Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Jan 25

PMID 31978344

Citations 81

Authors

Bo Xia

Yun Yan

Maayan Baron

Florian Wagner

Dalia Barkley

Marta Chiodin

Sang Y Kim

David L Keefe

Joseph P Alukal

Jef D Boeke

Itai Yanai

Affiliations

Soon will be listed here.

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.

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References

Kanatsu-Shinohara M, Shinohara T . Spermatogonial stem cell self-renewal and development. Annu Rev Cell Dev Biol. 2013; 29:163-87. DOI: 10.1146/annurev-cellbio-101512-122353. View

Klein A, Mazutis L, Akartuna I, Tallapragada N, Veres A, Li V . Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell. 2015; 161(5):1187-1201. PMC: 4441768. DOI: 10.1016/j.cell.2015.04.044. View

An J, Lin K, Zhu L, Werling D, Dong S, Brand H . Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science. 2018; 362(6420). PMC: 6432922. DOI: 10.1126/science.aat6576. View

Schuster-Bockler B, Lehner B . Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature. 2012; 488(7412):504-7. DOI: 10.1038/nature11273. View

Schmidt E, Schibler U . High accumulation of components of the RNA polymerase II transcription machinery in rodent spermatids. Development. 1995; 121(8):2373-83. DOI: 10.1242/dev.121.8.2373. View

Jonsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E . Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549(7673):519-522. DOI: 10.1038/nature24018. View

Buganim Y, Itskovich E, Hu Y, Cheng A, Ganz K, Sarkar S . Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors. Cell Stem Cell. 2012; 11(3):373-86. PMC: 3438668. DOI: 10.1016/j.stem.2012.07.019. View

Cleaver J . Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: Personal Reflections on the 50th anniversary of the discovery of xeroderma pigmentosum. DNA Repair (Amst). 2017; 58:21-28. DOI: 10.1016/j.dnarep.2017.08.004. View

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

10.

Pellin D, Loperfido M, Baricordi C, Wolock S, Montepeloso A, Weinberg O . A comprehensive single cell transcriptional landscape of human hematopoietic progenitors. Nat Commun. 2019; 10(1):2395. PMC: 6546699. DOI: 10.1038/s41467-019-10291-0. View

11.

Campbell C, Eichler E . Properties and rates of germline mutations in humans. Trends Genet. 2013; 29(10):575-84. PMC: 3785239. DOI: 10.1016/j.tig.2013.04.005. View

12.

Naro C, Jolly A, Di Persio S, Bielli P, Setterblad N, Alberdi A . An Orchestrated Intron Retention Program in Meiosis Controls Timely Usage of Transcripts during Germ Cell Differentiation. Dev Cell. 2017; 41(1):82-93.e4. PMC: 5392497. DOI: 10.1016/j.devcel.2017.03.003. View

13.

Ye L, Li X, Li L, Chen H, Ge R . Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells. Front Physiol. 2017; 8:430. PMC: 5487449. DOI: 10.3389/fphys.2017.00430. View

14.

Paoli D, Pelloni M, Gallo M, Coltrinari G, Lombardo F, Lenzi A . Sperm glyceraldehyde 3-phosphate dehydrogenase gene expression in asthenozoospermic spermatozoa. Asian J Androl. 2016; 19(4):409-413. PMC: 5507084. DOI: 10.4103/1008-682X.173934. View

15.

Djureinovic D, Fagerberg L, Hallstrom B, Danielsson A, Lindskog C, Uhlen M . The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol Hum Reprod. 2014; 20(6):476-88. DOI: 10.1093/molehr/gau018. View

16.

Cervantes R, Stringer J, Shao C, Tischfield J, Stambrook P . Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci U S A. 2002; 99(6):3586-90. PMC: 122567. DOI: 10.1073/pnas.062527199. View

17.

Nei M, Suzuki Y, Nozawa M . The neutral theory of molecular evolution in the genomic era. Annu Rev Genomics Hum Genet. 2010; 11:265-89. DOI: 10.1146/annurev-genom-082908-150129. View

18.

Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z . GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009; 10:48. PMC: 2644678. DOI: 10.1186/1471-2105-10-48. View

19.

Wang D, Eraslan B, Wieland T, Hallstrom B, Hopf T, Zolg D . A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol Syst Biol. 2019; 15(2):e8503. PMC: 6379049. DOI: 10.15252/msb.20188503. View

20.

Gray K, Seal R, Tweedie S, Wright M, Bruford E . A review of the new HGNC gene family resource. Hum Genomics. 2016; 10:6. PMC: 4739092. DOI: 10.1186/s40246-016-0062-6. View