Impacts of genomic networks governed by human-specific regulatory sequences and genetic loci harboring fixed human-specific neuro-regulatory single nucleotide mutations on phenotypic traits of Modern Humans

Abstract

Despite recent remarkable advances in identification and characterization of human-specific regulatory DNA sequences, their global impact on physiological and pathological phenotypes of Homo sapiens remains poorly understood. Gene set enrichment analyses of 8,405 genes linked with 35,074 human-specific (hs) neuroregulatory single-nucleotide changes (SNCs) revealed the staggering breadth of significant associations with morphological structures, physiological processes, and pathological conditions of Modern Humans.Significantly enriched 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 neuro-regulatory hsSNCs have been identified in this contribution, which represent essential genetic elements of the autosomal inheritance and offspring survival phenotypes. A total of 1,494 hsSNCs-linked genes have associated with either autosomal dominant or recessive inheritance and 2,273 hsSNCs-linked genes have been associated with premature death, embryonic lethality, as well as pre-, peri-, neo-, and post-natal lethality phenotypes 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. Interrogations of the Mouse Genome Informatics (MGI) database revealed readily available mouse models tailored for precise experimental definitions of regulatory effects of neuro-regulatory hsSNCs on genes causally affecting thousands of defined mammalian phenotypes and hundreds of common and rare human disorders. 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 differentiallyaccessible (DA) chromatin regions during human brain development.certified by peer review)

Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells

“…All statistical analyses of the publicly available genomic datasets, including error rate estimates, background and technical noise measurements and filtering, feature peak calling, feature selection, assignments of genomic coordinates to the corresponding builds of the reference human genome, and data visualization, were performed exactly as reported in the original publications [8][9][10][11][12][13][14] and associated references linked to the corresponding data visualization tracks (http://genome.ucsc.edu/). Any modifications or new elements of statistical analyses are described in the corresponding sections of the results.…”

Genomic and Molecular Maps of Stemness and Malignant Regulatory Signatures

“…Candidate HSRS comprise a coherent compendium of nearly one hundred thousand genomic regulatory elements, including 59,732 HSRS which are markedly distinct in their structure, function, and evolutionary origin [38] as well as 35,074 human-specific neuro-regulatory single nucleotide changes (hsSNCs) located in differentially-accessible (DA) chromatin regions during human brain development [39; 49]. Unified activities of HSRS may have contributed to development and manifestation of thousands human-specific phenotypic traits [39]. SCARS encoded by human endogenous retroviruses LTR7/HERV-H and LTR5_Hs/HERV-K as one of the significant sources of the evolutionary origin of HSRS [7; 25-27; 33-40], including human-specific transcription factor binding sites (TFBS) for NANOG, OCT4, and CTCF [33; 37].…”

“…One of the important questions is whether the patterns of significant associations with physiological and pathological phenotypes observed for genes linked with HSRS, hsSNCs, and SCARS are specific and not related to the size effects of relatively large gene sets subjected to the GSEA [39]. To address this questions, 42,847 human genes not linked by the GREAT algorithm with HSRS were randomly split into 21 control gene sets of various sizes ranging from 2,847 to 6,847 genes and subjected to the GSEA [39]. Importantly, no significant phenotypic…”

Genomic and Molecular Maps of Stemness and Malignant Regulatory Signatures

“…It was interest to determine whether genes previously linked to multiple classes of HSRS, which were identified without considerations of genes expression of which is regulated by SCARS, overlap with SCARS-regulated genes. To this end, 13,824 genes associated with different classes of HSRS were identified using the GREAT algorithm[38; 39], subjected to the GSEA, and compared with the sets of SCARS-regulated genes (Figure 3) identified by shRNA interference , and SCARS are specific and not related to the size effects of relatively large gene sets subjected to the GSEA[39]. To address this questions, 42,847 human genes not linked by the GREAT algorithm with HSRS were randomly split into 21 control gene sets of various sizes ranging from 2,847 to 6,847 genes and subjected to the GSEA[39].…”

“…To this end, 13,824 genes associated with different classes of HSRS were identified using the GREAT algorithm[38; 39], subjected to the GSEA, and compared with the sets of SCARS-regulated genes (Figure 3) identified by shRNA interference , and SCARS are specific and not related to the size effects of relatively large gene sets subjected to the GSEA[39]. To address this questions, 42,847 human genes not linked by the GREAT algorithm with HSRS were randomly split into 21 control gene sets of various sizes ranging from 2,847 to 6,847 genes and subjected to the GSEA[39]. Importantly, no significant phenotypic associations were observed for 21 control gene sets, indicating phenotypic associations attributed to genes linked with HSRS, hsSNCs, and SCARS are not likely due to non-specific gene set size effects captured by the GSEA.…”