Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk

Abstract

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

Tightly linked antagonistic-effect loci underlie polygenic phenotypic variation inC. elegans

“…Although this pattern may be most common in selfers, it should arise in any species in traits under stabilizing selection with tight linkage, as evidenced by excess repulsion‐phase linkage disequilibrium between coding and cis ‐regulatory variants in humans (Castel et al. ). Moreover, for the pattern that we observe—polygeny and tight linkage of antagonistic effects—to arise by stabilizing selection, some outcrossing and recombination is required; otherwise, antagonistic alleles could sit anywhere in the genome and we would not predict an alternating sequence.…”

“…Partial selfing may facilitate the evolution of these complexes, and they may contribute to the widely observed pattern of outbreeding depression in the partially selfing Caenorhabditis species (Dolgin et al 2007;Baird and Stonesifer 2012;Gimond et al 2013;Snoek et al 2014). Although this pattern may be most common in selfers, it should arise in any species in traits under stabilizing selection with tight linkage, as evidenced by excess repulsion-phase linkage disequilibrium between coding and cis-regulatory variants in humans (Castel et al 2018). Moreover, for the pattern that we observepolygeny and tight linkage of antagonistic effects-to arise by stabilizing selection, some outcrossing and recombination is required; otherwise, antagonistic alleles could sit anywhere in the genome and we would not predict an alternating sequence.…”

Functional and in-silico interrogation of rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

“…Indeed, splicing machinery may be influenced by cell-/tissue-specific factors or by genomic regions outside of the region inserted into the minigene vector, and variants may have pathogenic impacts on gene expression and/or regulation without any detrimental impact on splicing. 10,17,39 Such factors are outside of the scope of the assays performed in this study, and therefore, whilst we calculate NPVs for each of the variant prioritization strategies, future investigations may uncover pathogenic roles for variants reported here. Despite these limitations, we have validated the use of a customizable minigene assay within real-time clinical investigations and successfully identified variants causing aberrant splicing.…”

The burden of deleterious variants in a non-human primate biomedical model

“…The lack of manifestation in other vervets with a predicted penetrant disease allele may be due to the lack of systematic phenotyping of VRC monkeys, or because some of them did not reach the age when the symptoms are observed. It is also possible that this observation reflects variable penetrance resulting from the modulatory effect of cis-regulation (Castel et al 2018). protein-coding genes that are present in at least one vervet, and reporting the specific monkeys carrying these alleles, we offer the scientific community a starting point for a wide range of further possible studies.…”