Functional intronic polymorphisms: Buried treasure awaiting discovery within our genes

Antony and Cleopatra [Act I, Scene 2], William ShakespearePathological mutations occurring within the extended consensus sequences of exon-intron splice junctions account for ~10 per cent of all inherited lesions logged in The Human Gene Mutation Database (HGMD？; http://www.hgmd.org webcite)[1] and are frequently encountered in mutation screening studies [2]. Mutations residing in other intronic locations (including the canonical branch-point sequence,[3] 5'-YURAY-3'), however, may often go undetected unless patient RNA can be analysed and the mutations in question induce aberrant splicing (eg exon skipping or cryptic splice site utilisation) that is readily distinguishable qualitatively or quantitatively from normal (and/or normal alternative) splicing. Indeed, introns probably represent a substantially larger mutational target than has hitherto been appreciated, on account of their containing a multiplicity of functional elements, including intron splice enhancers and silencers that regulate alternative splicing,[4,5]trans-splicing elements [6] and other regulatory elements, some of which may be deeply embedded within very large introns [7].In addition to pathological mutations sensu stricto, introns also harbour functional polymorphisms that can influence the expression of the genes that host them. Some of these intronic variants may also confer susceptibility to disease or otherwise modulate the genotype-phenotype relationship. For the reasons discussed above, it is very likely that such variants will have been seriously under-ascertained to date. Although most of these variants are single nucleotide polymorphisms (SNPs), others may be of the insertion/deletion type [8]. With the advent of genome-wide association studies (GWAS), an increasing number of potentially functional intronic variants are being identified [9]. In the majority of cases, however, it is unclear whether such variants are of direct functional significance, as opposed to simply being in linkag