Allele‐specific m RNA Splicing in Human

Abstract Polymorphisms and de novo mutations in the genome sequence determine the genetic contribution to human phenotype and disease. Many functionally significant variants, rather than altering an encoded protein, affect the regulation of transcription or posttranscriptional processing, including messenger ribonucleic acid (mRNA) splicing. The effects of these mutations can be difficult to determine, yet they make a substantial contribution to human disease and other phenotypes of medical significance, such as interindividual differences in responses to pharmaceuticals. Progress towards understanding the regulation of splicing, coupled with the advent of high‐throughput technologies for interrogating the transcriptome have given rise to new opportunities to investigate allelic differences in mRNA splicing. Key Concepts Splicing is a tightly regulated process that can be disrupted by sequence variants (polymorphisms or rare mutations). Mutations and polymorphisms that affect mRNA splicing are thought to make a major contribution to human genetic diseases. Alternatively spliced mRNA isoforms are detectable for the majority of human multiexon genes. The contribution of sequence variants to the diversity of splice isoforms observed for a gene is often overlooked. Sequence variants that affect splicing can disrupt splicing of constitutively spliced exons or affect the regulation of alternative splicing. Variants with a quantitative effect on splicing are referred to as splicing quantitative trait loci (sQTLs). Most examples of allele‐specific splicing involve differences in the relative abundance of isoforms, rather than the creation or loss of an isoform. Because the balance of alternative splice isoforms is often evolutionarily conserved when the isoforms themselves are conserved, sQTLs of conserved isoforms may frequently have functional implications.