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Home , Evolution of primates

Phylogenomic evidence of adaptive in the ancestry of

Morris Goodmana,b,1 and Kirstin N. Sternera

aCenter for Molecular Medicine and and bDepartment of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201 In ’s tree model for ’s evolution, nomic studies of evolution. We then highlight the concepts adaptively modifies newly arisen species as they branch apart from that motivate our own efforts and discuss how phylogenomic evi- their common ancestor. In accord with this Darwinian concept, the dence has enhanced our understanding of adaptive evolution in the phylogenomic approach to elucidating adaptive evolution in genes ancestry of modern humans. and genomes in the ancestry of modern humans requires a well supported and well sampled phylogeny that accurately places Darwin’s Views humans and other and with respect to one In The Descent of Man, and Selection in Relation to Sex (5), Charles another. For more than a century, first from the comparative immu- Darwin suggested that Africa was the birthplace for humankind. nological work of Nuttall on blood sera and now from comparative The following five passages encapsulate for us Darwin’s thinking genomic studies, molecular findings have demonstrated the close about the place of humans in phylogeny and about the kinship of humans to . The close genetic correspond- uniqueness of modern humans. ence of chimpanzees to humans and the relative shortness of our evolutionary separation suggest that most distinctive features of If the anthropomorphous be admitted to form a natural subgroup, then as man agrees with them, not only in all those the modern human phenotype had already evolved during our characters which he possesses in common with the whole Cata- ancestry with chimpanzees. Thus, a phylogenomic assessment of rhine group, but in other peculiar characters, such as the absence being human should examine earlier stages of human ancestry as of a tail and of callosities, and in general appearance, we may well as later stages. In addition, with the availability of a number of infer that some ancient member of the anthropomorphous sub- mammalian genomes, similarities in phenotype between distantly group gave birth to man (ref. 5, p. 160). related taxa should be explored for evidence of convergent or par- It is therefore probable that Africa was formerly inhabited by allel adaptive evolution. As an example, recent phylogenomic evi- extinct apes closely allied to the and ; and as dence has shown that adaptive evolution of aerobic energy these two species are now man’s nearest allies, it is somewhat metabolism genes may have helped shape such distinctive modern more probable that our early progenitors lived on the African human features as long life spans and enlarged brains in the ances- continent than elsewhere (ref. 5, p. 161). tries of both humans and elephants. In regard to bodily size or strength, we do not know whether man is descended from some small species, like the chimpanzee, or from aerobic energy metabolism | brain | Charles Darwin | natural selection | one as powerful as the gorilla; and, therefore, we cannot say whether primate genomes man has become larger and stronger, or smaller and weaker, than his ancestors. We should, however, bear in mind that an animal harles Darwin proposed that natural selection favors inherited possessing great size, strength, and ferocity, and which, like the fi gorilla, could defend itself from all enemies, would not perhaps Cmodi cations that better adapt the organisms of a species to the have become social: and this would most effectually have checked environment of that species (1). Darwin also proposed the tree the acquirement of the higher mental qualities, such as sympathy ’ model for life s evolution. In this model, natural selection adaptively and the love of his fellows. Hence it might have been an immense modifies newly arisen species as they branch apart from their com- advantage to man to have sprung from some comparatively weak mon ancestor (1). Although there is now evidence that symbiotic creature (ref. 5, p. 65). fi merges produced the rst and that prokaryotic species As far as differences in certain important points of structure are engage in reticulate evolution (2–4), Darwin’s model of tree-like concerned, man may no doubt rightly claim the rank of a Suborder; branching appears to hold for the and other and this rank is too low, if we look chiefly to his mental faculties. vertebrates. Having deduced that species share common ancestors, Nevertheless, from a genealogical point of view it appears that this Darwin also reasoned that a truly natural system for classifying rank is too high, and that man ought to form merely a Family, or species would be genealogical, i.e., species should be classified possibly even only a Subfamily (ref. 5, p. 158). according to how recently they last shared a common ancestor. The Nevertheless the difference in mind between man and the higher hierarchical ranking in such a genealogical system could then be used