Here we provide an overview of the major findings related to human-lineage-specific (HLS) genomic and genetic changes and describe how these findings might relate to human-specific traits.
The range of HLS changes extends from large-scale (for example, cytogenetic) to small-scale (for example, single-nucleotide substitutions), and current advances in genomic technologies are allowing genomic comparisons to be made with unprecedented scope and detail.
A representative sampling of several types of genetic changes that can occur, as well as several important gene families that have undergone multiple HLS events, is presented alongside the possible phenotypic implications of these changes.
Associating HLS genetic changes with a trait is one of the most challenging tasks for human evolutionary genomic research. A discussion of strategies to connect the two is presented, along with a list of current data available.
There is emerging evidence that many HLS genetic and genomic changes colocalize with disease-associated genomic regions, suggesting a mechanistic link between the two.
Given the unprecedented tools that are now available for rapidly comparing genomes, the identification and study of genetic and genomic changes that are unique to our species have accelerated, and we are entering a golden age of human evolutionary genomics. Here we provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends, such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Finally, we discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.
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McLean, C. Y. et al. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471, 216–219 (2011).
Prabhakar, S. et al. Human-specific gain of function in a developmental enhancer. Science 321, 1346–1350 (2008). This paper demonstrates how a conserved non-coding sequence (namely, HACNS1 ), which evolved extremely rapidly in humans, may underlie human-specific aspects of limb development.
Varki, A., Geschwind, D. & Eichler, E. Human uniqueness: genome interactions with environment, behaviour and culture. Nature Rev. Genet. 9, 749–763 (2008). This earlier Review on the same subject cautions against a 'gene-centric' view of human evolution and suggests that some aspects of human genome evolution may be due to relaxed selection, resulting from masking by behaviour and culture.
Sikela, J. M. The jewels of our genome: the search for the genomic changes underlying the evolutionarily unique capacities of the human brain. PLoS Genet. 2, e80 (2006).
Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).
Reich, D. et al. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468, 1053–1060 (2010).
Enard, W. & Paabo, S. Comparative primate genomics. Annu. Rev. Genom. Hum. Genet. 5, 351–378 (2004).
Fortna, A. et al. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2, e207 (2004). This was the first genome-wide and first gene- based array CGH study of lineage-specific gene copy number gain and loss among human and great ape lineages. One hundred and forty genes were identified that showed HLS changes in copy number, including the MGC8902 gene that encodes DUF1220 protein domains.
Yunis, J. J. & Prakash, O. The origin of man: a chromosomal pictorial legacy. Science 215, 1525–1530 (1982).
Dumas, L. et al. Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 17, 1266–1277 (2007). This was the most extensive array CGH investigation to date of gene-based copy number change across primate species. Many of the >4,000 genes identified that showed lineage-specific changes in copy number are excellent candidates for underlying lineage-specific traits among these species.
Ventura, M. et al. The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. Genome Res. 22, 1036–1049 (2012).
Bhatt, B., Burns, J., Flannery, D. & McGee, J. Direct visualization of single copy genes on banded metaphase chromosomes by nonisotopic in situ hybridization. Nucleic Acids Res. 16, 3951–3961 (1988).
Jauch, A. et al. Reconstruction of genomic rearrangements in great apes and gibbons by chromosome painting. Proc. Natl Acad. Sci. USA 89, 8611–8615 (1992).
Wilson, G. M. et al. Identification of full-coverage array CGH of human DNA copy number increases relative to chimpanzee and gorilla. Genome Res. 16, 173–181 (2006).
Goidts, V. et al. Identification of large-scale human-specific copy number differences by inter-species array comparative genomic hybridization. Hum. Genet. 119, 185–198 (2006).
Linardopoulou, E. V. et al. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437, 94–100 (2005).
Mikkelsen, T. S. et al. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).
Clark, A. G., et al. Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios. Science 302, 1960–1963 (2003).
Berglund, J., Pollard, K. S. & Webster, M. T. Hotspots of biased nucleotide substitutions in human genes. PLoS Biol. 7, e26 (2009).
