Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

Abstract

Our ancestors acquired morphological, cognitive and metabolic modifications that enabled humans to colonize diverse habitats, develop extraordinary technologies and reshape the biosphere. Understanding the genetic, developmental and molecular bases for these changes will provide insights into how we became human. Connecting human-specific genetic changes to species differences has been challenging owing to an abundance of low-effect size genetic changes, limited descriptions of phenotypic differences across development at the level of cell types and lack of experimental models. Emerging approaches for single-cell sequencing, genetic manipulation and stem cell culture now support descriptive and functional studies in defined cell types with a human or ape genetic background. In this Review, we describe how the sequencing of genomes from modern and archaic hominins, great apes and other primates is revealing human-specific genetic changes and how new molecular and cellular approaches — including cell atlases and organoids — are enabling exploration of the candidate causal factors that underlie human-specific traits.

Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations

“…Furthermore, these candidates can serve as a basis for reconstructing the phenotypic characteristics of Denisovans and shedding light on the adaptive mechanisms within this archaic human group. These identified candidates present a valuable resource for functional testing through experimental assays 59,60 and can collaborate with prediction algorithms to further explore their phenotypic significance 61 . Ultimately, a significant expansion of available association data 62 will be a crucial component in advancing our understanding of the phenotypic potential of Denisovan DNA and its contribution to the adaptation of modern humans.…”

Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression

“…Genomic changes that drive evolution include gene birth (Kaessmann, 2010), gene loss (Albalat and Canestro, 2016), and changes in regulatory sequences (Prud’homme et al, 2007). The limited genomic differences but substantial phenotypic and behavioral divergence between humans and other hominids make what genomic changes at what time have critically driven human evolution an enduring puzzle (Anton et al, 2014; Pollen et al, 2023). Although waves of studies have identified genes promoting human brain development (Evans et al, 2005; Fiddes et al, 2018; Mekel-Bobrov et al, 2005; Pinson et al, 2022; Suzuki et al, 2018), conclusions from gene birth-centered studies are controversial (Currat et al, 2006; Timpson et al, 2007; Yu et al, 2007).…”

Leveraging primate-specific genomic information for genetic studies of complex diseases

“…Using human-specific genomic changes to inform studying human-specific features has been a hot topic ( Pollen et al, 2023 ) since the first discovery of human accelerated regions (HARs) that were highly conserved across vertebrates but with an accelerated rate of evolution from chimpanzees to humans in nucleotide substitution ( Pollard et al, 2006 ). The roles of HARs have been confirmed in regulation of human-specific morphological features such as limb and brain development ( Prabhakar et al, 2008 ; Boyd et al, 2015 ).…”