A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

Abstract

10Throughout the past decade, studying ancient genomes provided unique insights into human 11 prehistory, and differences between modern humans and other branches like Neanderthals can 12 enrich our understanding of the molecular basis of the human condition. Modern human variation 13 and the interactions between different hominin lineages are now well studied, making it reasonable 14 to explore changes that are observed at high frequency in present-day humans, but do not reach 15 fixation. Here, we put forward interpretation of putative single nucleotide changes in recent modern 16 human history, focusing on 571 genes with non-synonymous changes at high frequency. We 17 suggest that molecular mechanisms in cell division and networks affecting cellular features of 18 neurons were prominently modified by these changes. Complex phenotypes in brain growth 19 trajectory and cognitive traits are likely influenced by these networks and other changes presented 20here. We propose that at least some of these changes contributed to uniquely human traits.

7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

“…2C), thereby confirming craniofacial morphogenesis as the key domain of functionally relevant overlap between BAZ1B dosage and (self-)domestication 15 changes relevant to the evolution of AMHs. Third, despite the spuriously inflated number of apparently fixed mutations in archaics (12), the overall extent of overlap between genes impacted by BAZ1B dosage and our modern and archaic sets does not reveal significantly more hits for archaics. In fact, globally we found consistently more overlapping genes between the BAZ1B targets and the modern human data, and even no statistically significant overlap for any list of the 20 archaic-specific mutations when crossed against BAZ1B level-directly correlated genes.…”

“…10 Mild NC deficits have been put forth as a unifying explanatory framework for the defining features of the so-called domestication syndrome, with BAZ1B listed among the putative underlying genes due to its previously reported role in the NC of model organisms (3, 7, 8). The recent observation that its expression is impacted by domestication-related mobile element insertion (MEI) methylation in gray wolves (9) further supported its role in domestication, offering an intriguing 15 parallel to the paleogenomic results that had detected BAZ1B within the regions of the modern genome reflective of selective sweeps and found it enriched for putatively regulatory mutations in AMHs (12). These convergent lines of enticing evidence notwithstanding, neither the neurocristopathic basis of domestication nor its extension to the evolution of the modern human lineage (i.e., self-domestication) have been empirically tested, hence keeping also BAZ1B-based 20 domestication hypotheses to the theoretical ambit.…”

“…S1A) and cognitive/behavioral traits (4,5) are uniquely and symmetrically aligned to the domesticationrelated traits of AMHs. Structural variants in WBS genes have been shown to underlie stereotypical hypersociability in domestic dogs (6) and within the WBSCR the following lines of evidence point to the chromatin regulator BAZ1B as a key gene underlying domestication-relevant 15 craniofacial features: i) its crucial role in NC maintenance and migration in Xenopus Laevis and the craniofacial defects observed in knock-out mice (7,8); ii) the observation that its expression is impacted by domestication-related events in canines (9); iii) the first formulation of the neurocristopathic hypothesis of domestication, which included BAZ1B among the genes influencing NC development (3); iv) the most comprehensive studies focusing on regions of the 20 modern human genome associated with selective sweep signals compared to Neanderthals/Denisovans (hereafter 'archaics') (10,11), one of which specifically included BAZ1B within the detected portions of the WBSCR; and v) the thus far most detailed study 5 systematically exploring high frequency (> 90%) changes in modern humans for which archaic humans carry the ancestral state, which found BAZ1B enriched for mutations in modern humans (most of which fall in the regulatory regions of the gene) (12). Through the thus far largest cohort of 7q11.23 patient-derived induced pluripotent stem cell (iPSC) lines, our previous work had revealed major disease-relevant dysregulation that was already apparent at the pluripotent state 5 and was further exacerbated upon differentiation (13).…”

Modern human changes in regulatory regions implicated in cortical development

“…One such trait concerns the period of growth and maturation of the brain, which is a major factor underlying the characteristic ‘globular’ head shape of modern humans [2]. Comparative genomic analyses using high-quality Neanderthal/Denisovan genomes [3–5] have revealed missense changes in the modern human lineage affecting proteins involved in the division of neural progenitor cells, key for the proper generation of neurons in an orderly spatiotemporal manner [4, 6]. But the total number of fixed missense changes amounts to less than one hundred proteins [1, 6].…”

“…Comparative genomic analyses using high-quality Neanderthal/Denisovan genomes [3–5] have revealed missense changes in the modern human lineage affecting proteins involved in the division of neural progenitor cells, key for the proper generation of neurons in an orderly spatiotemporal manner [4, 6]. But the total number of fixed missense changes amounts to less than one hundred proteins [1, 6]. This suggests that changes falling outside protein-coding regions may be equally relevant to understand the genetic basis of modern human-specific traits, as proposed more than four decades ago [7].…”