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Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors

Hane Ryu, Fumitaka Inoue, Sean Whalen, Alex Williams, Martin Kircher, Beth Martin, Beatriz Alvarado, Md. Abul Hassan Samee, Kathleen Keough, Sean Thomas, Arnold Kriegstein, Jay Shendure, Alex Pollen, Nadav Ahituv, Katherine S. Pollard
doi: https://doi.org/10.1101/256313
Hane Ryu
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
3Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA, USA
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Fumitaka Inoue
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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Sean Whalen
4Gladstone Institutes, San Francisco, CA 94158, USA
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Alex Williams
4Gladstone Institutes, San Francisco, CA 94158, USA
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Martin Kircher
5Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
6Berlin Institute of Health, Berlin, Germany
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Beth Martin
5Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
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Beatriz Alvarado
7Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
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Md. Abul Hassan Samee
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
4Gladstone Institutes, San Francisco, CA 94158, USA
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Kathleen Keough
3Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA, USA
4Gladstone Institutes, San Francisco, CA 94158, USA
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Sean Thomas
4Gladstone Institutes, San Francisco, CA 94158, USA
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Arnold Kriegstein
7Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
9Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Jay Shendure
5Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
8Howard Hughes Medical Institute, Seattle, Washington 98195, USA
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Alex Pollen
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
7Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143
9Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Nadav Ahituv
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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  • For correspondence: nadav.ahituv@ucsf.edu katherine.pollard@gladstone.ucsf.edu
Katherine S. Pollard
2Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
4Gladstone Institutes, San Francisco, CA 94158, USA
10Department of Epidemiology and Biostatistics and Institute for Computational Health Sciences, University of California San Francisco, San Francisco, CA, USA
11Chan-Zuckerberg Biohub, San Francisco, CA, USA
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  • For correspondence: nadav.ahituv@ucsf.edu katherine.pollard@gladstone.ucsf.edu
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SUMMARY

How mutations in gene regulatory elements lead to evolutionary changes remains largely unknown. Human accelerated regions (HARs) are ideal for exploring this question, because they are associated with human-specific traits and contain multiple human-specific variants at sites conserved across mammals, suggesting that they alter or compensate to preserve function. We performed massively parallel reporter assays on all human and chimpanzee HAR sequences in human and chimpanzee iPSC-derived neural progenitors at two differentiation stages. Forty-three percent (306/714) of HARs function as neuronal enhancers, with two-thirds (204/306) showing consistent changes in activity between human and chimpanzee sequences. These changes were almost all sequence dependent and not affected by cell species or differentiation stage. We tested all evolutionary intermediates between human and chimpanzee sequences of seven HARs, finding variants that interact both positively and negatively. This study shows that variants acquired during human evolution interact to buffer and amplify changes to enhancer function.

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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 4.0 International license.
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Posted January 29, 2018.
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Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors
Hane Ryu, Fumitaka Inoue, Sean Whalen, Alex Williams, Martin Kircher, Beth Martin, Beatriz Alvarado, Md. Abul Hassan Samee, Kathleen Keough, Sean Thomas, Arnold Kriegstein, Jay Shendure, Alex Pollen, Nadav Ahituv, Katherine S. Pollard
bioRxiv 256313; doi: https://doi.org/10.1101/256313
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Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors
Hane Ryu, Fumitaka Inoue, Sean Whalen, Alex Williams, Martin Kircher, Beth Martin, Beatriz Alvarado, Md. Abul Hassan Samee, Kathleen Keough, Sean Thomas, Arnold Kriegstein, Jay Shendure, Alex Pollen, Nadav Ahituv, Katherine S. Pollard
bioRxiv 256313; doi: https://doi.org/10.1101/256313

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