Perspectives on Allele-Specific Expression

Abstract

Diploidy has profound implications for population genetics and susceptibility to genetic diseases. Although two copies are present for most genes in the human genome, they are not necessarily both active or active at the same level in a given individual. Genomic imprinting, resulting in exclusive or biased expression in favor of the allele of paternal or maternal origin, is now believed to affect hundreds of human genes. A far greater number of genes display unequal expression of gene copies due to cis-acting genetic variants that perturb gene expression. The availability of data generated by RNA sequencing applied to large numbers of individuals and tissue types has generated unprecedented opportunities to assess the contribution of genetic variation to allelic imbalance in gene expression. Here we review the insights gained through the analysis of these data about the extent of the genetic contribution to allelic expression imbalance, the tools and statistical models for gene expression imbalance, and what the results obtained reveal about the contribution of genetic variants that alter gene expression to complex human diseases and phenotypes. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 4 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Genetic variants of PKLR are associated with acute pain in sickle cell disease

“…We hypothesize that the intronic variants alter gene expression in cis, detectable as allelic imbalance in PKLR expression. 14,15 Screening of PKLR revealed a synonymous variant (R596R, rs1052176) in exon 11 (Figure 1A); its prevalence in almost 50% of NIH SCD patients, makes it a highly suitable marker for differentiating expression of the 2 alleles. We examined the pairwise LD between PKLR variants and found that all the six intron 2 variants were in tight linkage disequilibrium (LD), while R596R belongs to another LD block (Supplemental Figure 1).…”

“…22 Allelic variation in human gene expression is common and population-based studies provide increasing evidence that non-coding variants influence trait variance and quite likely, response to pharmacotherapy. 15,22 Studies have suggested that PK deficiency provides protection from malaria infection, accounting for the high frequency of PKLR variants in sub-Saharan African populations. 23,24 Indeed, the PKLR intron 2 variants described here have a minor allele frequency of 14-15% in African populations in 1000 Genomes Project, and almost absent in non-African populations.…”

IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology

“…It is plausible that differential expression can contribute to disease in monoallelic IRIDA when it favors the affected TMPRSS6 allele and reduces the expression of the functional allele. Generally, this provides an explanation for the clinical presentation of monoallelic-affected IRIDA patients to have a greater effect on the phenotype in these individuals [ 38 ].…”

DeCAF: a novel method to identify cell-type specific regulatory variants and their role in cancer risk

“…Fifth, any other clinical factor that's correlated with the cell fraction could be the causal mediator (for example -tumor stage, site of sampling and BMI), which could be further investigated by incorporating additional relevant interaction terms. Sixth, AI can be the consequence of many mechanisms such as nonsense-mediated decay, imprinting, post-translational effects and alternative splicing [67]. By assuming consistent AI/QTL effects in DeCAF, our approach may lose power when these deviating effects are present.…”