Mechanisms of formation of structural variation in a fully sequenced human genome

Hum Mutat. 2013 Feb;34(2):345-54. doi: 10.1002/humu.22240. Epub 2012 Nov 19.


Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1 kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10 kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10 kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint-resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Deletion
  • Chromosome Inversion
  • Chromosomes, Human, Pair 16 / genetics
  • Chymotrypsin / genetics
  • Chymotrypsin / metabolism
  • Chymotrypsinogen / genetics
  • Chymotrypsinogen / metabolism
  • Gene Frequency
  • Genetic Variation*
  • Genome, Human*
  • Haplotypes
  • Humans
  • Microsatellite Repeats
  • Minisatellite Repeats
  • Retroelements
  • Sequence Analysis, DNA / methods*
  • Trisomy / genetics


  • Retroelements
  • Chymotrypsinogen
  • Chymotrypsin
  • chymotrypsin B

Supplementary concepts

  • Chromosome 16, trisomy 16q