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Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome

Vera B. Kaiser, Lana Talmane, Yatendra Kumar, Fiona Semple, Marie MacLennan, Deciphering Developmental Disorders Study, David R. FitzPatrick, Martin S. Taylor, Colin A. Semple
doi: https://doi.org/10.1101/2021.06.10.447556
Vera B. Kaiser
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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  • For correspondence: vera.kaiser@ed.ac.uk
Lana Talmane
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Yatendra Kumar
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Fiona Semple
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Marie MacLennan
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
2The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
David R. FitzPatrick
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Martin S. Taylor
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Colin A. Semple
1MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK
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Abstract

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell-type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9-binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (>=5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

Competing Interest Statement

The authors have declared no competing interest.

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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-ND 4.0 International license.
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Posted June 10, 2021.
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Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome
Vera B. Kaiser, Lana Talmane, Yatendra Kumar, Fiona Semple, Marie MacLennan, Deciphering Developmental Disorders Study, David R. FitzPatrick, Martin S. Taylor, Colin A. Semple
bioRxiv 2021.06.10.447556; doi: https://doi.org/10.1101/2021.06.10.447556
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Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome
Vera B. Kaiser, Lana Talmane, Yatendra Kumar, Fiona Semple, Marie MacLennan, Deciphering Developmental Disorders Study, David R. FitzPatrick, Martin S. Taylor, Colin A. Semple
bioRxiv 2021.06.10.447556; doi: https://doi.org/10.1101/2021.06.10.447556

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