Study / S4SDNXNTW2021-01-27
A Human Accelerated Region is a Leydig cell GLI2 Enhancer that Affects Male-Typical Behavior
Andrew R. Norman, Ann H. Ryu, Kirsty Jamieson, Sean Thomas, Yin Shen et al.
About this study
Human accelerated regions (HARs) are sequences that have evolved at an accelerated rate in the human lineage. Some HARs are developmental enhancers. We used a massively parallel reporter assay (MPRA) to identify HARs with enhancer activity in a mammalian testis cell line. A subset of HARs exhibited differential activity between the human and chimpanzee orthologs, representing candidates for underlying unique human male reproductive biology. We further characterized one of these candidate testis enhancers, 2xHAR.238. CRISPR/Cas9-mediated deletion in a testis cell line and mice revealed that 2xHAR.238 enhances expression of Gli2, encoding a Hedgehog pathway effector, in testis Leydig cells. 4C-seq revealed that 2xHAR.238 contacts the Gli2 promoter, consistent with enhancer function. In adult male mice, deletion of 2xHAR.238 disrupted mouse male-typical behavior and male interest in female odor. Combined, our work identifies a HAR that promotes the expression of Gli2 in Leydig cells and may have contributed to the evolution of human male reproductive biology.
Full author list & citation
Andrew R. Norman, Ann H. Ryu, Kirsty Jamieson, Sean Thomas, Yin Shen, Nadav Ahituv, Katherine S. Pollard, Jeremy F. Reiter. A Human Accelerated Region is a Leydig cell GLI2 Enhancer that Affects Male-Typical Behavior. 2021-01-27. https://doi.org/10.1101/2021.01.27.428524
Experiments 1
E6ULWDPUH
A triplicate lentiviral MPRA tested human and chimpanzee orthologs of 714 human accelerated regions in the GC-1spg mouse testis somatic cell line. The paper normalized RNA barcode reads to DNA barcode reads and reported 38 species-biased HAR hits in Figure 1C; because no target count matrix was deposited, table.csv is a hit-level extraction from that figure joined to the referenced 714-HAR library design for sequence and coordinate context.