animals, great as it is, certainly is one of degree and not of kind to indicate how relatively close or distant in geological time extant (ref. 5, p. 130). species are from their last common ancestor (LCA). Darwin’s application of the theory of evolution by natural In accord with this Darwinian framework, the phylogenomic selection to discussions of our own origins and place within approach to elucidating adaptive evolution in the ancestry of laid the foundation for modern phylogenetic and phylo- modern humans involves identifying the changes in genes and genomic studies of . He proposed that human- genomes on a that accurately places humans within the order Primates and, more widely, within the class Mammalia. Viewing the ancestries of many mammals, not just the ancestry of modern humans, could provide examples of convergent This paper results from the Arthur M. Sackler Colloquium of the National Academy of fi Sciences, “In the Light of Evolution IV: The Human Condition,” held December 10–12, adaptive evolution, which may point to speci c categories of genetic 2009, at the Arnold and Mabel Beckman Center of the National Academies of Sciences changes that are associated with important phenotypic changes. and Engineering in Irvine, CA. The complete program and audio files of most presentations This phylogenomic approach could help identify the positively are available on the NAS Web site at www.nasonline.org/SACKLER_Human_Condition. selected genetic changes that shaped such distinctive modern Author contributions: M.G. and K.N.S. designed research; M.G. analyzed data; and M.G. human features as prolonged prenatal and postnatal development, and K.N.S. wrote the paper. lengthened life spans, strong social bonds, enlarged brains, and high The authors declare no conflict of interest. cognitive abilities. In this article, we first briefly sketch out the his- This article is a PNAS Direct Submission. torical background of ideas and findings that have led to phyloge- 1To whom correspondence should be addressed. E-mail: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.0914626107 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 kind originated from man-like apes (first quote) in Africa and molecular clock model the LCA of humans, chimpanzees, and that humans are most allied to chimpanzees and (second gorillas was placed at only 5 Mya (13, 14). quote). Further, Darwin seems to have thought that our pro- The determination of the actual amino acid sequences of genitors were more like chimpanzees than gorillas (third quote). proteins began in the 1950s (15) and, in the ensuing decades, Darwin challenged the then orthodox view that a whole taxo- provided important information about human evolution. Phylo- nomic order, the Bimana, should consist of only one species, our genetic analysis of hemoglobin amino acid sequences pointed to own sapiens. Instead, Darwin noted that genealogically, the possibility that chimpanzees and humans were more closely we humans should have no more than a family or even just a related to each other than either was to gorillas (16–18). This subfamily to ourselves (fourth quote), suggesting that Darwin analysis grouped chimpanzee and gorilla with human rather than might have been willing to have a family that grou- with hemoglobin (17, 18) and showed human and ped modern humans with man-like apes. Moreover, Darwin also chimpanzee hemoglobin to be identical and slightly divergent commented on the most widely cited example of human from gorilla hemoglobin (16–18). uniqueness, the modern human mind. He postulated that the Estimates of interspecies genetic similarities were also obtained by difference between the modern human mind and the mind of DNA–DNA hybridization data. An initial set of such data reported other higher animals was one of degree not of kind (fifth quote). in 1972 (19), similar to the hemoglobin amino acid sequence data, Nearly a century after Darwin first proposed the theory of evo- suggested that instead of a human–chimpanzee–gorilla trichotomy, lution by natural selection, emerged as a humans and chimpanzees shared the more recent common ancestor. scientific field and molecular methods began to be used toward During the 1980s, extensive DNA–DNA hybridization data clearly the study of human evolution. Molecular evidence inferred from placed chimpanzees closer to humans than to gorillas (20, 21). Direct proteins and DNA data generated during the past 50 years have measurements of interspecies genetic similarities were provided by vindicated Darwin’s foresightedness and have decisively estab- the actual nucleotide sequences of orthologous DNAs, each set of lished that among living species modern humans have their these DNA orthologues apparently having descended from the same closest kinship to common and bonobo chimpanzees. genomic locus in the LCA of the examined contemporary species. By the late 1980s and early 1990s, phylogenetic analysis of such data Use of Molecular Methods to Infer Our Place in Nature greatly strengthened the evidence that chimpanzees (common and More than 100 years ago, Nuttall (6) observed that rabbit anti- bonobo) have humans, not gorillas, as their closest relatives (22–24). serum produced against human whole-blood serum yielded larger With the advent of next-generation sequencing technologies, precipitates when mixed with serum from human, chimpanzee, or genomic-level sequence data have provided strong evidence that gorilla blood than from orangutan, , or other mammalian chimpanzees are our closest living relatives and only slightly blood. Although Nuttall did not comment on the possible phylo- diverge from us (25–30). Large amounts of nucleotide sequence genetic and taxonomic significance of his antihuman serum cross- data have also been used to infer the evolutionary relationships reacting more strongly with chimpanzee and gorilla sera than with among almost all extant primate genera (26, 31) and among the Asian sera, he did foresee a promising future for molecular major of placental mammals (32–34). These data reveal studies of evolution (6). that rates of molecular evolution were slower in apes than in Old By the middle of the 20th century, molecular biologists had World monkeys and, within the ape , slower in chimpanzees established that DNA contained the genetic information for an than in gorillas and and slowest in the human lineage organism and that nucleotide sequences in genes encoded the (27, 35). This slowdown can be attributed to the decreased annual amino acid sequences of proteins. Immunologists could then rates that must have resulted from lengthened gen- deduce that a protein’s antigenic divergencies among species eration times. There may also have been selection for more effi- reflected amino acid sequence divergencies, the source of which cient mechanisms of DNA repair and maintenance of genome were nucleotide sequence substitutions. An immunological method integrity (36). that was much improved over Nuttall’s was used to examine protein A number of recent studies have used calibration points divergencies among primate and other mammalian species (7–11). and a variable-rate molecular clock to infer divergence dates The observed protein divergencies, interpreted as genetic diver- across primate phylogeny (e.g., refs. 31, 37–39). Dates inferred gencies, challenged the reigning view (12) that the human lineage from the fossil record and molecular data suggest the human– diverged markedly from the ancestral ape state to occupy an entirely chimpanzee LCA is more recent than the LCA age for the species new structural–functional adaptive zone. Whereas the then-pre- of a strepsirrhine genus (either lemuriform or lorisiform) and is vailing view placed chimpanzees and gorillas with orangutans in the close to the LCA age for the species of an Old World family Pongidae, with humans alone among living species in the genus such as Macaca or Cercopithecus or a family Hominidae (12), the immunologically detected genetic genus such as Ateles or Callicebus. This objective view of our spe- affinities showed humans, chimpanzees, and gorillas to be highly cies recalls Darwin’s vision of our place in a genealogical classi- similar and more closely related to one another than to orangutans fication of primates. However, these data suggest that, rather than or other primates, thus supporting chimpanzees and gorillas being having a mere subfamily to ourselves, we modern humans should grouped with humans in the family Hominidae (9–11). The indi- perhaps have no more than a genus or just a subgenus to ourselves, cated genetic kinship between chimpanzees and gorillas was not any i.e., common and bonobo chimpanzees and modern humans would closer than the close kinship of either to humans. Indeed some be the only extant members of either subtribe Hominina or genus immunological results placed chimpanzees closer to humans than to Homo (30, 40, 41). The rules (42) for such an age-based genea- gorillas (e.g., Fig. 4 in ref. 10), and they also suggested that rates of logical classification are that each should represent a clade, molecular evolution had slowed in hominoid lineages (7–10). Thus, and clades at an equivalent evolutionary age should be assigned these first substantial molecular data did not support the claim that the same taxonomic rank. An intragenus sister-grouping of the human lineage had diverged radically from an ancestral ape humans and chimpanzees is concordant with the ages of origin of state. Instead, in their proteins, humans, chimpanzees, and gorillas many other mammalian genera (43) and captures the close genetic diverged only slightly from one another. The degrees of interspecies correspondence of humans to chimpanzees. In accord with this antigenic divergence of serum albumin challenged the conventional close correspondence, chimpanzees are highly social, have simple view that many millions of years of evolution separated modern material cultures, inhabit a wide range of habitats that range from humans from our nearest nonhuman relatives (13, 14). Instead forests to savannas, and have the ability to use rudimentary forms when these immunologic divergence data were analyzed by a of (44–49).

