High-resolution comparative analysis of great ape genomes

Abstract

Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly, full-length cDNA sequencing with a multi-platform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. Comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single base-pair to megabase-sized variants. We identified ~17 thousand fixed human-specific structural variants identifying genic and putative regulatory changes that emerged in humans since divergence from nonhuman apes. Interestingly, these fixed human-specific structural variants are enriched near genes that are downregulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.

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

“…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 and initial structuralfunctional characterization of nearly hundred thousand candidate HSRS (Kronenberg et al, 2018;Glinsky, 2019;Kanton et al, 2019; this contribution) 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). Technological advances enabled the exquisite degree of accuracy of molecular definition of 35,074…”

“…No reuse allowed without permission. specific regulatory sequences (HSRS) in contrast to the relatively modest impact of human-specific changes of a limited number of coding genes (Kronenberg et al, 2018;Glinsky, 2019;Kanton et al, 2019). 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.…”

“…Importantly, human-specific GRNs utilized in these analyses were defined employing vastly different experimental, analytical, and computational approaches that were applied within the broad range of experimental settings (Glinsky, 2019). Specifically, the interrogated human-specific GRNs include the following data sets: i) Great Apes' whole-genome sequencing-guided identification of human-specific insertions and deletions (Kronenberg et al, 2018); ii) genome-wide analysis of retrotransposon's transcriptome in postmortem samples of human dorsolateral prefrontal cortex (Guffanti et al, 2018); iii) shRNA-mediated silencing of LTR7/HERVH retrovirus-derived long non-coding RNAs in hESC (Wang et al, 2014); iv) single-cell expression profiling analyses of human preimplantation embryos ; v) network of genes associated with regulatory transposable elements (TE) operating in naïve and primed hESC (Theunissen et al, 2016;Pontis et al, 2019); vi) pluripotency-related network of genes manifesting concordant expression changes in human fetal brain and adult neocortex (Glinsky, 2017); vii) network of genes governing human neurogenesis in vivo (Nowakowski et al, 2017); viii) network of genes differentially expressed during human corticogenesis in vitro (van de Leemput et al, 2014). Thus, selected for these analyses human-specific GRNs appear to function in a developmentally and physiologically diverse spectrum of human cells that are biologically and anatomically certified by peer review) is the author/funder.…”

“…DNA sequences of coding genes defining the structure of 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 (Chimpanzee Sequencing and Analysis Consortium, 2005;Kronenberg et al, 2018). In striking contrast, a compendium of nearly hundred thousand candidate human-specific regulatory sequences (HSRS) has been assembled in recent years (Glinsky et al, 2015Kanton et al, 2019), thus validating 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).…”

Improving Illumina assemblies with Hi‐C and long reads: An example with the North African dromedary

“…For example, the latest assembled goat genome has taken advantage of long‐read sequences and Hi‐C libraries in its assembly (Bickhart et al, ). Additionally, long‐read sequence assembly of great ape genomes facilitated high‐resolution comparative analyses between humans and great apes (Kronenberg et al, ). Genetic variation that influences phenotypic traits can be identified with genome‐wide association studies (GWAS) that benefit from more contiguous assemblies.…”