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 overlooked. Results: On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and discovered monumental colonies (distance between each repeat <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 directional incremented trend in density and complexity of numerous colonies in human versus other species, such as a colony of 99 (GCC)2 on chromosome 20, that specifically expanded in great apes, and directionally incremented to 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.
(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.
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 on those STRs, (GGC)3 and (GCC)3 STRs remain widely unexplored. In a genome-wide search in human, here we mapped GGC and GCC STRs of ≥3-repeats, and report islands of up to 45 of those STRs, populating spans of 1 to 2 kb of genomic DNA with extraordinary density and periodicity. RGPD4 and NOC4L harbored the densest (GGC)3 (probability 3.09061E-71) and (GCC)3 (probability 1.72376E-61) STR islands, respectively, and were human-specific. We also found a prime instance of directional incremented density of STRs at a specific locus in human versus other species, that was the FOXK2 (GGC)3 island (probability 5.93916E-12). 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. In conclusion, (GGC)3 and (GCC)3 STRs form unprecedented islands of extraordinary density and periodicity, which may be of evolutionary significance in human evolution. These islands remain to be explored in evolutionary, mechanistic, and functional platforms.
: During pregnancy, the embryo implantation stage is a highly dynamic and molecularly controlled phenomenon. Several genes are involved in the implantation process, among which the leukemia inhibitory factor (LIF) is a marker of implantation. LIF is a multi-functional cytokine located on chromosome 22. The expression of this gene is increased in the middle of the secretion phase from the sexual cycle, and any defect in its expression will cause the implantation failure. LIF receptor or LIFR gene, as the LIF receptor, consists of two membrane proteins called LIFR and GP130. LIFR acts as a signal receptor for LIF in a low-affinity level. In this study, we focused on the screening of polymorphisms in the promoter region of the LIF and LIFR genes in the infertile women using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. In this study, blood samples were collected from 100 women with primary and secondary infertility and 50 healthy women as a control group. Extraction of DNA was done by the phenol-chloroform method, and in the next step, using specific primers for upstream regions of the LIF and LIFR genes, target sequences were amplified and analyzed by the SSCP method. Finally, PCR products with different configurations were selected for sequencing analysis. The results showed two polymorphisms in the upstream region of LIF and LIFR genes of two women, but there were no genetic changes in the control group. The present study was the first in this field, and the results indicated the importance of examining such genes in infertility with an unknown cause.
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