Increased mutation and gene conversion within human segmental duplications
Authors: Vollger Mitchell R. , Dishuck Philip C. , Harvey William T. , DeWitt William S. , Guitart Xavi , Goldberg Michael E. , Rozanski Allison N. , Lucas Julian , Asri Mobin ,   Human Pangenome Reference Consortium, Abel Haley J. , Antonacci-Fulton Lucinda L. , Baid Gunjan , Baker Carl A. , Belyaeva Anastasiya , Billis Konstantinos , Bourque Guillaume , Buonaiuto Silvia , Carroll Andrew , Chaisson Mark J. P. , Chang Pi-Chuan , Chang Xian H. , Cheng Haoyu , Chu Justin , Cody Sarah , Colonna Vincenza , Cook Daniel E. , Cook-Deegan Robert M. , Cornejo Omar E. , Diekhans Mark , Doerr Daniel , Ebert Peter , Ebler Jana , Eizenga Jordan M. , Fairley Susan , Fedrigo Olivier , Felsenfeld Adam L. , Feng Xiaowen , Fischer Christian , Flicek Paul , Formenti Giulio , Frankish Adam , Fulton Robert S. , Gao Yan , Garg Shilpa , Garrison Erik , Garrison Nanibaa’ A. , Giron Carlos Garcia , Green Richard E. , Groza Cristian , Guarracino Andrea , Haggerty Leanne , Hall Ira M. , Haukness Marina , Haussler David , Heumos Simon , Hickey Glenn , Hourlier Thibaut , Howe Kerstin , Jain Miten , Jarvis Erich D. , Ji Hanlee P. , Kenny Eimear E. , Koenig Barbara A. , Kolesnikov Alexey , Korbel Jan O. , Kordosky Jennifer , Koren Sergey , Lee HoJoon , Li Heng , Liao Wen-Wei , Lu Shuangjia , Lu Tsung-Yu , Lucas Julian K. , Magalhães Hugo , Marco-Sola Santiago , Marijon Pierre , Markello Charles , Marschall Tobias , Martin Fergal J. , McCartney Ann , McDaniel Jennifer , Miga Karen H. , Mitchell Matthew W. , Monlong Jean , Mountcastle Jacquelyn , Mwaniki Moses Njagi , Nattestad Maria , Novak Adam M. , Nurk Sergey , Olsen Hugh E. , Olson Nathan D. , Paten Benedict , Pesout Trevor , Phillippy Adam M. , Popejoy Alice B. , Prins Pjotr , Puiu Daniela , Rautiainen Mikko , Regier Allison A. , Rhie Arang , Sacco Samuel , Sanders Ashley D. , Schneider Valerie A. , Schultz Baergen I. , Shafin Kishwar , Sibbesen Jonas A. , Sirén Jouni , Smith Michael W. , Sofia Heidi J. , Abou Tayoun Ahmad N. , Thibaud-Nissen Françoise , Tomlinson Chad , Tricomi Francesca Floriana , Villani Flavia , Vollger Mitchell R. , Wagner Justin , Walenz Brian , Wang Ting , Wood Jonathan M. D. , Zimin Aleksey V. , Zook Justin M. , Munson Katherine M. , Lewis Alexandra P. , Hoekzema Kendra , Logsdon Glennis A. , Porubsky David , Paten Benedict , Harris Kelley , Hsieh PingHsun , Eichler Evan E. 
Published: May 2023

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. 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 regions3,4. 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 sequences5,6.