A primate-specific (CCG) repeat in DISP2 is subject to natural selection in human and harbors divergent genotypes in late-onset neurocognitive disorder.

Abstract

Abstract (CCG)-repeats are predominantly enriched in genic regions, mutation hotspots for C to T truncating substitutions, and involved in various neurological and neurodevelopmental disorders. However, intact blocks of this class of STRs are widely overlooked with respect to their link with natural selection. The human DISP2 (dispatched RND transporter family member 2) has the highest level of expression in the brain, and contains a (CCG)-repeat, which is in the top 1 percent of STRs with respect to length. Here we sequenced this STR in a sample of 448 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 203) and controls (N = 245). The region spanning the (CCG)-repeat was highly mutated, resulting in several CCG residues. However, an 8-repeat of the (CCG)-repeat was predominantly abundant (frequency = 0.92) across the two groups. While the overall distribution of genotypes was not different between the two groups (p > 0.05), we detected four genotypes in the NCD group only (2% of the NCD genotypes, Mid-p = 0.02), consisting of allele lengths that were not detected in the control group. The patients harboring those genotypes received the diagnoses of probable Alzheimer’s disease and vascular dementia. We also found six genotypes in the control group only (2.5% of the control genotypes, Mid p = 0.01). We report a potential novel locus for late-onset NCD and indication of natural selection at this locus in human. These findings reinforce the hypothesis that a collection of rare alleles and genotypes in a number of genes may contribute to a divergent genotype compartment in the pathogenesis of late-onset NCD.