A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Genotyping inversions and tandem duplications

“…Then, PðG i jA þ ðRÞÞ is the probability for genotype G i under the assumption that the read is mapped correctly and PðG i jA À ðRÞÞ, the probability for a genotype under the assumption that the alignment of the read is wrong. Using Bayes' theorem and the assumption of constant priors over the genotypes, the probability for a particular genotype given all reads can be expressed as follows (Hehir-Kwa et al, 2016):…”

“…GenomeStrip (Handsaker et al, 2011) has been in use at the 1000 Genomes project (The 1000Genomes Project Consortium, 2015 for genotyping large deletions. MATE-CLEVER can genotype midsize and long deletions and has been in use at the Genome of the Netherlands project (Hehir-Kwa et al, 2016); the most recent version implements the framework that inspired the present paper.…”

“…While genotyping single nucleotide polymorphisms (SNPs) from NGS data already is a routine procedure, genotyping more complex and larger variants is not. Recent advances have pointed out how to do this for shorter ( 20-30 bp) insertions and deletions (indels), larger deletions and mobile element insertions (Hehir-Kwa et al, 2016;The 1000Genomes Project Consortium, 2015. However, the majority of inversions, duplications and translocations are still lacking sound models that allow to determine their genotypes from NGS data.…”

LINE- andAlu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV

“…In addition to insertional mutagenesis and nonpathogenic intraand interindividual variation, mobile elements can act as substrates for homology-driven rearrangements. Similar to low-copy repeats or segmental duplications, LINE-1 (L1) and endogenous retroviral elements (ERVs) can predispose the genome to copy-number variant (CNV) deletions and reciprocal duplications via nonallelic homologous recombination (NAHR; Belancion, Deininger, & Roy-Engel, 2009;Boone et al, 2014;Burwinkel & Kilimann 1998;Campbell et al, 2014;Gilbert, Lutz, Morrish, & Moran, 2005;Hedges & Deininger 2007;Hehir-Kwa et al, 2016;Higashimoto et al, 2013;Kohmoto et al, 2017;Lupski 2010;Quadri et al, 2015;Startek et al, 2015;Szafranski et al, 2016;Temtamy et al, 2008;Vissers et al, 2009). Other rearrangements mediated by L1s and ERVs include translocations (Buysse et al, 2008;Robberecht et al, 2013), insertions (Gu et al, 2016), inversions , and complex genomic rearrangements (Gu et al, 2015;Liu et al, 2011).…”

Human Y chromosome copy number variation in the next generation sequencing era and beyond

“…In the 1000 Genomes Project Phase 3, only six structural variants on the Y chromosome were described by genome-wide analyses (Sudmant et al 2015; The 1000 Genomes Project Consortium 2015). In the latest structural variation (SV) data release by the Genomes of the Netherlands Project (Francioli et al 2015; The Genome of the Netherlands Consortium 2014), which also produced a dedicated study of structural variants (Hehir-Kwa et al 2016), only 4556 out of 1,851,571 structural variants (less than 0.25%) were mapped to the Y chromosome. Such studies focused on the diploid genome; it is only recently that similar high-throughput, unbiased studies have focused on the Y chromosome.

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