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

Abstract Intact blocks of (CCG)-repeats are among the top short tandem repeats (STRs), which have undergone natural selection. The above stems from the facts that these STRs are mutation hotspots for C to T truncating substitutions, and are predominantly enriched in the exons. The human DISP2 (dispatched RND transporter family member 2) has the highest level of expression in the brain, and contains a (CCG)-repeat at the interval between + 1 and + 60 of the transcription start site (ENST00000267889.5 DISP2-201), which ranks in the top 1 percent of (CCG) STRs in respect of length. Here we sequenced this STR in a sample of 448 Iranian individuals, consisting of late-onset NCDs (N = 203) and controls (N = 245). While the region spanning the (CCG)-repeat was highly mutated and contained several C to T transitions, which resulted in several (CCG)-residues, a 8-repeat of the (CCG)-STR was the predominantly abundant allele (frequency = 0.92) across the two groups. The overall distribution of alleles was not different between the two groups (p > 0.05). However, we detected four genotypes that belonged to the NCD group only (2% of the NCD genotypes, Mid-p = 0.02), and consisted of allele lengths that were not detected in the control group. We also found six genotypes that were detected in the control group only (2.5% of the control genotypes, Mid p = 0.01). While the group-specific genotypes formed a small percentage of the overall genotypes, they unveil an underappreciated feature, in which complex disorders such as late-onset NCDs may be linked with unambiguous genotypes.