Impacts of genomic networks governed by human-specific regulatory sequences and genetic loci harboring fixed human-speci
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ORIGINAL ARTICLE
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 Gennadi V. Glinsky Received: 4 June 2020 / Revised: 27 August 2020 / Accepted: 30 August 2020 # Springer Nature B.V. 2020
Abstract Recent advances in identification and characterization of human-specific regulatory DNA sequences set the stage for the assessment of their global impact on physiology and pathology of modern humans. Gene set enrichment analyses (GSEA) of 8405 genes linked with 35,074 human-specific neuroregulatory single-nucleotide changes (hsSNCs) revealed numerous significant associations with morphological structures, physiological processes, and pathological conditions of modern humans. Significantly enriched traits include more than 1000 anatomically distinct regions of the adult human brain, many different types of cells and tissues, more than 200 common human disorders, and more than 1000 records of rare diseases. Thousands of genes connected with neuro-regulatory hsSNCs have been identified, which represent essential genetic elements of the autosomal inheritance and offspring survival phenotypes. A total of 1494 hsSNClinked genes are associated with either autosomal
Responsible Editor: Beth Sullivan Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10577-020-09639-w) contains supplementary material, which is available to authorized users. G. V. Glinsky (*) Institute of Engineering in Medicine, University of California, San Diego, 9500 Gilman Dr. MC 0435, La Jolla, CA 92093-0435, USA e-mail: [email protected] URL: http://iem.ucsd.edu/people/profiles/guennadi-vglinskii.html
dominant or recessive inheritance, and 2273 hsSNClinked 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. Differential GSEA implemented on hsSNC-linked loci and associated genes identify a set of 7990 hsSNC-target genes linked to evolutionary distinct classes of human-specific regulatory sequences (HSRS). Notably, the expression of a majority of these genes (5389 genes; 67%) is regulated by stem cell– associated retroviral sequences (SCARS) and SCARSregulated genes captured a dominant fraction (91%) of significant phenotypic associations linked with hsSNCs. Interrogations of the MGI database revealed readily available mouse models tailored for precise experimental definitions of functional effects of hsSNCs and SCARS on genes causally affecting thousands of mammalian phenotypes and implicated in hundreds of common and rare human disorders. These observations suggest that a preponderance of human-specific traits evolved under a combinatorial regulatory control of distinct classes of HSRS and neuro-regulatory loci harboring hsSNCs that are fixed in humans, distinct from other primates, and located in differentially accessible chroma
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