Figure 3. The effects of STR variation on local gene expressivity.

(A) Bi-allelic variation in a gene through single nucleotide polymorphisms often result in small and discrete differences in gene expression, offering limited phenotypic differences across a population with slow evolutionary timescales. In contrast, STRs in promoters and 5’UTRs can influence protein expression over a broader dynamic range, with an inverse correlation between repeat length and protein output within transcribed regions and with differential effects on transcription dependent on the repeat and local epigenetic context. Unstable repeats change rapidly from generation to generation (and even within an individual through somatic variation), creating a mechanism by which mRNA or protein expression can vary broadly and subtly across a population, offering greater genetic and phenotypic diversity and a greater propensity for disease-causing aberrancies at the extremes. (B) Predicted effects of CGG repeat length on FMR1 gene expression. CGG repeat length influences FMR1 promoter epigenetic state (more open chromatin with initial expansion, then DNA methylation and closed chromatin at >200 CGG repeats), FMR1 mRNA expression, and FMRP protein expression across the polymorphic range.