'Anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews disciplinary barriers and rejects artificial 'genes versus environment' dichotomies.
The genomic and genetic approach towards this goal is made quite difficult by the discovery of much greater molecular variation than originally expected, both within and between species.
As only a few simple molecular differences have been identified that might underlie human uniqueness, both traditional and novel approaches are needed to understand the genetic aspects of human evolution.
It is fruitless to argue over whether differences in gene expression, in protein and RNA sequence variation, or in genomic deletions, duplications and insertions are more important in exploring human uniqueness. Examples of each have been found, and it is likely that final answers will involve many more in each category.
Integrated molecular studies along with parallel organ-systems approaches are required to identify and characterize candidate genes.
Genome interactions with environment, behaviour and culture are likely to be more prominent in humans than in other species.
Aspects of human uniqueness might have arisen because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture, rather than hard-wired instinctual behaviours.
This, in turn, might have relaxed allowable thresholds for large-scale genomic structural variation in primates in general, and humans in particular.
In addition to conventional Darwinian mechanisms, there are potential roles for the Baldwin effect; humans might have escaped the second phase of the Baldwin effect, wherein there is genetic hard-wiring of learned behaviour that is beneficial to a population.
The unusual degree of exaptation of the human mind might require consideration of additional novel mechanisms, as originally suggested by Alfred Russel Wallace.
What makes us human? Specialists in each discipline respond through the lens of their own expertise. In fact, 'anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews such barriers. Here we take a genomic and genetic perspective towards molecular variation, explore systems analysis of gene expression and discuss an organ-systems approach. Rejecting any 'genes versus environment' dichotomy, we then consider genome interactions with environment, behaviour and culture, finally speculating that aspects of human uniqueness arose because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture — perhaps relaxing allowable thresholds for large-scale genomic diversity.
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Huxley, T. H. Evidence as to Man's place in Nature (Williams and Norgate, London, 1863).
Darwin, C. The Descent of Man, and Selection in Relation to Sex (D. Appleton, New York, 1871).
Sarich, V. M. & Wilson, A. C. Immunological time scale for hominid evolution. Science 158, 1200–1203 (1967).
Syner, F. N. & Goodman, M. Differences in the lactic dehydrogenases of primate brains. Nature 209, 426–428 (1966).
de Waal, F. B. A century of getting to know the chimpanzee. Nature 437, 56–59 (2005).
King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975). Synthesizes diverse data sets to show that the level of molecular change that exists between chimpanzees and humans is dissonant with the numerous morphological differences seen between species. It concludes that regulatory differences in gene expression probably underlie species differences.
Maresco, D. L. et al. Localization of FCGR1 encoding Fcγ receptor class I in primates: molecular evidence for two pericentric inversions during the evolution of human chromosome 1. Cytogenet. Cell Genet. 82, 71–74 (1998).
Chou, H. H. et al. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo–Pan divergence. Proc. Natl Acad. Sci. USA 95, 11751–11756 (1998). This is the first paper to report that a genetic difference between humans and other hominids results in a definite biochemical change — in human cell-surface sialic acids. Subsequently, more than 10 uniquely human changes in sialic-acid biology have been discovered, as described in reference 89.
Szabo, Z. et al. Sequential loss of two neighboring exons of the tropoelastin gene during primate evolution. J. Mol. Evol. 49, 664–671 (1999).
McConkey, E. H. & Goodman, M. A Human Genome Evolution Project is needed. Trends Genet. 13, 350–351 (1997).
Vigilant, L. & Pääbo, S. A chimpanzee millennium. Biol. Chem. 380, 1353–1354 (1999).
McConkey, E. H. & Varki, A. A primate genome project deserves high priority. Science 289, 1295–1296 (2000).
Varki, A. A chimpanzee genome project is a biomedical imperative. Genome Res. 10, 1065–1070 (2000).
The Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005). Presents a detailed comparison of human and chimpanzee genomes, including confirmation (see also reference 21) that structural and copy-number changes affect four times the number of base pairs than single-nucleotide differences.
