Author:
Kloosterman Wigard P.,Francioli Laurent C.,Hormozdiari Fereydoun,Marschall Tobias,Hehir-Kwa Jayne Y.,Abdellaoui Abdel,Lameijer Eric-Wubbo,Moed Matthijs H.,Koval Vyacheslav,Renkens Ivo,van Roosmalen Markus J.,Arp Pascal,Karssen Lennart C.,Coe Bradley P.,Handsaker Robert E.,Suchiman Eka D.,Cuppen Edwin,Thung Djie Tjwan,McVey Mitch,Wendl Michael C.,Uitterlinden André,van Duijn Cornelia M.,Swertz Morris A.,Wijmenga Cisca,van Ommen GertJan B.,Slagboom P. Eline,Boomsma Dorret I.,Schönhuth Alexander,Eichler Evan E.,de Bakker Paul I.W.,Ye Kai,Guryev Victor,
Abstract
Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1–20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.
Funder
Netherlands Organization for Scientific Research
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics(clinical),Genetics