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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.

Original publication

DOI

10.1101/gr.185041.114

Type

Journal article

Journal

Genome research

Publication Date

06/2015

Volume

25

Pages

792 - 801

Addresses

Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;

Keywords

Genome of Netherlands Consortium, Humans, Retroelements, Sequence Alignment, Sequence Analysis, DNA, Genomics, Amino Acid Sequence, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Molecular Sequence Data, Female, Male, INDEL Mutation, Genetic Variation, Mutation Rate