Noonan, J. P. et al. Sequencing and analysis of Neanderthal genomic DNA. Science 314, 1113–1118 (2006).
Green, R. E. et al. Analysis of one million base pairs of Neanderthal DNA. Nature 444, 330–336 (2006).
Varki, A. et al. Great Ape Phenome Project? Science 282, 239–240 (1998).
Ridley, M. Nature via Nurture: Genes, Experience, and What Makes us Human (HarperCollins, New York, 2003).
Olson, M. V. & Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nature Rev. Genet. 4, 20–28 (2003).
Varki, A. & Altheide, T. K. Comparing the human and chimpanzee genomes: searching for needles in a haystack. Genome Res. 15, 1746–1758 (2005). Includes a list of several phenotypic features that show apparent or real differences between humans and great apes.
Britten, R. J. Divergence between samples of chimpanzee and human DNA sequences is 5%, counting indels. Proc. Natl Acad. Sci. USA 99, 13633–13635 (2002).
Cheng, Z. et al. A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature 437, 88–93 (2005).
Gibbs, R. A. et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science 316, 222–234 (2007).
Prabhakar, S., Noonan, J. P., Pääbo, S. & Rubin, E. M. Accelerated evolution of conserved noncoding sequences in humans. Science 314, 786 (2006).
Fortna, A. et al. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2, e207 (2004).
Newman, T. L. et al. A genome-wide survey of structural variation between human and chimpanzee. Genome Res. 15, 1344–1356 (2005).
Dumas, L. et al. Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 17, 1266–1277 (2007).
Hahn, M. W., Demuth, J. P. & Han, S. G. Accelerated rate of gene gain and loss in primates. Genetics 177, 1941–1949 (2007).
Khaitovich, P. et al. Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science 309, 1850–1854 (2005).
Clark, A. G. et al. Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science 302, 1960–1963 (2003). In this key paper, the mouse is used as an outgroup to identify genes undergoing positive selection in humans.
Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004).
Shi, P., Bakewell, M. A. & Zhang, J. Did brain-specific genes evolve faster in humans than in chimpanzees? Trends Genet. 22, 608–613 (2006).
Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005).
Bakewell, M. A., Shi, P. & Zhang, J. More genes underwent positive selection in chimpanzee evolution than in human evolution. Proc. Natl Acad. Sci. USA 104, 7489–7494 (2007).
Boyko, A. R. et al. Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 4, e1000083 (2008).
Yu, X. J., Zheng, H. K., Wang, J., Wang, W. & Su, B. Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup. Genomics 88, 745–751 (2006).
Wang, H. Y. et al. Rate of evolution in brain-expressed genes in humans and other primates. PLoS Biol. 5, e13 (2007).
Bustamante, C. D. et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005).
Altheide, T. K. et al. System-wide genomic and biochemical comparisons of sialic acid biology among primates and rodents: evidence for two modes of rapid evolution. J. Biol. Chem. 281, 25689–25702 (2006).
Yang, Z., Nielsen, R., Goldman, N. & Pedersen, A. M. Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155, 431–449 (2000).
Pan, Q. et al. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol. Cell 16, 929–941 (2004).
Zhang, X. H. & Chasin, L. A. Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons. Proc. Natl Acad. Sci. USA 103, 13427–13432 (2006).
Calarco, J. A. et al. Global analysis of alternative splicing differences between humans and chimpanzees. Genes Dev. 21, 2963–2975 (2007).
Lu, Z. X., Peng, J. & Su, B. A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory. Hum. Mutat. 28, 978–984 (2007).
Keightley, P. D., Lercher, M. J. & Eyre-Walker, A. Evidence for widespread degradation of gene control regions in hominid genomes. PLoS Biol. 3, e42 (2005). A surprising finding of poor evolutionary conservation in the regulatory regions of human and chimpanzee genes. The authors suggest that there is “a widespread degradation of the genome during the evolution of humans and chimpanzees”, a proposal that fits with our speculations here about relaxation of constraints on genomic diversity owing to buffering by culture and learning.
