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.

Predominant monomorphism of the RIT2 and GPM6B exceptionally long GA blocks in human and enriched divergent alleles in the disease compartment.

Across human protein-coding genes, the human neuron-specific genes, RIT2 and GPM6B, contain the two longest GA short tandem repeats (STRs) of 11 and 9-repeats, respectively, the length ranges of which are functional, and result in gene expression alteration. Here we sequenced the RIT2 and GPM6B STRs in 600 human subjects, consisting of late-onset neurocognitive disorder (n = 200), multiple sclerosis (n = 200), and controls (n = 200). Furthermore, we selected two large human databases, including the general-population-based gnomAD ( https://gnomad.broadinstitute.org ) and a mainly disease-phenotype-archiving database, TOPMed ( https://www.nhlbiwgs.org ), to compare allele frequencies in the general populations vs. the disease compartment. The RIT2 and GPM6B GA-repeats were monomorphic in the human subjects studied, at lengths of 11 and 9-repeats, respectively, and were predominantly human-specific in formula. Exception included a 9/11 genotype of the RIT2 GA-STR in an isolate case of female multiple sclerosis. Exceedingly rare alleles of the two GA repeats were significantly enriched in TOPMed vs. the gnomAD. We report prime instances of predominant monomorphism for specific lengths of STRs in human, and possible enrichment of rare divergent alleles in the disease phenotype compartment. While STRs are most attended because of their high polymorphic nature, STR monomorphism is an underappreciated feature, which may have a link with natural selection and disease.