Gennadi V. Glinsky | Searcharxiv

arXiv2019

A genomic dominion with regulatory dependencies on human-specific single-nucleotide changes in Modern Humans

Gene set enrichment analyses of 8,405 genes linked with 35,074 human-specific (hs) regulatory single-nucleotide changes (SNCs) revealed the staggering breadth of significant associations with morphological structures, physiological processes, and pathological conditions of Modern Humans. Significant enrichment traits include more than 1,000 anatomically-distinct regions of the adult human brain, many different types of human cells and tissues, more than 200 common human disorders and more than 1,000 records of rare diseases. Thousands of genes connected with regulatory hsSNCs have been identified in this contribution, which represent essential genetic elements of the autosomal inheritance and survival of species phenotypes: a total of 1,494 genes linked with either autosomal dominant or recessive inheritance as well as 2,273 genes associated with premature death, embryonic lethality, as well as pre-, peri-, neo-, and post-natal lethality of both complete and incomplete penetrance. Therefore, thousands of heritable traits and critical genes impacting the offspring survival appear under the human-specific regulatory control in genomes of Modern Humans. These observations highlight the remarkable translational opportunities afforded by the discovery of genetic regulatory loci harboring hsSNCs that are fixed in humans, distinct from other primates, and located in differentially-accessible (DA) chromatin regions during human brain development.

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arXiv2014

Integrative genomics analysis identifies pericentromeric regions of human chromosomes affecting patterns of inter-chromosomal interactions

Genome-wide analysis of distributions of densities of long-range interactions of human chromosomes with each other, nucleoli, nuclear lamina, and binding sites of chromatin state regulatory proteins, CTCF and STAT1, identifies non-random highly correlated patterns of density distributions along the chromosome length for all these features. Marked co-enrichments and clustering of all these interactions are detected at discrete genomic regions on selected chromosomes, which are located within pericentromeric heterochromatin and designated Centromeric Regions of Interphase Chromatin Homing (CENTRICH). CENTRICH manifest 199-716-fold higher density of inter-chromosomal binding sites compared to genome-wide or chromosomal averages (p = 2.10E-101-1.08E-292). Sequence alignment analysis shows that CENTRICH represent unique DNA sequences of 3.9 to 22.4 Kb in size which are: 1) associated with nucleolus; 2) exhibit highly diverse set of DNA-bound chromatin state regulators, including marked enrichment of CTCF and STAT1 binding sites; 3) bind multiple intergenic disease-associated genomic loci (IDAGL) with documented long-range enhancer activities and established links to increased risk of developing epithelial malignancies and other common human disorders. Using distances of SNP loci homing sites within genomic coordinates of CENTRICH as a proxy of likelihood of disease-linked SNP loci binding to CENTRICH, we demonstrate statistically significant correlations between the probability of SNP loci binding to CENTRICH and GWAS-defined odds ratios of increased risk of a disease for cancer, coronary artery disease, and type 2 diabetes. Our analysis suggests that centromeric sequences and pericentromeric heterochromatin may play an important role in human cells beyond the critical functions in chromosome segregation.

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