Berezikov, E. et al. Diversity of microRNAs in human and chimpanzee brain. Nature Genet. 38, 1375–1377 (2006).
Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006). A ranking of regions in the human genome manifesting significant evolutionary acceleration shows that most of these human accelerated regions (HARs) do not code for proteins. The most dramatic change is seen in HAR1, which is part of a novel RNA gene ( HAR1F ) that is expressed specifically in the developing human neocortex.
Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
Gerstein, M. B. et al. What is a gene, post-ENCODE? History and updated definition. Genome Res. 17, 669–681 (2007).
Asthana, S. et al. Widely distributed noncoding purifying selection in the human genome. Proc. Natl Acad. Sci. USA 104, 12410–12415 (2007).
Margulies, E. H. et al. Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome. Genome Res. 17, 760–774 (2007).
Pheasant, M. & Mattick, J. S. Raising the estimate of functional human sequences. Genome Res. 17, 1245–1253 (2007).
Cheng, J. et al. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science 308, 1149–1154 (2005).
Wu, J. Q. et al. Systematic analysis of transcribed loci in ENCODE regions using RACE sequencing reveals extensive transcription in the human genome. Genome Biol. 9, R3 (2008).
Stone, E. A., Cooper, G. M. & Sidow, A. Trade-offs in detecting evolutionarily constrained sequence by comparative genomics. Annu. Rev. Genomics Hum. Genet. 6, 143–164 (2005).
Karaman, M. W. et al. Comparative analysis of gene-expression patterns in human and African great ape cultured fibroblasts. Genome Res. 13, 1619–1630 (2003).
Enard, W. et al. Intra- and interspecific variation in primate gene expression patterns. Science 296, 340–343 (2002).
Khaitovich, P. et al. Regional patterns of gene expression in human and chimpanzee brains. Genome Res. 14, 1462–1473 (2004). This paper was among the first to report comparisons of gene expression in multiple brain regions, including different cerebral cortical areas. The data permit an initial estimation of expression differences between cortical and sub-cortical structures and inter-individual variability.
Uddin, M. et al. Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc. Natl Acad. Sci. USA 101, 2957–2962 (2004).
Caceres, M. et al. Elevated gene expression levels distinguish human from non-human primate brains. Proc. Natl Acad. Sci. USA 100, 13030–13035 (2003).
Preuss, T. M., Qi, H. & Kaas, J. H. Distinctive compartmental organization of human primary visual cortex. Proc. Natl Acad. Sci. USA 96, 11601–11606 (1999). Demonstrates fundamental differences in the organization of a primary sensory region between humans and other primates.
Preuss, T. M., Caceres, M., Oldham, M. C. & Geschwind, D. H. Human brain evolution: insights from microarrays. Nature Rev. Genet. 5, 850–860 (2004).
Khaitovich, P., Enard, W., Lachmann, M. & Pääbo, S. Evolution of primate gene expression. Nature Rev. Genet. 7, 693–702 (2006).
Oldham, M. C. & Geschwind, D. H. in New Encyclopedia of Neuroscience (ed. Squire, L.) (Elsevier Science, Oxford, UK, 2008) (in the press).
Gu, J. & Gu, X. Induced gene expression in human brain after the split from chimpanzee. Trends Genet. 19, 63–65 (2003).
Oldham, M. C. & Geschwind, D. H. Evolutionary genetics: the human brain — adaptation at many levels. Eur. J. Hum. Genet. 13, 520–522 (2005).
Khaitovich, P. et al. Positive selection on gene expression in the human brain. Curr. Biol. 16, R356–R358 (2006).
Liao, B. Y. & Zhang, J. Evolutionary conservation of expression profiles between human and mouse orthologous genes. Mol. Biol. Evol. 23, 530–540 (2006).
Jordan, I. K., Marino-Ramirez, L. & Koonin, E. V. Evolutionary significance of gene expression divergence. Gene 345, 119–126 (2005).
Enard, W. et al. Differences in DNA methylation patterns between humans and chimpanzees. Curr. Biol. 14, R148–R149 (2004).
