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.

Fig. 1. Humans have diverged from the other great apes, colonized diverse habitats and exploded in population.

a, Cellular organism superfamilies in the tree of life, as organized by the NCBI Taxonomy database (left), illustrate the recent emergence of apes. Over the past 20 million years, the ape lineage has split multiple times, giving rise to present-day gibbon, orangutan, gorilla, chimpanzee/bonobo and human populations. We depict the ape phylogeny with branches scaled by substitutions per site and we include divergence time estimates (right). b, Human populations have expanded across the world, colonizing diverse ecosystems over the past 100,000 years. Time scales are approximate and under continuous debate, as indicated by the asterisk (*). c, Several populations of non-human great apes are confined to portions of central and west Africa (chimpanzee, bonobo and gorilla) and islands in Southeast Asia (orangutan and gibbon). kya, thousand years ago; mya, million years ago. Part b is reprinted from ref. , Springer Nature Limited. Part c is adapted from ref. , Springer Nature Limited.

Fig. 2. A selection of human-specific traits.

a–b, Pencil drawings of a juvenile orangutan (part a, left), chimpanzee and human facial (part a, right) and eye (part b) structures highlight similarities and differences between humans and closest living relatives. For example, human facial morphology changed to reduce the size of the jaw and to support rapid social communication, and changes in orbital areas around the eye together with loss of pigmentation of membranes covering the sclera in humans make the direction of eye gaze more prominent. c, Shown are an assortment of phenotypes that differ between human (grey) and chimpanzee (beige) and are associated with human specializations. Artwork in parts a and b, images courtesy of E. G. Triay. In part c, shoulder structure is reprinted from ref. , Springer Nature Limited; pelvis structure is adapted with permission from ref. , Elsevier and tongue/vocal cord structures are adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 3. Comparative great ape genomics can identify human alleles of interest.

a, Comparisons between humans, chimpanzees and other great apes, as well as other primate or mammalian outgroups have revealed distinct classes of human-specific genetic changes. Light grey block represents DNA, mid-grey represents genes or regulatory elements of interest and dark grey bars represent single nucleotide changes. b, Schematic illustrates that humans could have inherited interesting and impactful alleles that are human specific (left), or alleles shared with either chimpanzees or gorillas through incomplete lineage sorting. This implies that some of the diversity we observe in human populations has not arisen since the split with chimpanzees but rather could be far more ancient. c, Comparisons with ancient genomes from archaic hominins, such as Denisovans and Neanderthals, can help to understand the age and history of human-specific changes. Part b is adapted from ref. .

Fig. 4. Single-cell genomic atlases to map and identify human-specific features.

a, Illustration of genome organization, highlighting features that could influence gene regulation and function throughout the life cycle. b, Entire human tissues, such as the brain, can be mapped using transcriptome and chromatin accessibility measurements at the resolution of individual cells. These atlases can then be used to identify which cell types might be affected by a human-specific genetic change. c, Cell atlases can be generated from chimpanzees and other great apes, and cell types and states can be directly compared between species to identify gene and regulatory features enriched in humans. d, Cell atlas efforts across great apes, as well as primate and mammalian outgroups, promise to identify human-specific cell types and states and differential activity of genes and other genetic features.

Fig. 5. Functional studies of human-specific genetic changes.

a, The molecular effects of human-specific genetic change can be assayed through transgenesis of model organisms. In this way, small segments of human DNA can be introduced into models and the effects can be studied in controlled experiments. For example, human and non-human regulatory regions can be assayed using reporter assays in developing mouse embryos. Human-specific changes can also be stably introduced into mice or non-human primates (NHPs) through genetic engineering approaches. b,c, Examples of genetic changes between great apes that have been linked to human phenotypes through experimental exploration in mice and NHP models. Blue represents regulatory regions (part b), and orange represents protein-coding variants (part c). These and further examples can be found in Table 1.

Fig. 6. Great ape organoids to explore the evolution and development of human traits.

a, Pencil drawing that conceptualizes organoids generated from chimpanzee stem cells. b, Induced pluripotent stem cells (iPSCs) can be generated from great apes, which can be used to differentiate diverse cell types or 3D organoid tissues in controlled culture environments that can recapitulate aspects of great ape development and physiology. c, Functionalized iPSC lines can be used for ancestralization of human or humanization of ape iPSCs at targeted loci. Shown is a schematic strategy using CRISPR–Cas genome editing to target an endogenous locus using pairs of guide RNAs (g1 and g2), whereby the region between the target sites is replaced by an exogenously supplied donor sequence. d, Great ape iPSCs could be used to explore modern human phenotypes. Shown are examples of currently available human in vitro model systems (arrow, system) and the potential for exploring and understanding human-specific traits (star, potential). Such stem cell and organoid systems can be applied across great apes, and other primates and mammals, to explore human molecular, cellular and tissue physiology in controlled environments. Artwork in part a, image courtesy of E. G. Triay. Skin organoid image in part d adapted from ref. , Springer Nature Limited.

Fig. 7. Milestones in using great ape stem cells to explore uniquely human physiology.

The figure shows a timeline of milestones using stem cells from great apes to explore human-specific development. Additional ref. . eQTL, expression quantitative trait loci; iPSC, induced pluripotent stem cell.