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Many of these skeletal modifications underpin key events in human evolution, enabling our species to walk upright, manipulate tools with precision, and support enlarged brains. Identifying the genomic changes that underlie these features remains an outstanding challenge due to the substantial number of differences between the human and chimpanzee genomes. To identify human-chimp sequence differences that modulate gene expression in the developing postcranial skeleton, we used a massively parallel reporter assay to screen the human and chimp versions of 70,000 regulatory elements present in the prenatal skeletal template for differential activity. After testing our library in two cartilage (CHON002 and T\/C-28a2) and one control cell line (K562), we identify 30,736 regions (45.2%) with activity in our assay. Of the active regions, we find that 11,542 (37.6%; or 17% of the entire pool) regions exhibited differential activity between the human and chimpanzee. We find that human ancestor quickly evolved regions were predictive of differential activity while human accelerated regions were not and both sets failed to predict the magnitude of effect, unlike the total number of base pair differences between species, which was weakly correlated with effect size. These findings are consistent with a polygenic model of human skeletal evolution based on widespread regulatory changes distributed across thousands of elements rather than concentrated effects at a few key loci.<\/jats:p>","DOI":"10.1093\/gbe\/evag121","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:41:13Z","timestamp":1778586073000},"source":"Crossref","is-referenced-by-count":2,"title":["In Vitro Massively Parallel Screening of Human Regulatory Elements Involved in Postcranial Skeletal Development for Differential Activity Compared to Chimpanzee"],"prefix":"10.1093","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4630-7548","authenticated-orcid":false,"given":"Alexander S","family":"Okamoto","sequence":"first","affiliation":[{"name":"Department of Human Evolutionary Biology, Harvard University , Cambridge, MA 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