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Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity

View ORCID ProfileSeverin Uebbing, Jake Gockley, Steven K. Reilly, Acadia A. Kocher, Evan Geller, Neeru Gandotra, Curt Scharfe, Justin Cotney, View ORCID ProfileJames P. Noonan
doi: https://doi.org/10.1101/865519
Severin Uebbing
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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  • ORCID record for Severin Uebbing
Jake Gockley
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Steven K. Reilly
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Acadia A. Kocher
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Evan Geller
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Neeru Gandotra
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Curt Scharfe
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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Justin Cotney
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
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James P. Noonan
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
2Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, USA
3Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
4Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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  • ORCID record for James P. Noonan
  • For correspondence: james.noonan@yale.edu
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Abstract

Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of the human brain. However, identifying the particular changes that modified regulatory activity during neurodevelopment remains challenging. Here we used massively parallel enhancer assays in human neural stem cells to measure the impact of 32,776 human-specific substitutions on enhancer activity in 1,363 Human Accelerated Regions (HARs) and 3,027 Human Gain Enhancers (HGEs), which include enhancers with novel activities in humans. We found that 31.9% of active HARs and 36.4% of active HGEs exhibited differential activity between human and chimpanzee. This enabled us to isolate the effects of 401 human-specific substitutions from other types of genetic variation in HARs and HGEs. Substitutions acted in both an additive and non-additive manner to alter enhancer activity. Human-specific substitutions altered predicted binding sites for a specific set of human transcription factors (TFs) that were a subset of TF binding sites associated with enhancer activity in our assay. Substitutions within HARs, which are overall highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions may be buffered in enhancers with constrained ancestral functions. Our findings yield insight into the mechanisms by which human-specific genetic changes impact enhancer function and provide a rich set of candidates for experimental studies of regulatory evolution in humans.

Footnotes

  • We previously uploaded old figure versions. This error has been corrected.

  • https://github.com/NoonanLab/Uebbing_Gockley_et_al_MPRA

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 4.0 International license.
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Posted December 05, 2019.
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Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity
Severin Uebbing, Jake Gockley, Steven K. Reilly, Acadia A. Kocher, Evan Geller, Neeru Gandotra, Curt Scharfe, Justin Cotney, James P. Noonan
bioRxiv 865519; doi: https://doi.org/10.1101/865519
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Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity
Severin Uebbing, Jake Gockley, Steven K. Reilly, Acadia A. Kocher, Evan Geller, Neeru Gandotra, Curt Scharfe, Justin Cotney, James P. Noonan
bioRxiv 865519; doi: https://doi.org/10.1101/865519

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