High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements

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

Data from: Stocking impacts the expression of candidate genes and physiological condition in introgressed brook charr (Salvelinus fontinalis) populations

Translocation of plants and animal populations between environments is one of the major forms of anthropogenic perturbation experienced by pristine populations, and consequently, human mediated hybridization by stocking practices between wild and exogenous conspecifics is of increasing concern. In this study, we compared the expression of seven candidate genes involved in multifactorial traits and regulatory pathways for growth as a function of level of introgressive hybridization between wild and domestic brook charr to test the null hypothesis of no effect of introgression on wild fish. Our analyses revealed that the expression of two of the genes tested, cytochrome c oxidase VIIa and the growth hormone receptor isoform I, was positively correlated with the level of introgression. We also observed a positive relationship between the extent of introgression and physiological status quantified by the Fulton’s condition index. The expression of other genes was influenced by other variables, including year of sampling (reflecting different thermal conditions), sampling method and lake of origin. This is the first demonstration in nature that introgression from stocked populations has an impact on the expression of genes playing a role in important biological functions that may be related with fitness in wild introgressed populations

Microsatellites data

The 23 microsatellites used for the Bayesian clustering analyses. The populations, refere to Méthot Lake (MET), Petit Saint-Bernard Lake (BER), Lac des Écorces aquaculture facility (LDE), Bourassa Lake (BOU) and Jacques Cartier aquaculture facility (JC)

Data from: Neutral and selective processes shape MHC gene diversity and expression in stocked brook charr populations (Salvelinus fontinalis)

The capacity of an individual to battle infection is an important fitness determinant in wild vertebrate populations. The major histocompatibility complex (MHC) genes are crucial for a host’s adaptive immune system to detect pathogens. However, anthropogenic activities may disrupt natural cycles of co-evolution between hosts and pathogens. In this study we investigated the dynamic sequence and expression variation of host parasite interactions in brook charr (Salvelinus fontinalis) in a context of past human disturbance via population supplementation from domestic individuals. To do so, we developed a new method to examine selection shaping MHC diversity within and between populations and found a complex interplay between neutral and selective processes that varied among lakes that were investigated. We provided evidence for a lower introgression rate of domestic alleles and found that parasite infection increased with domestic genomic background of individuals. We also documented an association between individual MHC alleles and parasite taxa. Finally, longer cis regulatory minisatellites were positively correlated with MHC II down-regulation and domestic admixture, suggesting that inadvertent selection during domestication resulted in a lower immune response capacity, through a trade-off between growth and immunity, which explained the negative selection of domestic alleles at least under certain circumstances

Data from: Neutral and selective processes shape MHC gene diversity and expression in stocked brook charr populations (Salvelinus fontinalis)

The capacity of an individual to battle infection is an important fitness determinant in wild vertebrate populations. The major histocompatibility complex (MHC) genes are crucial for a host’s adaptive immune system to detect pathogens. However, anthropogenic activities may disrupt natural cycles of co-evolution between hosts and pathogens. In this study we investigated the dynamic sequence and expression variation of host parasite interactions in brook charr (Salvelinus fontinalis) in a context of past human disturbance via population supplementation from domestic individuals. To do so, we developed a new method to examine selection shaping MHC diversity within and between populations and found a complex interplay between neutral and selective processes that varied among lakes that were investigated. We provided evidence for a lower introgression rate of domestic alleles and found that parasite infection increased with domestic genomic background of individuals. We also documented an association between individual MHC alleles and parasite taxa. Finally, longer cis regulatory minisatellites were positively correlated with MHC II down-regulation and domestic admixture, suggesting that inadvertent selection during domestication resulted in a lower immune response capacity, through a trade-off between growth and immunity, which explained the negative selection of domestic alleles at least under certain circumstances

Data from: Standing chromosomal variation in Lake Whitefish species pairs: the role of historical contingency and relevance for speciation

The role of chromosome changes in speciation remains a debated topic, although demographic conditions associated with divergence should promote their appearance. We tested a potential relationship between chromosome changes and speciation by studying two Lake Whitefish (Coregonus clupeaformis) lineages that recently colonized postglacial lakes following allopatry. A dwarf limnetic species evolved repeatedly from the normal benthic species, becoming reproductively isolated. Lake Whitefish hybrids experience mitotic and meiotic instability, which may result from structurally divergent chromosomes. Motivated by this observation, we test the hypothesis that chromosome organization differs between Lake Whitefish species pairs using cytogenetics. While chromosome and fundamental numbers are conserved between the species (2n = 80, NF = 98), we observe extensive polymorphism of subtle karyotype traits. We describe intrachromosomal differences associated with heterochromatin and repetitive DNA, and test for parallelism among three sympatric species pairs. Multivariate analyses support the hypothesis that differentiation at the level of subchromosomal markers mostly appeared during allopatry. Yet we find no evidence for parallelism between species pairs among lakes, consistent with colonization effect or postcolonization differentiation. The reported intrachromosomal polymorphisms do not appear to play a central role in driving adaptive divergence between normal and dwarf Lake Whitefish. We discuss how chromosomal differentiation in the Lake Whitefish system may contribute to the destabilization of mitotic and meiotic chromosome segregation in hybrids, as documented previously. The chromosome structures detected here are still difficult to sequence and assemble, demonstrating the value of cytogenetics as a complementary approach to understand the genomic bases of speciation

2009 data

This dataset contains: gene expression values, physiological parameters, Q_values, Minisatellites length, MHCIIb alleles, parasitological parameters

MHCIIb_genotypes_data

This dataset was generated with the genotyping pipeline described in the manuscript. It contains MHCIIb genotypes for all populations. Lakes refere to : Amanites (AMA), Belles-de-Jour (BEL), Methot (MET), Arcand (ARC), Rivard (RIV), Veillette (VEI), Caribou (CAR), Main de fer (MAI), Sorbier (SOR) and Petit saint Bernard (BER)