Linked origins but distinct roles for extreme length and sequence variation at a tandem repeat in CACNA1C

Length variation in tandem repeats is a well-established driver of disease risk and is commonly assumed to arise from persistent genomic instability. Here, we characterize TRACT, a 30-bp variable number tandem repeat (VNTR) intronic to the calcium channel gene CACNA1C. TRACT exhibits extreme length variation (3-30+ kb) and has been previously linked to risk for bipolar disorder and schizophrenia. By examining multiple human cohorts, we find that TRACT alleles are strikingly bimodal in both length and sequence composition. Short alleles (TRACT^S, ~6 kb) and long alleles (TRACT^L, ~24 kb) are enriched for distinct 30-bp variants and are found on separate haplotypes that arose prior to the human migration out of Africa. Our data suggest that these ancient alleles expanded via perfect repeat tracts that were disrupted by accumulated mutations to result in relative length stability in extant humans, where there is no evidence for overt germline or somatic instability. Interestingly, neuropsychiatric disease risk is associated with specific 30-bp variants within TRACT^S alleles, but not with overall TRACT length or with 30-bp variants enriched in TRACT^L alleles. Instead, TRACT^L alleles are associated with decreased gene expression in fibroblasts and testis. Together, these findings motivate joint examination of both sequence composition and length variation to fully understand the effects of VNTRs on evolution, trait variation, and disease risk.