Functional Mechanisms of Microsatellite DNA in Eukaryotic Genomes.

Microsatellite repeat DNA is best known for its length mutability, which is implicated in several neurological diseases and cancers, and often exploited as a genetic marker. Less well-known is the body of work exploring the widespread and surprisingly diverse functional roles of microsatellites. Recently, emerging evidence includes the finding that normal microsatellite polymorphism contributes substantially to the heritability of human gene expression on a genome-wide scale, calling attention to the task of elucidating the mechanisms involved. At present, these are underexplored, but several themes have emerged. I review evidence demonstrating roles for microsatellites in modulation of transcription factor binding, spacing between promoter elements, enhancers, cytosine methylation, alternative splicing, mRNA stability, selection of transcription start and termination sites, unusual structural conformations, nucleosome positioning and modification, higher order chromatin structure, noncoding RNA, and meiotic recombination hot spots.

Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.

BACKGROUND: The genetic and environmental influences on human personality and behaviour are a complex matter of ongoing debate. Accumulating evidence indicates that short tandem repeats (STRs) in regulatory regions are good candidates to explain heritability not accessed by genome-wide association studies. METHODS: We tested for associations between the genotypes of four selected repeats and 18 traits relating to personality, behaviour, cognitive ability and mental health in a well-studied longitudinal birth cohort (n = 458-589) using one way analysis of variance. The repeats were a highly conserved poly-AC microsatellite in the upstream promoter region of the T-box brain 1 (TBR1) gene and three previously studied STRs in the activating enhancer-binding protein 2-beta (AP2-ß) and androgen receptor (AR) genes. Where significance was found we used multiple regression to assess the influence of confounding factors. RESULTS: Carriers of the shorter, most common, allele of the AR gene's GGN microsatellite polymorphism had fewer anxiety-related symptoms, which was consistent with previous studies, but in our study this was not significant following Bonferroni correction. No associations with two repeats in the AP2-ß gene withstood this correction. A novel finding was that carriers of the minor allele of the TBR1 AC microsatellite were at higher risk of conduct problems in childhood at age 7-9 (p = 0.0007, which did pass Bonferroni correction). Including maternal smoking during pregnancy (MSDP) in models controlling for potentially confounding influences showed that an interaction between TBR1 genotype and MSDP was a significant predictor of conduct problems in childhood and adolescence (p < 0.001), and of self-reported criminal behaviour up to age 25 years (p ≤ 0.02). This interaction remained significant after controlling for possible confounders including maternal age at birth, socio-economic status and education, and offspring birth weight. CONCLUSIONS: The potential functional importance of the TBR1 gene's promoter microsatellite deserves further investigation. Our results suggest that it participates in a gene-environment interaction with MDSP and antisocial behaviour. However, previous evidence that mothers who smoke during pregnancy carry genes for antisocial behaviour suggests that epistasis may influence the interaction.