2of6 | www.pnas.org/cgi/doi/10.1073/pnas.0914626107 Goodman and Sterner Downloaded by guest on September 29, 2021 Phylogenomic Assessment of Being Human Human Terminal (~6Ma - present) The extensive sequencing of genomes from primates (Fig. 1) and Ape Stem (~25Ma - ~6Ma) other vertebrates makes possible a phylogenomic search for the Primate Stem ↓ Human genetic basis of modern human traits. The close genetic corre- (~91Ma - ~25Ma) ↓ spondence of chimpanzees to humans and the relative shortness of ↓ Chimpanzee our evolutionary separation from chimpanzees suggest that most of the adaptive evolution that produced the distinctive modern Macaque human phenotype had already occurred by the time of the LCA of chimpanzees and humans. Thus, an assessment of the genetic Rodents underpinnings of being human should not just focus on the ter- minal human lineage but should also encompass earlier periods of 100 75 50 25 Ma human ancestry (Fig. 2). Moreover, there are other mammals with aspects of their phenotypes (e.g., enlarged brains) that are similar Fig. 2. Lineages of interest when examining the evolutionary origins of distinctly human traits using currently available high-quality genomic data. to aspects of the distinctive modern human phenotype. Examining the ancestries of these mammals is a further way to assess the genetic underpinnings of distinctive modern human phenotypic and prolonged growth of brain mass. Whereas the chimpanzee brain features and suggests that all such features are not necessarily reaches 40% of its adult size by the end of fetal life, the modern unique to modern humans. human brain at birth has reached only 30% of its adult size (50). Nevertheless, although far from its adult size, the newborn human Phylogenomic Assessment of Human Brain Evolution Reveals brain is still larger than the newborn chimpanzee brain (50). Adaptive Evolution in Multiple Stages of Human Ancestry Anthropoid primates have large brains relative to body size, Expanded cognitive abilities are hallmarks of modern humans. Why invasive hemochorial placentation, and long gestations. During such abilities were selected for in modern humans and in the human this long gestation, the fetal brain consumes approximately 65% of lineage, and how they are maintained, is of great interest. As noted by the fetal body’s total metabolic energy (51). The invasive hemo- Darwin more than 135 years ago, differences observed between the chorial placenta facilitates the transfer of nutrients from mother to modern human mind and the mind of our closest living relatives can fetus. Among anthropoids, modern humans have the largest brain, be more appropriately characterized as differences in degree, not the most invasive placentation, and the longest gestation. In the differences in absolute kind. As such, we expect that the roots earlier ancestry of humans, the threat of destructive maternal of the adaptive evolution that led to the modern human mind trace immune attacks on the fetus would have necessitated the evolution back to ancient stem lineages in primate and mammalian phylogeny. of mechanisms for immune tolerance at the maternal–fetal inter- For example, humans have a phenomenal ability to design and use face. Genes that code for galectins, proteins that promote immune complex tools, but this ability depends on the opposable thumb, cell death, may have provided the anthropoid fetus with an addi- which had evolved in the early primates, as attested to by its presence tional immune tolerance mechanism for averting maternal in slow and other primate species. immune attacks (52). Anthropoid primates have placental-specific A striking morphological feature that separates modern humans galectins that induce apoptosis of T lymphocytes (52). These genes from other primates is our enlarged cerebral cortex. An initial originated from gene duplications that occurred in the anthropoid enlargement of the cerebral cortex in the stem lineage of the stem lineage, and then in that lineage, regulatory evolution of these anthropoid infra-order was followed by further marked genes produced placental-specific expression. Moreover, there was enlargements in the hominid lineage to the chimpanzee/human also positive selection for amino acid replacements in the placental LCA. After a period of stasis, a further marked expansion occurred galectins of the common ancestor of anthropoids, of catarrhines, during the past 3 million years in the terminal descent to modern and of humans. This adaptive evolution contributed to distinctive humans. This last neocortical expansion resulted from more rapid but not unique modern human features such as lengthened ges- tation and increased brain-to-body size ratio. Paradoxically, because of the selection that brought about distinctive modern human features, which also include prolonged postnatal develop- Microcebus murinus (mouse ) +

