Non-Coding Loss-of-Function Variation in Human Genomes

Abstract

Whole-genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation. By understanding this tolerance, it has become increasingly possible to identify genes that would make safe therapeutic targets and to identify rare genetic risk factors and phenotypes at the scale of individual genomes. To date, the vast majority of surveyed loss-of-function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative ease of interpretability. As whole-genome sequencing becomes more prevalent, new strategies will be required to uncover impactful variation in non-coding regions of the genome where the architecture of genome function is more complex. In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole-genome sequencing data to identify rare and impactful non-coding loss-of-function variants.

Scoring of pathogenic non-coding variants in Mendelian diseases through supervised learning on ancient, recent and ongoing purifying selection signals in human

“…The curation process showed that current sets of high confidence large-effect pathogenic noncoding SNVs associated to monogenic Mendelian diseases are mostly constituted of proximal cis-regulatory variants associated to the closest protein-coding gene, in line with previous reports 19 . Such distribution most probably reflects a historical ascertainment bias towards such regions in previously described Mendelian genes, which is expected to be steadily overcome by unbiased WGS approaches 5 . However, in the time being, the current status posses limits to the supervised learning and benchmark on distal cis-and trans-acting pathogenic regulatory variants with clinical implications in Mendelian diseases, and warns about the applicability of our approach and reference methods in such scope.…”

“…Moreover, every year approximately 300 new Mendelian diseases are described, whereas the pace for discovery of the causal molecular mechanisms fluctuates at around 200 yearly 3 . Despite the progress achieved through Whole Exome Sequencing (WES)-based studies, recent reviews show highly heterogeneous diagnostic rates across disease types 4,5 , ranging from <15% (e.g. congenital diaphragmatic hernia or syndromic congenital heart disease) to >70% (e.g.…”

“…ciliary dyskinesia). In those scenarios, a common working hypothesis is that non-coding variants could explain the etiology of many of the unresolved cases 5 . Whole Genome Sequencing (WGS) permits to expand the survey of pathogenic variants to non-coding genomic regions in an unbiased way.…”

Detection of quantitative trait loci and putative causal variants affecting somatic cell score in dairy sheep by using a 50K SNP chip and whole-genome sequencing

“…We acknowledge that noncoding or intergenic regions were not considered in the later steps of assessment of potential causal mutations. Although different studies have shown that noncoding variants may directly affect gene expression and protein abundance (Zappala and Montgomery, 2016;Igartua et al, 2017), and therefore represent impactful variation, we considered that focusing on the coding region was an appropriate initial approach to evaluate the high density variability study performed on this work. Among the genes harboring the potential functional relevant variants, we highlighted those related to immunity based on our reference candidate gene list (Supplemental Table S10, https: / / doi .org/ 10 .3168/ jds .2018 -14736; a total of 85 variants highlighted in yellow).…”

Next-Generation Sequencing and Emerging Technologies

“…This allows for considered sub-analyses of the other approaches (targeted and WES) in silico, in addition to analysis of the non-coding regions. With developing bioinformatics tools and approaches, interrogating non-coding regions of the genome and transcriptome is becoming increasingly possible and is beginning to show a vast amount of small-and large-scale variation that could hold the key to unknown and unsolved disease (reviewed in [9][10][11] ).…”