TY - JOUR T1 - Human-specific regulatory features of brain development manifest staggering breadth of associations with physiological processes and pathological conditions of <em>H. sapiens</em> JF - bioRxiv DO - 10.1101/848762 SP - 848762 AU - Gennadi V. Glinsky Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/20/848762.abstract N2 - In recent years, elucidation of genetic and molecular mechanisms defining the phenotypic uniqueness of Modern Humans attained a significant progress in illuminating the essential role of human-specific regulatory sequences (HSRS). The macromolecules comprising the essential building blocks of life at the cellular and organismal levels remain highly conserved during the evolution of humans and other Great Apes. Identification of nearly hundred thousand candidate HSRS validate the idea that unique to human phenotypes may result from human-specific changes to genomic regulatory sequences defined as “regulatory mutations” (King and Wilson, 1975). The exquisite degree of accuracy of the state-of-art molecular definition of HSRS is illustrated by identification of 35,074 single nucleotide changes (SNCs) that are fixed in humans, distinct from other primates, and located in differentially-accessible (DA) chromatin regions during the human brain development (Kanton et al., 2019). Annotation of SNCs derived and fixed in modern humans that overlap DA chromatin regions during brain development revealed that 99.8% of candidate regulatory SNCs are shared with the archaic humans. This remarkable conservation on the human lineage of candidate regulatory SNCs associated with early stages of human brain development suggest that coding genes expression of which is regulated by human-specific SNCs may have a broad effect on human-specific traits beyond embryonic development. Gene set enrichment analyses of 8,405 genes linked with 35,074 human-specific SNCs revealed the staggering breadth of significant associations with morphological structures, physiological processes, and pathological conditions of Modern Humans, including more than 1,000 anatomically-distinct regions of the adult human brain, many types of human cells and tissues, more than 200 common human disorders and more than 1,000 rare diseases. Thousands of genes connected with human-specific regulatory SNCs 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 survival, and perinatal, neonatal, and postnatal lethality of both complete and incomplete penetrance have been identified in this contribution. Therefore, thousands of heritable traits and critical genes impacting the offspring survival appear placed under the human-specific regulatory control in genomes of Modern Humans. These observations highlight the remarkable translational opportunities with clinical utility potentials afforded by the discovery of genetic regulatory loci harboring human-specific SNCs in the ground-breaking fundamental study of great ape’s cerebral organoids. ER -