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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, Nadav Ahituv, Katherine S. Pollard, Jeremy F. Reiter
doi: https://doi.org/10.1101/2021.01.27.428524
Andrew R. Norman
1Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
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Ann H. Ryu
2Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA
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Kirsty Jamieson
3Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
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Sean Thomas
4Altius Institute for Biomedical Sciences, Washington, USA
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Yin Shen
3Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
5Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
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Nadav Ahituv
2Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA
5Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
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Katherine S. Pollard
6Gladstone Institute of Data Science & Biotechnology, San Francisco, CA
7Department of Epidemiology & Biostatistics, University of California, San Francisco, CA
8Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Jeremy F. Reiter
1Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
8Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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  • For correspondence: jeremy.reiter@ucsf.edu
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ABSTRACT

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 27, 2021.
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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, Nadav Ahituv, Katherine S. Pollard, Jeremy F. Reiter
bioRxiv 2021.01.27.428524; doi: https://doi.org/10.1101/2021.01.27.428524
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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, Nadav Ahituv, Katherine S. Pollard, Jeremy F. Reiter
bioRxiv 2021.01.27.428524; doi: https://doi.org/10.1101/2021.01.27.428524

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