Local exome sequences facilitate imputation of less common variants and increase power of genome wide association studies

The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1–10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28–38%, for SNPs with a minor allele frequency in the range 1–3%

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may b

Whole exome sequencing in an isolated population from the Dalmatian island of Vis

We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP. The majority of these variants (76%) are singletons. Comparable to data obtained from UK10K-Generation Scotland that were sequenced and analysed using the same protocols, we detected an enrichment of potentially damaging variants (non-synonymous and loss-of-function) in the low frequency and common variant categories. On average 115 (range 93–140) genotypes with loss-of-function variants, 23 (15–34) of which were homozygous, were identified per person. The landscape of loss-of-function variants across an exome revealed that variants mainly accumulated in genes on the xenobiotic-related pathways, of which majority coded for enzymes. The frequency of loss-of-function variants was additionally increased in Vis runs of homozygosity regions where variants mainly affected signalling pathways. This work confirms the isolate status of Vis population by means of whole-exome sequence and reveals the pattern of loss-of-function mutations, which resembles the trails of adaptive evolution that were found in other species. By cataloguing the exomic variants and describing the allelic structure of the Vis population, this study will serve as a valuable resource for future genetic studies of human diseases, population genetics and evolution in this population

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Mean accuracy of imputation (r² of allelic dosage across all samples for a SNP) averaged across SNPs split by Minor Allele Frequency (MAF).

<p>MAF bins increase by factors of √10, to create four exponentially increasing bins.</p><p>N SNPs: number of SNPs in MAF bin.</p><p>1kG: 1000 Genomes used as reference panel.</p><p>1kG+LRP: 1000 Genomes plus local reference panel.</p><p>Increase r²: Average across all SNPs in MAF bin increase in r².</p><p>Std dev: The standard deviation (across SNPs) of the increase in r² at each SNP.</p><p>Inc. Sample: Increase in effective sample size for GWAS.</p><p>The standard errors of mean increases are less than 0.003. All improvements in r² are significantly different from zero and significantly different between MAF bands (P<0.001, two-sided t tests).</p

Illustration of the procedure to estimate imputation accuracy.

<p>We used a drop one-out crossvalidation approach. For the imputation step each subject was removed from the reference panel in turn, and this subject’s exome sequence SNPs were then imputed using either the 1000 Genomes reference panel alone or in conjunction with a second local reference panel. All subjects’ imputed allelic dosages were then compared with the exome sequence genotype data (“gold standard”).</p

Preparation of array data and local reference panel for imputation.

<p>The genotype data were quality controlled and phased. These data were then used in further downstream analysis.</p

Frequency plot of imputation accuracy (r²) using 1000 Genomes data alone against 1000 Genomes plus a local reference panel for SNPs with Minor Allele Frequencies (MAF) of 1–3.2%.

<p>Frequency plot of imputation accuracy (r²) using 1000 Genomes data alone against 1000 Genomes plus a local reference panel for SNPs with Minor Allele Frequencies (MAF) of 1–3.2%.</p

Plot of mean improvement in imputation accuracy (r²) for SNPs with minor allele frequency (MAF) in the range 1–10% in our exome sequence data.

<p>Plot of mean improvement in imputation accuracy (r²) for SNPs with minor allele frequency (MAF) in the range 1–10% in our exome sequence data.</p

Revealing the Impact of Structural Variants in Multiple Myeloma

International audienceThe landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAMF and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis