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Increased mutation and gene conversion within human segmental duplications

2023; Nature Portfolio; Volume: 617; Issue: 7960 Linguagem: Inglês

10.1038/s41586-023-05895-y

1476-4687

Mitchell R. Vollger, Philip C. Dishuck, William T. Harvey, William S. DeWitt, Xavi Guitart, Michael E. Goldberg, Allison N. Rozanski, Julian Lucas, Mobin Asri, Haley Abel, Lucinda Antonacci-Fulton, Gunjan Baid, Carl Baker, Anastasiya Belyaeva, Konstantinos Billis, Guillaume Bourque, Silvia Buonaiuto, Andrew Carroll, Mark Chaisson, Pi-Chuan Chang, Xian Chang, Haoyu Cheng, Justin Chu, Sarah Cody, Vincenza Colonna, Daniel E. Cook, Robert Cook‐Deegan, Omar E. Cornejo, Mark Diekhans, Daniel Doerr, Peter Ebert, Jana Ebler, Jordan M. Eizenga, Susan Fairley, Olivier Fédrigo, Adam L. Felsenfeld, Xiaowen Feng, Christian Fischer, Paul Flicek, Giulio Formenti, Adam Frankish, Robert S. Fulton, Yan Gao, Shilpa Garg, Erik Garrison, Nanibaa’ A. Garrison, Carlos García Girón, Richard E. Green, Cristian Groza, Andrea Guarracino, Leanne Haggerty, Ira M. Hall, Marina Haukness, David Haussler, Simon Heumos, Glenn Hickey, Thibaut Hourlier, Kerstin Howe, Miten Jain, Erich D. Jarvis, Hanlee P. Ji, Eimear E. Kenny, Barbara A. Koenig, Alexey Kolesnikov, Jan O. Korbel, Jennifer Kordosky, Sergey Koren, HoJoon Lee, Heng Li, Wen‐Wei Liao, Shuangjia Lu, Tsung-Yu Lu, Julian Lucas, Hugo Magalhães, Santiago Marco‐Sola, Pierre Marijon, Charles Markello, Tobias Marschall, Fergal J. Martin, Ann M. Mc Cartney, Jennifer McDaniel, Karen H. Miga, Matthew W. Mitchell, Jean Monlong, Jacquelyn Mountcastle, Moses Njagi Mwaniki, Maria Nattestad, Adam M. Novak, Sergey Nurk, Hugh E. Olsen, Nathan D. Olson, Benedict Paten, Trevor Pesout, Adam M. Phillippy, Alice B. Popejoy, Pjotr Prins, Daniela Puiu, Mikko Rautiainen, Allison Regier, Arang Rhie, Samuel Sacco, Ashley D. Sanders, Valérie Schneider, Baergen I. Schultz, Kishwar Shafin, Jonas A. Sibbesen, Jouni Sirén, Michael W. Smith, Heidi J. Sofia, Ahmad Abou Tayoun, Françoise Thibaud-Nissen, Chad Tomlinson, Francesca Floriana Tricomi, Flavia Villani, Mitchell R. Vollger, Justin Wagner, Brian P. Walenz, Ting Wang, Jonathan Wood, Aleksey V. Zimin, Justin M. Zook, Katherine M. Munson, Alexandra P. Lewis, Kendra Hoekzema, Glennis A. Logsdon, David Porubský, Benedict Paten, Kelley Harris, PingHsun Hsieh, Evan E. Eichler,

Genetic factors in colorectal cancer

Abstract Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data 1,2 . Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions 3,4 . We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have ‘relocated’ on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences 5,6 .