@article{5d81bd77fc37419093645080ecd4a479,
title = "Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates",
abstract = "The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.",
author = "Bo Xia and Yun Yan and Maayan Baron and Florian Wagner and Dalia Barkley and Marta Chiodin and Kim, {Sang Y.} and Keefe, {David L.} and Alukal, {Joseph P.} and Boeke, {Jef D.} and Itai Yanai",
note = "Funding Information: We thank Yael Kramer, Xavier Sanchez, and Fang Wang for coordinating the human testicular tissue collection. We thank Molly Przeworski, Hannah Klein, Evgeny Nudler, Matthew Maurano, Jane Skok, Iannis Aifantis, Ziyue Gao, Huiyuan Zhang, and the members of the Yanai lab for constructive comments and suggestions to the manuscript. We thank Megan Hogan, Raven Luther, and Matthew Maurano for assistance with sequencing. We also thank the anonymous reviewers for providing constructive comments and suggestions. This work was supported by the NYU Grossman School of Medicine with funding to I.Y. J.D.B. was supported in part by CEGS grant 1 RM1 HG009491. B.X. and I.Y. conceived and designed the project, interpreted the results, and drafted the manuscript. B.X. led and conducted most of the experimental and analysis components. Y.Y. contributed to the RNA velocity and pseudotime analysis and built the pipeline for processing raw germline variants data with contributions from B.X. and I.Y. M.B. D.B. and M.C. contributed expertise in the inDrop experiments. M.B. and F.W. helped with scRNA-seq data analysis. F.W. built the inDrop sequencing data mapping pipeline. J.P.A. S.Y.K. and D.L.K. contributed to the sample collection. J.D.B. contributed to interpreting the results. All authors edited the manuscript. I.Y. is a shareholder of One Cell Medical, Ltd. J.D.B. is a founder and director of Neochromosome, Inc.; the Center of Excellence for Engineering Biology; and CDI Labs, Inc. and serves or has recently served on the scientific advisory board of Modern Meadow, Inc.; Recombinetics, Inc.; Sample6, Inc.; and Sangamo, Inc. These arrangements are reviewed and managed by the committee on conflict of interest at NYULH. All other authors declare no competing interests. Funding Information: We thank Yael Kramer, Xavier Sanchez, and Fang Wang for coordinating the human testicular tissue collection. We thank Molly Przeworski, Hannah Klein, Evgeny Nudler, Matthew Maurano, Jane Skok, Iannis Aifantis, Ziyue Gao, Huiyuan Zhang, and the members of the Yanai lab for constructive comments and suggestions to the manuscript. We thank Megan Hogan, Raven Luther, and Matthew Maurano for assistance with sequencing. We also thank the anonymous reviewers for providing constructive comments and suggestions. This work was supported by the NYU Grossman School of Medicine with funding to I.Y. J.D.B. was supported in part by CEGS grant 1 RM1 HG009491 . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = jan,
day = "23",
doi = "10.1016/j.cell.2019.12.015",
language = "English (US)",
volume = "180",
pages = "248--262.e21",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}