Summary Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype-blocks in 26 human populations. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.
Motivation: The discovery of genomic structural variants (SVs) at high sensitivity and specificity is an essential requirement for characterizing naturally occurring variation and for understanding pathological somatic rearrangements in personal genome sequencing data. Of particular interest are integrated methods that accurately identify simple and complex rearrangements in heterogeneous sequencing datasets at single-nucleotide resolution, as an optimal basis for investigating the formation mechanisms and functional consequences of SVs.Results: We have developed an SV discovery method, called DELLY, that integrates short insert paired-ends, long-range mate-pairs and split-read alignments to accurately delineate genomic rearrangements at single-nucleotide resolution. DELLY is suitable for detecting copy-number variable deletion and tandem duplication events as well as balanced rearrangements such as inversions or reciprocal translocations. DELLY, thus, enables to ascertain the full spectrum of genomic rearrangements, including complex events. On simulated data, DELLY compares favorably to other SV prediction methods across a wide range of sequencing parameters. On real data, DELLY reliably uncovers SVs from the 1000 Genomes Project and cancer genomes, and validation experiments of randomly selected deletion loci show a high specificity.Availability: DELLY is available at www.korbel.embl.de/software.htmlContact: tobias.rausch@embl.de
Copy-number variants (CNVs) form an abundant class of genetic variation with a presumed widespread impact on individual traits. While recent advances, such as the population-scale sequencing of human genomes, facilitated the fine-scale mapping of CNVs, the phenotypic impact of most of these CNVs remains unclear. By relating copy-number genotypes to transcriptome sequencing data, we have evaluated the impact of CNVs, mapped at fine scale, on gene expression. Based on data from 129 individuals with ancestry from two populations, we identified CNVs associated with the expression of 110 genes, with 13% of the associations involving complex, multiallelic CNVs. Categorization of CNVs according to variant type, size, and gene overlap enabled us to examine the impact of different CNV classes on expression variation. While many small (<4 kb) CNVs were associated with expression variation, overall we observed an enrichment of large duplications and deletions, including large intergenic CNVs, relative to the entire set of expression-associated CNVs. Furthermore, the copy number of genes intersecting with CNVs typically correlated positively with the genes' expression, and also was more strongly correlated with expression than nearby single nucleotide polymorphisms, suggesting a frequent causal role of CNVs in expression quantitative trait loci (eQTLs). We also elucidated unexpected cases of negative correlations between copy number and expression by assessing the CNVs' effects on the structure and regulation of genes. Finally, we examined dosage compensation of transcript levels. Our results suggest that association studies can gain in resolution and power by including fine-scale CNV information, such as those obtained from population-scale sequencing.
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.
Accurate estimates of mutation rates provide critical information to analyze genome evolution and organism fitness. We used whole-genome DNA sequencing, pulse-field gel electrophoresis, and comparative genome hybridization to determine mutation rates in diploid vegetative and meiotic mutation accumulation lines of Saccharomyces cerevisiae. The vegetative lines underwent only mitotic divisions while the meiotic lines underwent a meiotic cycle every ∼20 vegetative divisions. Similar base substitution rates were estimated for both lines. Given our experimental design, these measures indicated that the meiotic mutation rate is within the range of being equal to zero to being 55-fold higher than the vegetative rate. Mutations detected in vegetative lines were all heterozygous while those in meiotic lines were homozygous. A quantitative analysis of intra-tetrad mating events in the meiotic lines showed that inter-spore mating is primarily responsible for rapidly fixing mutations to homozygosity as well as for removing mutations. We did not observe 1–2 nt insertion/deletion (in-del) mutations in any of the sequenced lines and only one structural variant in a non-telomeric location was found. However, a large number of structural variations in subtelomeric sequences were seen in both vegetative and meiotic lines that did not affect viability. Our results indicate that the diploid yeast nuclear genome is remarkably stable during the vegetative and meiotic cell cycles and support the hypothesis that peripheral regions of chromosomes are more dynamic than gene-rich central sections where structural rearrangements could be deleterious. This work also provides an improved estimate for the mutational load carried by diploid organisms.
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