Otolemur garnettii (bushbaby) + ment and longer generation times, we are genetically closer to the

Tarsius syrichta () ^ human/chimpanzee LCA than are chimpanzees (27, 32, 35).

Callithrix jacchus (marmoset) ^ Potential genetic correlates to increased brain size in the primate

Saimiri sp. (squirrel monkey) * lineage that descended to humans is provided by the evolutionary Macaca mulatta (rhesus macaque) + history of Abnormal Spindle-Like Microcephaly-Associated (ASPM) Macaca fascicularis (cynomolgus macaque) ^ and microcephalin (MCPH1), two genes that have mutant forms Papio hamadryas (baboon) ^ associated with the severe reduction of brain size that characterizes Chlorocebus aethiops (vervet) ^ microcephaly in humans (53, 54). During descent of the ape stem Nomascus leucogenys (gibbon) ^ portion of the primate lineage to humans (approximately 25 to 6 Pongo pygmaeus (orangutan) ^ Mya), positive selection acted on microcephalin’s protein-coding Gorilla gorilla (gorilla) ^ ^ in progress sequence, and during the past 6 million years in descent from the paniscus (bonobo) ^ + completed chimpanzee/human LCA to modern humans, positive selection acted * not started Pan troglodytes (chimpanzee) + ASPM’ – Homo sapiens (human) + on s protein-coding sequence (55 59).

Homo neanderthalensis (Neanderthal) ^ ** Language is also considered to be a distinctive human trait. There is evidence of accelerated evolution in the human terminal of the Fig. 1. Summary of primate genome sequencing projects based on the protein-coding sequence of Forkhead Box P2 (FOXP2)(60–62). National Human Genome Research Institute list of the status of approved This gene encodes a transcription factor that influences the sequencing targets (current as of December 15, 2009). Species shown in expression levels of many brain-expressed genes. FOX2P mutants purple (+) are completed, those in pink (^) are in progress, and that in green – (*) has not yet been started. **Sequencing of the Neanderthal genome is have been found in humans with language dysfunction (63 65), currently in progress, although not listed by the National Human Genome suggesting that adaptive evolution of FOXP2 may have contributed Research Institute. Nodes of particular interest for examining the evolu- to the origin of modern human spoken language abilities (60, 61). tionary origins of distinctive human traits are noted by a black oval. This adaptive evolution may have occurred in archaic humans

Goodman and Sterner PNAS Early Edition | 3of6 Downloaded by guest on September 29, 2021 ancestral to both Neanderthals and modern humans, an inference (74). Glutamate is the most common neurotransmitter in the drawn from the finding that Neanderthal FOXP2 has the same two brain. It is believed that positively selected amino acid sub- amino acid replacements that distinguish modern human FOXP2 stitutions in GLUD2 allow for more efficient energy metabolism of from the orthologous chimpanzee protein (66). The chimpanzee glutamate in the brain (74–76). FOXP2 patterns of brain transcriptional regulation differ somewhat from the modern human FOXP2 patterns (67), although there is no Aerobic Energy Metabolism Genes and Brain Evolution direct evidence that the two amino acid difference of chimpanzee Neurons are the most energy-demanding cells of the modern FOXP2 from modern human FOXP2 causes language dysfunction. human body (77). The proliferation and pruning of neurons and In addition to evidence suggesting FOXP2 has evolved adaptively in their dendrites and the formation of the synaptic connections humans, five of the genes that FOXP2 regulates had themselves involved in learning are all energy-intensive processes. Thus it was been under positive selection (67). Several genes involved in the not unexpected that aerobic energy metabolism (AEM) genes development of the auditory system also show evidence of adaptive were found to be major targets of positive selection in the adaptive evolution in modern humans (68). evolution of enlarged brains. This finding was made in a phylo- A number of recent studies have examined gene expression in genomic study that examined protein-coding sequence evolution the brain transcriptomes of different primate species. More ex- during human ancestry (78). In the time between the Old World pression changes were observed in the human brain than in other monkey–ape LCA and the chimpanzee–human LCA, the most primate brains (69). In general, the majority of these changes favored targets of positive selection were brain-expressed genes involved increased expression (70). Among the genes found to be that code for mitochondrial functioning proteins, e.g., proteins of up-regulated in modern humans are genes involved in neuronal the oxidative phosphorylation pathway (78, 79). Although not activity and metabolic processes (70, 71). Genes involved in oxi- brain-specific, many of these AEM genes are highly expressed in dative phosphorylation (electron transport) are especially up- the adult human brain (78). Moreover, these genes not only show regulated in humans (71). Most recently, Nowick and colleagues evidence of adaptive evolution on the lineage to the LCA of suggested that major differences in expression of brain-expressed humans and chimpanzees, but also on both the terminal human genes observed between human and chimpanzee may be coordi- and terminal chimpanzee lineages. Considering that mitochondria nated by a small number of transcription factors that show dif- play an essential central role in the aerobic production of energy, it ferential expression between humans and chimpanzees (72). may be inferred that the adaptive evolution of AEM genes Interestingly, many of these transcription factors are associated improved the molecular machinery that facilitates the functioning with pathways involved in energy metabolism (72). of a high energy–demanding encephalized brain. In addition to changes in gene expression level, gene duplication Phylogenomic analysis of approximately 15,000 human coding events during human ancestry may have also contributed sig- sequences confirmed that AEM genes were favored targets of nificantly to our brain evolution. All mammals possess a gene that positive selection in the ape stem period of human ancestry (i.e., encodes glutamate dehydrogenase 1 (GLUD1). Whereas GLUD1 between 25 Mya and 6 Mya), with 52 AEM genes (cellular com- is localized to both the mitochondria and cytoplasm where it ponent GO:0005739; mitochondrion) in the most enriched cluster functions in the metabolism of glutamate, a retrotransposon- of genes showing the signatures of positive selection, i.e., faster rate mediated duplication event in the hominoid ancestor approx- of nonsynonymous substitutions (dN) than synonymous (dS) (79). imately 18 to 25 Mya (73) resulted in a second GLUD-encoding In the human terminal lineage (from 6 Mya to present), there were gene (GLUD2) that is targeted specifically to the mitochondria also many positively selected AEM genes but not significantly more