Bailey, J. A. & Eichler, E. E. Genome-wide detection and analysis of recent segmental duplications within mammalian organisms. Cold Spring Harb. Symp. Quant. Biol. 68, 115–124 (2003).
She, X. et al. A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications. Genome Res. 16, 576–583 (2006).
Li, W. H. & Tanimura, M. The molecular clock runs more slowly in man than in apes and monkeys. Nature 326, 93–96 (1987).
Elango, N., Thomas, J. W. & Yi, S. V. Variable molecular clocks in hominoids. Proc. Natl Acad. Sci. USA 103, 1370–1375 (2006).
Armengol, L., Pujana, M. A., Cheung, J., Scherer, S. W. & Estivill, X. Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements. Hum. Mol. Genet. 12, 2201–2208 (2003).
Bailey, J. A., Baertsch, R., Kent, W. J., Haussler, D. & Eichler, E. E. Hotspots of mammalian chromosomal evolution. Genome Biol. 5, R23 (2004).
Kehrer-Sawatzki, H. & Cooper, D. N. Structural divergence between the human and chimpanzee genomes. Hum. Genet. 120, 759–778 (2007).
Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002). This is the first validated map of segmental duplication in the human genome. It shows an abundance of interspersed, high-identity duplications and identifies hot spots of disease-associated CNVs.
Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).
Yohn, C. T. et al. Lineage-specific expansions of retroviral insertions within the genomes of African great apes but not humans and orangutans. PLoS Biol. 3, e110 (2005).
Jiang, Z. et al. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Nature Genet. 39, 1361–1368 (2007).
Horvath, J. E. et al. Punctuated duplication seeding events during the evolution of human chromosome 2p11. Genome Res. 15, 914–927 (2005).
Wang, H. et al. SVA elements: a hominid-specific retroposon family. J. Mol. Biol. 354, 994–1007 (2005).
Kaiser, S. M., Malik, H. S. & Emerman, M. Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein. Science 316, 1756–1758 (2007).
Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).
Wang, X., Grus, W. E. & Zhang, J. Gene losses during human origins. PLoS Biol. 4, e52 (2006).
Angata, T., Margulies, E. H., Green, E. D. & Varki, A. Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms. Proc. Natl Acad. Sci. USA 101, 13251–13256 (2004).
Chou, H. H. et al. Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution. Proc. Natl Acad. Sci. USA 99, 11736–11741 (2002).
Varki, A. Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins. Nature 446, 1023–1029 (2007).
Stedman, H. H. et al. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428, 415–418 (2004).
McCollum, M. A., Sherwood, C. C., Vinyard, C. J., Lovejoy, C. O. & Schachat, F. Of muscle-bound crania and human brain evolution: the story behind the MYH16 headlines. J. Hum. Evol. 50, 232–236 (2006).
Perry, G. H., Verrelli, B. C. & Stone, A. C. Comparative analyses reveal a complex history of molecular evolution for human MYH16. Mol. Biol. Evol. 22, 379–382 (2005).
Ohno, S., Wolf, U. & Atkin, N. B. Evolution from fish to mammals by gene duplication. Hereditas 59, 169–187 (1968).
Locke, D. P. et al. Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization. Genome Res. 13, 347–357 (2003).
Bailey, J. A. & Eichler, E. E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Rev. Genet. 7, 552–564 (2006).
Bosch, N. et al. Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events. Hum. Mol. Genet. 16, 2572–2582 (2007).
Linardopoulou, E. V. et al. Human subtelomeric WASH genes encode a new subclass of the WASP family. PLoS Genet. 3, e237 (2007).
Popesco, M. C. et al. Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains. Science 313, 1304–1307 (2006).
Johnson, M. E. et al. Positive selection of a gene family during the emergence of humans and African apes. Nature 413, 514–519 (2001).
Johnson, M. E. et al. Recurrent duplication-driven transposition of DNA during hominoid evolution. Proc. Natl Acad. Sci. USA 103, 17626–17631 (2006).
Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004). This paper and reference 102 show extensive genome-wide copy-number polymorphisms within the general human population.
Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).
Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008).
Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).
Perry, G. H. et al. Hotspots for copy number variation in chimpanzees and humans. Proc. Natl Acad. Sci. USA 103, 8006–8011 (2006).
Lee, A. S. et al. Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies. Hum. Mol. Genet. 17, 1127–1136 (2008).
Graubert, T. A. et al. A high-resolution map of segmental DNA copy number variation in the mouse genome. PLoS Genet. 3, e3 (2007).
She, X., Cheng, Z., Zollner, S., Church, D. M. & Eichler, E. E. Mouse segmental duplication and copy number variation. Nature Genet. 40, 909–914 (2008).
Nguyen, D. Q., Webber, C. & Ponting, C. P. Bias of selection on human copy-number variants. PLoS Genet. 2, e20 (2006).
de Smith, A. J. et al. Array CGH analysis of copy number variation identifies 1,284 new genes variant in healthy white males: implications for association studies of complex diseases. Hum. Mol. Genet. 16, 2783–2794 (2007).
Hayakawa, T. et al. A human-specific gene in microglia. Science 309, 1693 (2005).
Perry, G. H. et al. Diet and the evolution of human amylase gene copy number variation. Nature Genet. 39, 1256–1260 (2007).
Yu, H. & Gerstein, M. Genomic analysis of the hierarchical structure of regulatory networks. Proc. Natl Acad. Sci. USA 103, 14724–14731 (2006).
Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).
Barabasi, A. L. & Oltvai, Z. N. Network biology: understanding the cell's functional organization. Nature Rev. Genet. 5, 101–113 (2004).
Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, Article 17 (2005).
Oldham, M. C., Horvath, S. & Geschwind, D. H. Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc. Natl Acad. Sci. USA 103, 17973–17978 (2006). The first demonstration that network-based approaches permit a functional assessment of changes in gene expression in an evolutionary context.
Horvath, S. et al. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc. Natl Acad. Sci. USA 103, 17402–17407 (2006).
Miller, J. A., Oldham, M. C. & Geschwind, D. H. A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J. Neurosci. 28, 1410–1420 (2008).
Kim, P. M., Korbel, J. O. & Gerstein, M. B. Positive selection at the protein network periphery: evaluation in terms of structural constraints and cellular context. Proc. Natl Acad. Sci. USA 104, 20274–20279 (2007).
Wood, B. & Collard, M. Anthropology — the human genus. Science 284, 65–66 (1999).
Tramo, M. J. et al. Brain size, head size, and intelligence quotient in monozygotic twins. Neurology 50, 1246–1252 (1998).
Bates, E. et al. Differential effects of unilateral lesions on language production in children and adults. Brain Lang. 79, 223–265 (2001).
Semendeferi, K., Lu, A., Schenker, N. & Damasio, H. Humans and great apes share a large frontal cortex. Nature Neurosci. 5, 272–276 (2002).
Abrahams, B. S. et al. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Natl Acad. Sci. USA 104, 17849–17854 (2007).
Sun, T. et al. Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 308, 1794–1798 (2005).
Rilling, J. K. et al. The evolution of the arcuate fasciculus revealed with comparative DTI. Nature Neurosci. 11, 426–428 (2008).
Sherwood, C. C. et al. Scaling of inhibitory interneurons in areas v1 and v2 of anthropoid primates as revealed by calcium-binding protein immunohistochemistry. Brain Behav. Evol. 69, 176–195 (2007).
Preuss, T. M. Taking the measure of diversity: comparative alternatives to the model-animal paradigm in cortical neuroscience. Brain Behav. Evol. 55, 287–299 (2000).
Caceres, M., Suwyn, C., Maddox, M., Thomas, J. W. & Preuss, T. M. Increased cortical expression of two synaptogenic thrombospondins in human brain evolution. Cereb. Cortex 17, 2312–2321 (2007).
