Human-specific Regulatory Sequences Research Articles

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.

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 neuro-regulatory 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 hsSNC-linked genes are associated with either autosomal dominant or recessive inheritance, and 2273 hsSNC-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. 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 SCARS-regulated 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 chromatin regions during brain development.Electronic supplementary materialThe online version of this article (10.1007/s10577-020-09639-w) contains supplementary material, which is available to authorized users.

A Catalogue of 59,732 Human-Specific Regulatory Sequences Reveals Unique-to-Human Regulatory Patterns Associated with Virus-Interacting Proteins, Pluripotency, and Brain Development.

Extensive searches for genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) identified thousands' HSRS using high-resolution next-generation sequencing technologies and methodologically diverse comparative analyses of human and nonhuman primates' (NHPs) reference genomes. In this study, a comprehensive catalogue of 59,732 genomic loci harboring candidate HSRS has been assembled to facilitate the systematic analyses of genomic sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes. These analyses identified thousands of candidate HSRS and HSRS-harboring loci that appear inherited from ECAs, yet absent in genomes of our closest evolutionary relatives, chimpanzee and bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. This pattern is particularly prominent for HSRS-harboring loci that have been putatively associated with human-specific gene expression changes in cerebral organoid models. A prominent majority of regions harboring human-specific mutations associated with human-specific expression changes during brain development is highly conserved in chimpanzee, bonobo, and gorilla genomes. Among NHPs, dominant fractions of HSRS-harboring loci associated with human-specific gene expression in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the gorilla genome. Analysis of 4433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of human-specific regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult dorsolateral prefrontal cortex. These analyses demonstrate that modern humans captured unique genome-wide combinations of regulatory sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Genes encoding VIPs appear to represent a principal genomic target during evolution of human-specific regulatory networks, which contribute to fitness of Homo sapiens and affect a functionally diverse spectrum of biological and cellular processes controlled by VIP-containing liquid-liquid phase-separated condensates.

Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence ofHomo sapiens

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human-specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8–10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P < 0.0001 in all instances). Present analysis supports the idea that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: (i) recombination-associated exaptation of the highly conserved ancestral regulatory DNA segments; (ii) human-specific insertions of transposable elements.

Activation of endogenous human stem cell-associated retroviruses (SCARs) and therapy-resistant phenotypes of malignant tumors

Recent reports revealed consistent activation of specific endogenous retroviral elements in human preimplantation embryos and embryonic stem cells. Activity of stem cell associated retroviruses (SCARs) has been implicated in seeding thousands of human-specific regulatory sequences in the hESC genome. Activation of specific SCARs has been demonstrated in patients diagnosed with multiple types of cancer, autoimmune diseases, and neurodegenerative disorders, and appears associated with clinically lethal therapy resistant death-from-cancer phenotypes in a sub-set of cancer patients diagnosed with different types of malignant tumors. A hallmark feature of human-specific SCAR integration sites is deletions of ancestral DNA. Analysis of human-specific genetic loci of SCARs' stemness networks in tumor samples of TCGA cohorts representing 29 cancer types suggests that this approach may facilitate identification of pan-cancer genomic signatures of clinically-lethal disease defined by the presence of somatic non-silent mutations, gene-level copy number changes, and transcripts and proteins' expression of SCAR-regulated host genes. Present analyses indicate that multiple lines of strong circumstantial evidence support the hypothesis that activation of SCARs' networks may play an important role in cancer progression and metastasis, perhaps contributing to the emergence of clinically-lethal therapy-resistant death-from-cancer phenotypes.

Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs.

Despite significant progress in the structural and functional characterization of the human genome, understanding of the mechanisms underlying the genetic basis of human phenotypic uniqueness remains limited. Here, I report that transposable element-derived sequences, most notably LTR7/HERV-H, LTR5_Hs, and L1HS, harbor 99.8% of the candidate human-specific regulatory loci (HSRL) with putative transcription factor-binding sites in the genome of human embryonic stem cells (hESC). A total of 4,094 candidate HSRL display selective and site-specific binding of critical regulators (NANOG [Nanog homeobox], POU5F1 [POU class 5 homeobox 1], CCCTC-binding factor [CTCF], Lamin B1), and are preferentially located within the matrix of transcriptionally active DNA segments that are hypermethylated in hESC. hESC-specific NANOG-binding sites are enriched near the protein-coding genes regulating brain size, pluripotency long noncoding RNAs, hESC enhancers, and 5-hydroxymethylcytosine-harboring regions immediately adjacent to binding sites. Sequences of only 4.3% of hESC-specific NANOG-binding sites are present in Neanderthals’ genome, suggesting that a majority of these regulatory elements emerged in Modern Humans. Comparisons of estimated creation rates of novel TF-binding sites revealed that there was 49.7-fold acceleration of creation rates of NANOG-binding sites in genomes of Chimpanzees compared with the mouse genomes and further 5.7-fold acceleration in genomes of Modern Humans compared with the Chimpanzees genomes. Preliminary estimates suggest that emergence of one novel NANOG-binding site detectable in hESC required 466 years of evolution. Pathway analysis of coding genes that have hESC-specific NANOG-binding sites within gene bodies or near gene boundaries revealed their association with physiological development and functions of nervous and cardiovascular systems, embryonic development, behavior, as well as development of a diverse spectrum of pathological conditions such as cancer, diseases of cardiovascular and reproductive systems, metabolic diseases, multiple neurological and psychological disorders. A proximity placement model is proposed explaining how a 33–47% excess of NANOG, CTCF, and POU5F1 proteins immobilized on a DNA scaffold may play a functional role at distal regulatory elements.