A Hypermutable Region in the DISP2 Gene Links to Natural Selection and Late-Onset Neurocognitive Disorders in Humans

(CCG) short tandem repeats (STRs) 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 neuron-specific gene, DISP2 (dispatched RND transporter family member 2), contains a (CCG) repeat in its 5' untranslated region. 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). We found that the region spanning the (CCG) repeat was highly mutated, resulting in several flanking (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 extreme short alleles, 5- and 6-repeats, 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) that consisted of the 8-repeat and extreme long alleles, 9- and 10-repeats, of which the 10-repeat was not detected in the NCD group. The (CCG) repeat specifically expanded in primates. In conclusion, we report an indication of natural selection at a novel hypermutable region in the human genome and divergent alleles and genotypes in late-onset NhCDs and controls. These findings reinforce the hypothesis that a collection of rare alleles and genotypes in a number of genes may unambiguously contribute to the cognition impairment component of late-onset NCDs.