A C 140

Human Euarchontoglires Mouse 100 elephant Dog human Cow tenrec mouse Armadillo Tenrec 60 Afrotheria Elephant Number of Sequences Opossum

Platypus 20 Chicken Frog

150 5075100125 25 Ma 0.3-0.4 0.4-0.5 0.5-1.0 >1.0 0-0.0250.025-0.050.05-0.075 0.075-0.1 0.1-0.15 0.15-0.2 0.2-0.3 purifying dN/dS Bins positive selection < > selection

B Taxon Gestation (days) Life Span (years) Body Weight (g) Brain Weight (g) Encephalization Quotient elephant 660 60 3505000 4420 1.6 human 270 75 44000 1300 8.7 tenrec 46 13 88 0.62 0.3 mouse 20 2 21 0.43 0.5

Fig. 3. An example of convergent patterns of adaptive evolution in two large-brained taxa (elephants and humans). All data presented and images are adapted from previously published work (79). (A) Species phylogeny based on DNA and fossil evidence (32–34, 84). Lineages of interest are highlighted. (B) Life history and phenotype variables among study taxa. Values given are averages. More information and references for these values can be found in Table S1 of ref. 79. (C) Lineage protein-coding sequence evolution for 501 mitochondria-related genes.

4of6 | www.pnas.org/cgi/doi/10.1073/pnas.0914626107 Goodman and Sterner Downloaded by guest on September 29, 2021 than expected for any category of genes in the human genome. the species and genera in each extant mammalian order. The phy- However, when these analyses were confined to only those positively logenetic tree of mammals inferred from genome sequences can then selected genes that also show brain expression levels equivalent to or be used to uncover in each evolved lineage the genetic changes that greater than the median of all modern human brain–expressed had occurred between ancestral and descendent genomes. Of par- genes (80), the most enriched clusters in the ape stem and human ticular interest will be those adaptive genetic changes in protein- terminal lineages consisted of 20 and 23 AEM genes, respectively. coding sequences, promoters, and other regulatory sequences. Of these brain expressed AEM genes, 14 and 10 in the ape stem and Phylogenomic research provides an opportunity to identify those human terminal lineage, respectively, were involved in oxidative parallel or convergent patterns of adaptive genetic evolution that phosphorylation (Kyoto Encyclopedia of Genes and Genomes correlate with parallel or convergent patterns of adaptive pheno- pathway map00190; oxidative phosphorylation). For more detailed typic evolution. As an example, brain size increased in parallel in the information about these data and the methods used to infer stem catarrhines and stem platyrrhines (82). Encephalization then enrichment for Gene Ontology terms and Kyoto Encyclopedia of increased further in ape ancestry, in some Old World monkeys and Genes and Genomes pathways, refer to Goodman et al. (79). some New World monkeys (e.g., Cebus) (83). In addition to humans, If the evolutionary origins of enlarged hominid brains depended a number of primate species also exhibit a great deal of phenotypic on adaptively evolved AEM genes, then other large-brained and behavioral plasticity, including chimpanzees, baboons, mac- mammals should also have in their ancestry AEM genes as prin- aques, and capuchins. Parallel or convergent patterns of adaptive cipal targets of positive selection. An opportunity to test this genetic evolution among these species might help elucidate mech- hypothesis was provided by the addition of two afrotherian anisms contributing to enhanced brain plasticity in modern humans genomes to the growing set of publically available sequenced during childhood when the capacity for learning is greatest. Nev- genomes. These two afrotherian genomes are from a large-brained ertheless, the search for genetic correlates of distinctive human , the African