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.

Dyads of GGC and GCC form hotspot colonies that coincide with the evolution of human and other great apes.

BACKGROUND: GGC and GCC short tandem repeats (STRs) are of various evolutionary, biological, and pathological implications. However, the fundamental two-repeats (dyads) of these STRs are widely unexplored. RESULTS: On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and found monumental colonies (distance between each dyad < 500 bp) of extraordinary density, and in some instances periodicity. The largest (GCC)2 and (GGC)2 colonies were intergenic, homogeneous, and human-specific, consisting of 219 (GCC)2 on chromosome 2 (probability < 1.545E-219) and 70 (GGC)2 on chromosome 9 (probability = 1.809E-148). We also found that several colonies were shared in other great apes, and directionally increased in density and complexity in human, such as a colony of 99 (GCC)2 on chromosome 20, that specifically expanded in great apes, and reached maximum complexity in human (probability 1.545E-220). Numerous other colonies of evolutionary relevance in human were detected in other largely overlooked regions of the genome, such as chromosome Y and pseudogenes. Several of the genes containing or nearest to those colonies were divergently expressed in human. CONCLUSION: In conclusion, (GCC)2 and (GGC)2 form unprecedented genomic colonies that coincide with the evolution of human and other great apes. The extent of the genomic rearrangements leading to those colonies support overlooked recombination hotspots, shared across great apes. The identified colonies deserve to be studied in mechanistic, evolutionary, and functional platforms.

Novel islands of GGC and GCC repeats coincide with human evolution.

BACKGROUND: Because of high mutation rate, overrepresentation in genic regions, and link with various neurological, neurodegenerative, and movement disorders, GGC and GCC short tandem repeats (STRs) are prone to natural selection. Among a number of lacking data, the 3-repeats of these STRs remain widely unexplored. RESULTS: In a genome-wide search in human, here we mapped GGC and GCC STRs of ≥3-repeats, and found novel islands of up to 45 of those STRs, populating spans of 1 to 2 kb of genomic DNA. RGPD4 and NOC4L harbored the densest (GGC)3 (probability 3.09061E-71) and (GCC)3 (probability 1.72376E-61) islands, respectively, and were human-specific. We also found prime instances of directional incremented density of STRs at specific loci in human versus other species, including the FOXK2 and SKI GGC islands. The genes containing those islands significantly diverged in expression in human versus other species, and the proteins encoded by those genes interact closely in a physical interaction network, consequence of which may be human-specific characteristics such as higher order brain functions. CONCLUSION: We report novel islands of GGC and GCC STRs of evolutionary relevance to human. The density, and in some instances, periodicity of these islands support them as a novel genomic entity, which need to be further explored in evolutionary, mechanistic, and functional platforms.

A GCC repeat in RAB26 undergoes natural selection in human and harbors divergent genotypes in late-onset Alzheimer's disease.

Although mainly located in genic regions and being mutation hotspots, intact blocks of CG-rich trinucleotide short tandem repeats (STRs) are largely overlooked with respect to their link with natural selection. The human RAB26 (member RAS oncogene family) directs synaptic and secretory vesicles into preautophagosomal structures, inhibition of which specifically disrupts axonal transport of degradative organelles and leads to an axonal dystrophy, resembling Alzheimer's disease (AD). Human RAB26 contains a GCC repeat in the top 1st percent in respect of length. Here we sequenced this STR in 441 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 216) and controls (N = 225). In both groups, the 12-repeat allele and the 12/12 genotype were predominantly abundant. We found excess of homozygosity for non-12 alleles in the NCD group (Mid-P exact = 0.027). Furthermore, divergent genotypes were detected that were specific to the NCD group (2.8% of genotypes) (Mid-P exact = 0.006) or controls (3.1% of genotypes) (Mid-P exact = 0.004). The patients harboring divergent genotypes received the diagnosis of AD. Based on the predominant abundance of the 12-repeat and 12/12 genotype in both groups, excess of non-12 homozygosity in the NCD group, and divergent genotypes across the NCD and control groups, we propose natural selection at this locus and link with late-onset AD. Our findings strengthen the hypothesis that a collection of rare genotypes unambiguously contribute to the pathogenesis of late-onset NCDs, such as AD.