Clinical and Phenotypic Relevance of cis ‐Acting Regulatory Polymorphisms

Abstract Genetic variants that regulate the expression level of a transcript are known as expression quantitative trait loci (eQTLs) or regulatory single nucleotide polymorphisms. Cis ‐variants are those that only act on a target gene (or genes) on the same chromosomal homologue. They cause additive differences in gene expression that are tightly associated with the three genotypes of the regulatory eQTL, and cause allelic expression imbalance in heterozygous samples. Unlike trans ‐variants, which can act on many genes located at a distance, cis ‐acting variants are less likely to have all‐or‐none effects if inactivated, and these may be tissue specific and thus less severe. Such cis ‐variants are found occasionally in Mendelian disease and now increasingly implicated in polygenic disorders. The interactions of these regulatory variations with other genetic and also environmental factors are likely to account for some of the complexity of multifactorial diseases. Key Concepts: Regulatory polymorphisms, otherwise known as eQTLs (expression quantitative trait loci), are DNA sequence variations that alter the level of expression of particular transcripts. Cis ‐eQTLs are cis ‐acting polymorphisms that cause variation in the expression of a nearby gene or genes on the same chromosomal homologue. In heterozygous individuals there is a difference in the level of expression from each of the pair of genes transcribed from the two chromosomal homologues. This difference in expression in heterozygous individuals can be observed as allelic expression imbalance (AEI) if there are also allelic sequence differences in the transcript. Such AEI is distinguishable from imprinting in that unlike the case of imprinting the higher expressing transcript can come from either the mother or the father. Cis ‐acting polymorphisms can affect expression in a tissue‐specific and developmentally specific manner. They are strong candidates for positive selection and evolutionary adaptation but such variants might be maladaptive in different environments. Cis ‐acting regulatory sequence changes have been identified as a class of rare mutations in Mendelian disorders, and more common variants are increasingly implicated as causal polymorphisms involved in multifactorial diseases.