savanna elephant (Loxodonta africana) and phenotypic features should explore the possibility that some a small-brained mammal, the lesser hedgehog tenrec (Echinops molecular aspects of modern human brain plasticity might be telfairi ). The clade Afrotheria, within which are elephants and uniquely human. The hypothesis could be tested that adaptive tenrecs, is anciently separated from the clade Euarchontoglires, evolution in our recent ancestry increased the diversity of macro- A within which are humans and mice (Fig. 3 ). Although elephants molecular specificities involved in neuronal connectivity and neural and tenrecs are phylogenetically closer to each other than to plasticity. In testing this hypothesis, genes such as those concerned humans or mice, elephants resemble modern humans by having with cell–cell interaction, adhesion, and receptor–ligand binding such features as large brains, empathetic social bonds, high intel- and their cis-regulatory motifs should be examined. However, we B ligence, and prolonged development and long life spans (Fig. 3 ; would not be surprised if phylogenomic studies reveal that the as discussed in ref. 79). In contrast, tenrecs, as insectivore-grade genetic underpinnings for the basic mechanisms of brain plasticity mammals, have small, poorly encephalized brains and short life are essentially the same as in other catarrhine primates and that the spans. The phylogenomic patterns of adaptive evolution are more modern human mind differs from the other species primarily similar between elephant and human than between either ele- because of the modern human brain’slargernumberofneuronsand phant and tenrec lineages or human and mouse lineages, with dendritic connections and much longer periods of postnatal devel- adaptively evolved AEM genes being especially well represented opment in a social nurturing environment. in the elephant and human patterns (Fig. 3C) (79). In correlation with brain oxygen consumption and brain mass being largest in A Modern Voyage elephants and next largest in humans, positively selected AEM With the advent of large-scale sequencing technologies and new genes were most evident in the elephant lineage (indeed more bioinformatic tools for processing genomic sequence data, we overrepresented than any other gene category), next most evident are poised to embark on a new voyage of exploration and inquiry in the human lineage, and not evident (i.e., not overrepresented) in just as Darwin did in 1831. The last decade in particular has seen tenrec and mouse lineages or in the other examined mammalian Bos taurus Canis familiaris) exponential growth in genome sequence collection and charac- pair (the two laurasiatherians and . terization. As we work toward a more complete understanding of The Human Brain, Different by Degree and Not Kind genome structure, biology, and evolution, we become better able to develop and test hypotheses concerning a number of funda- Darwin’s insight that the modern human mind does not differ in kind mental questions in and human evolution. but rather in degree from other mammalian minds, in our opinion, At the forefront of our interests are those molecular mechanisms should serve as the main guidepost for pursuing a phylogenomic and that have resulted in the modern human mind. search for the genetic roots of the modern human mind. The prospect that high-quality genome sequences will be obtained from thousands ACKNOWLEDGMENTS. We thank Derek Wildman and Larry Grossman for of different mammals (81) promises to make possible such a phylo- insightful discussion. This study was supported by National Science Founda- genomic search. Key to the search will be dense representation of tion Grants BCS0550209 and BCS0827546.

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