Herrmann, E., Call, J., Hernandez-Lloreda, M. V., Hare, B. & Tomasello, M. Humans have evolved specialized skills of social cognition: the cultural intelligence hypothesis. Science 317, 1360–1366 (2007).
Penn, D. C. & Povinelli, D. J. On the lack of evidence that non-human animals possess anything remotely resembling a 'theory of mind'. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 362, 731–744 (2007).
Mundy, P. Annotation: the neural basis of social impairments in autism: the role of the dorsal medial–frontal cortex and anterior cingulate system. J. Child. Psychol. Psychiatry 44, 793–809 (2003).
Allman, J. M., Watson, K. K., Tetreault, N. A. & Hakeem, A. Y. Intuition and autism: a possible role for Von Economo neurons. Trends Cogn. Sci. 9, 367–373 (2005).
Geschwind, D. H. & Levitt, P. Autism spectrum disorders: developmental disconnection syndromes. Curr. Opin. Neurobiol. 17, 103–111 (2007).
Geschwind, N. The organization of language and the brain. Science 170, 940–944 (1970).
Nimchinsky, E. A. et al. A neuronal morphologic type unique to humans and great apes. Proc. Natl Acad. Sci. USA 96, 5268–5273 (1999). Demonstrates that a neuronal type, although not specific to humans, is likely to be an important feature of human brain evolution. This paper is a critical proof of principle study that, similar to reference 61, highlights the importance of phenotype discovery.
Seeley, W. W. et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann. Neurol. 60, 660–667 (2006).
Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002). Together with reference 143, this paper reports human-specific rapid evolution in a gene known to be defective in humans who have speech articulation defects.
Zhang, J., Webb, D. M. & Podlaha, O. Accelerated protein evolution and origins of human-specific features: FOXP2 as an example. Genetics 162, 1825–1835 (2002).
Krause, J. et al. The derived FOXP2 variant of modern humans was shared with Neandertals. Curr. Biol. 17, 1908–1912 (2007).
White, S. A., Fisher, S. E., Geschwind, D. H., Scharff, C. & Holy, T. E. Singing mice, songbirds, and more: models for FOXP2 function and dysfunction in human speech and language. J. Neurosci. 26, 10376–10379 (2006).
Teramitsu, I. & White, S. A. FoxP2 regulation during undirected singing in adult songbirds. J. Neurosci. 26, 7390–7394 (2006).
Webb, D. M. & Zhang, J. FoxP2 in song-learning birds and vocal-learning mammals. J. Hered. 96, 212–216 (2005).
Haesler, S. et al. Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X. PLoS Biol. 5, e321 (2007).
Li, G., Wang, J., Rossiter, S. J., Jones, G. & Zhang, S. Accelerated FoxP2 evolution in echolocating bats. PLoS ONE 2, e900 (2007).
Teramitsu, I., Kudo, L. C., London, S. E., Geschwind, D. H. & White, S. A. Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J. Neurosci. 24, 3152–3163 (2004).
Spiteri, E. et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am. J. Hum. Genet. 81, 1144–1157 (2007).
Evans, P. D. et al. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309, 1717–1720 (2005).
Mekel-Bobrov, N. et al. Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science 309, 1720–1722 (2005).
Yu, F. et al. Comment on “Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens”. Science 316, 370 (2007).
Woods, R. P. et al. Normal variants of Microcephalin and ASPM do not account for brain size variability. Hum. Mol. Genet. 15, 2025–2029 (2006).
Gilad, Y., Man, O. & Glusman, G. A comparison of the human and chimpanzee olfactory receptor gene repertoires. Genome Res. 15, 224–230 (2005).
Go, Y. & Niimura, Y. Similar numbers but different repertoires of olfactory receptor genes in humans and chimpanzees. Mol. Biol. Evol. 25, 1897–1907 (2008).
Keller, A., Zhuang, H., Chi, Q., Vosshall, L. B. & Matsunami, H. Genetic variation in a human odorant receptor alters odour perception. Nature 449, 468–472 (2007).
Menashe, I., Man, O., Lancet, D. & Gilad, Y. Different noses for different people. Nature Genet. 34, 143–144 (2003).
