TY - JOUR
T1 - Characteristics of de novo structural changes in the human genome
AU - Kloosterman, Wigard P.
AU - Francioli, Laurent C.
AU - Hormozdiari, Fereydoun
AU - Marschall, Tobias
AU - Hehir-Kwa, Jayne Y.
AU - Abdellaoui, Abdel
AU - Lameijer, Eric-Wubbo
AU - Moed, Matthijs H.
AU - Koval, Vyacheslav
AU - Renkens, Ivo
AU - van Roosmalen, Markus J.
AU - Arp, Pascal
AU - Karssen, Lennart C.
AU - Coe, Bradley P.
AU - Handsaker, Robert E.
AU - Suchiman, Eka D.
AU - Cuppen, Edwin
AU - Thung, Djie Tjwan
AU - McVey, Mitch
AU - Wendl, Michael C.
AU - Uitterlinden, Andre
AU - van Duijn, Cornelia M.
AU - Swertz, Morris A.
AU - Wijmenga, Cisca
AU - van Ommen, GertJan B.
AU - Slagboom, P. Eline
AU - Boomsma, Dorret I.
AU - Schoenhuth, Alexander
AU - Eichler, Evan E.
AU - de Bakker, Paul I. W.
AU - Ye, Kai
AU - Guryev, Victor
AU - Genome Netherlands Consortium
PY - 2015/6
Y1 - 2015/6
N2 - 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.
AB - 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.
KW - COPY NUMBER VARIATION
KW - INTELLECTUAL DISABILITY
KW - POPULATION-SCALE
KW - INDIVIDUAL HUMAN
KW - SEQUENCING DATA
KW - MUTATION-RATES
KW - VARIANTS
KW - DISCOVERY
KW - GENE
KW - IDENTIFICATION
U2 - 10.1101/gr.185041.114
DO - 10.1101/gr.185041.114
M3 - Article
SN - 1088-9051
VL - 25
SP - 792
EP - 801
JO - Genome Research
JF - Genome Research
IS - 6
ER -