","sequence":"additional","affiliation":[{"name":"UCSF Center for Birth Justice, University of California San Francisco, CA, USA"},{"name":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areca","family":"Smit","sequence":"additional","affiliation":[{"name":"UCSF Center for Birth Justice, University of California San Francisco, CA, USA"},{"name":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Sun","sequence":"additional","affiliation":[{"name":"Center of Reproductive Sciences, Department of Pediatrics, Cincinnati Children\u2019s Hospital, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David K.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Frolova","sequence":"additional","affiliation":[{"name":"Division of Maternal-Fetal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah 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