Wang, X., Thomas, S. D. & Zhang, J. Relaxation of selective constraint and loss of function in the evolution of human bitter taste receptor genes. Hum. Mol. Genet. 13, 2671–2678 (2004).
Fischer, A., Gilad, Y., Man, O. & Pääbo, S. Evolution of bitter taste receptors in humans and apes. Mol. Biol. Evol. 22, 432–436 (2005).
Go, Y., Satta, Y., Takenaka, O. & Takahata, N. Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates. Genetics 170, 313–326 (2005).
Hedlund, M. et al. N-glycolylneuraminic acid deficiency in mice: implications for human biology and evolution. Mol. Cell Biol. 27, 4340–4346 (2007).
Bramble, D. M. & Lieberman, D. E. Endurance running and the evolution of Homo. Nature 432, 345–352 (2004).
Brinkman-Van der Linden, E. C. et al. Human-specific expression of Siglec-6 in the placenta. Glycobiology 17, 922–931 (2007).
Nguyen, D. H., Hurtado-Ziola, N., Gagneux, P. & Varki, A. Loss of Siglec expression on T lymphocytes during human evolution. Proc. Natl Acad. Sci. USA 103, 7765–7770 (2006).
Maggioncalda, A. N., Czekala, N. M. & Sapolsky, R. M. Male orangutan subadulthood: a new twist on the relationship between chronic stress and developmental arrest. Am. J. Phys. Anthropol. 118, 25–32 (2002).
Harlow, H. F. & Suomi, S. J. Social recovery by isolation-reared monkeys. Proc. Natl Acad. Sci. USA 68, 1534–1538 (1971).
Hannah, A. C. & Brotman, B. Procedures for improving maternal behavior in captive chimpanzees. Zoo Biol. 9, 233–240 (1990).
Hrdy, S. Mother Nature: a History of Mothers, Infants, and Natural Selection (Pantheon Books, New York, 1999). A comprehensive and revealing analysis of motherhood, discussing some unusual aspects of primate and human mothering, and of mother–infant interactions.
Cohen, J. Biomedical research. The endangered lab chimp. Science 315, 450–452 (2007).
Goossens, B. et al. Survival, interactions with conspecifics and reproduction in 37 chimpanzees released into the wild. Biol. Conserv. 123, 461–475 (2005).
Custance, D. M., Whiten, A. & Fredman, T. Social learning and primate reintroduction. Int. J. Primatol. 23, 479–499 (2002).
McConkey, E. H. & Varki, A. Thoughts on the future of great ape research. Science 309, 1499–1501 (2005).
Gagneux, P., Moore, J. J. & Varki, A. The ethics of research on great apes. Nature 437, 27–29 (2005).
Switzer, W. M. et al. Ancient co-speciation of simian foamy viruses and primates. Nature 434, 376–380 (2005).
Gao, F. et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397, 436–441 (1999).
Boneva, R. S. et al. Clinical and virological characterization of persistent human infection with simian foamy viruses. AIDS Res. Hum. Retroviruses 23, 1330–1337 (2007).
Gagneux, P. & Varki, A. Evolutionary considerations in relating oligosaccharide diversity to biological function. Glycobiology 9, 747–755 (1999).
Bishop, J. R. & Gagneux, P. Evolution of carbohydrate antigens — microbial forces shaping host glycomes? Glycobiology 17, 23R–34R (2007).
Baldwin, J. M. A New factor in evolution. Am. Nat. 30, 441–451, 536–553 (1896).
Waddington, C. H. Genetic assimilation of an acquired character. Evolution 4, 118–126 (1953).
Simpson, G. G. The Baldwin effect. Evolution 7, 110–117 (1953).
Weber, B. H. & Depew, D. J. Evolution and Learning: the Baldwin Effect Reconsidered (MIT Press, Cambridge, Massachusetts, 2003). A compendium of interesting articles discussing many aspects of the definitions and implications of the Baldwin effect.
Dennett, D. C. Darwin's Dangerous Idea: Evolution and the Meanings of Life (Simon & Schuster, New York, 1995).
Deacon, T. W. The Symbolic Species: the Co-Evolution of Language and the Brain (W. W. Norton, New York, 1997).
Wiles, J., Watson, J., Tonkes, B. & Deacon, T. Transient phenomena in learning and evolution: genetic assimilation and genetic redistribution. Artif. Life 11, 177–188 (2005).
Yamauchi, H. How does niche construction reverse the Baldwin effect? Lecture Notes Comput. Sci. 4648, 315–324 (2007).
Flannery, T. The Future Eaters: an Ecological History of the Australasia Lands and People (Grove Press, New York, 2002).
Beccaloni, G. W. & Smith, V. S. Celebrations for Darwin downplay Wallace's role. Nature 451, 1050 (2008).
Wallace, A. R. in Contributions to the Theory of Natural Selection. A Series of Essays (Macmillan, London, 1870).
Kutschera, U. Darwin–Wallace principle of natural selection. Nature 453, 27 (2008).
Gould, S. J. & Vrba, E. S. Exaptation: a missing term in the science of form. Paleobiology 8, 4–15 (1982).
The authors gratefully acknowledge comments from P. Gagneux, R. Bingham, D. Nelson, P. Churchland, F. Ayala, S. Hrdy, and two anonymous reviewers; M. Oldham for adapting the figure in Box 4; and funding from the Howard Hughes Medical Institute (HHMI), the Mathers Foundation and the Gordon and Virginia MacDonald Foundation (to D.H.G.). The authors have National Institutes of Health grant funding: GM32373 to A.V., H60233 to D.H.G. and GM58815 to E.E.E.
The term that is now often used to refer to the clade that includes both humans and great apes (that is, chimpanzees, bonobos, gorillas and orangutans). The term hominoid is also no longer routinely used for great apes. In recognition of these changes, we have introduced the term non-human hominids in place of great apes in most places. However, we recognize that the nomenclature is still in flux.
- Positive selection
A form of natural selection that increases the frequency of beneficial alleles in a population.
A related but taxonomically distinct species that can be used to infer the ancestral state of a particular characteristic.
- Tissue heterogeneity
The presence of a large and variable number of cell types within a given tissue. Tissue heterogeneity in the brain might blunt the ability to detect the most variable low abundant genes in the brain relative to less complex tissue.
- Neutral theory
The word 'neutral' has two different meanings in population genetics literature. The strictly neutral model assumes that all mutations are neutral, whereas the biologically neutral model assumes that all mutations are either neutral or deleterious.
An increase in brain size relative to body size.
- Array comparative genomic hybridization
(ArrayCGH). A technique used to measure the relative copy number of a test and reference DNA sample based on differential hybridization to DNA molecules fixed on a microarray.
- Copy-number variant
(CNV). A gain or loss of a >1 kb DNA region that contains genes. Most copy-number polymorphisms tend to be small (<10 kb) in size. De novo CNVs are variants that largely arise by new mutation, as opposed to hereditary transmission.
- Gene conversion
A non-reciprocal recombination process that results in an alteration of the sequence of a gene to that of its homologue during meiosis.
A hierarchical organization of concepts. The Gene Ontology framework provides one means for determining whether gene expression differences represent enrichment for specific functional categories.
- Scale-free network
A network in which a few nodes (for example, genes) are central (that is, they act as 'hubs') and therefore serve as control points in the network, whereas most nodes are more peripheral and have few connections.
- Parallel distributed circuits
Interconnected brain regions that work coordinately, to yield cognition and behaviour.
- Frontotemporal dementia
A degenerative disease that frequently involves dilapidation of social cognition.
Changes within the coding region of a gene that prevent transcription of a functional protein product.
When a useful feature arises during evolution for a different reason, but is subsequently co-opted for its current function.
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Varki, A., Geschwind, D. & Eichler, E. Human uniqueness: genome interactions with environment, behaviour and culture. Nat Rev Genet 9, 749–763 (2008). https://doi.org/10.1038/nrg2428
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