Grossman, S. R. et al. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327, 883–886 (2010).
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).
Chen, F. C., Chen, C. J., Li, W. H. & Chuang, T. J. Human-specific insertions and deletions inferred from mammalian genome sequences. Genome Res. 17, 16–22 (2007).
Marques-Bonet, T. et al. A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457, 877–881 (2009).
Alkan, C. et al. Personalized copy number and segmental duplication maps using next-generation sequencing. Nature Genet. 41, 1061–1067 (2009).
Sudmant, P. H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).
Treangen, T. J. & Salzberg, S. L. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nature Rev. Genet. 13, 36–46 (2011).
Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).
Khodosevich, K., Lebedev, Y. & Sverdlov, E. Endogenous retroviruses and human evolution. Comp. Funct. Genomics. 3, 494–498 (2002).
Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nature Rev. Genet. 10, 691–703 (2009).
Lee, J. et al. Different evolutionary fates of recently integrated human and chimpanzee LINE-1 retrotransposons. Gene 390, 18–27 (2007).
Brouha, B. et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl Acad. Sci. USA 100, 5280–5285 (2003).
Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature. 460, 1127–1131 (2009).
Singer, T. et al. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes. Trends Neurosci. 33, 345–354 (2010).
Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. Genet. 11, 446–450 (2010).
Lin, L., et al. Evolution of alternative splicing in primate brain transcriptomes. Hum. Mol. Genet. 19, 2958–2973 (2010).
Blekhman, R., Marioni, J. C., Zumbo, P., Stephens, M. & Gilad, Y. Sex-specific and lineage-specific alternative splicing in primates. Genome Res. 20, 180–189 (2010).
Kim, D. S. & Hahn, Y. Identification of human-specific transcript variants induced by DNA insertions in the human genome. Bioinformatics 27, 14–21 (2011).
Huh, J. W. et al. Gain of new exons and promoters by lineage-specific transposable elements-integration and conservation event on CHRM3 gene. Mol. Cells 28, 111–117 (2009).
Ohno, S. Evolution by Gene Duplication (Springer,1970). This classic text provides some of the first arguments making the case that gene duplication is a major mechanism underlying genome evolution.
Li, W. H. Molecular Evolution (Sinauer Associates, 1997).
Popesco, M. C. et al. Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains. Science 313, 1304–1307 (2006). This was the first report to describe the striking HLS increase in copy number of DUF1220 protein domains.
O'Bleness, M. S. et al. Evolutionary history and genome organization of DUF1220 protein domains. G3 2, 977–986 (2012).
Vandepoele, K., van Roy, N., Staes, K., Speleman, F. & van Roy, F. A novel gene family NBPF: intricate structure generated by gene duplications during primate evolution. Mol. Biol. Evol. 22, 2265–2274 (2005).
Andries, V., Vandepoele, L. & van Roy, F. in Neuroblastoma — Present and Future Ch. 9 (ed. Shimada, H.) (InTech Publishing, 2012).
Dumas, L. & Sikela, J. M. DUF1220 domains, cognitive disease, and human brain evolution. Cold Spring Harb. Symp. Quant. Biol. 74, 375–382 (2009).
Dumas, L. et al. DUF1220-domain copy number implicated in human brain-size pathology and evolution. Am. J. Hum. Genet. 91, 444–454 (2012). This paper provides support for the view that DUF1220 domain copy number (specifically, DUF1220 domain dosage) is a key driver of primate brain size and may be largely responsible for the dramatic evolutionary expansion in brain size that occurred in the human lineage.
Rizzuto, R., Nakase, H., Zeviani, M., DiMauro, S. & Schon, E. A. Subunit Va of human and bovine cytochrome c oxidase is highly conserved. Gene 69, 245–256 (1988).
Uddin, M. et al. Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates. BMC Evol. Biol. 8, 8 (2008).
Cioffi, F., Lanni, A. & Goglia, F. Thyroid hormones, mitochondrial bioenergetics and lipid handling. Curr. Opin. Endocrinol. Diabetes Obes. 17, 402–407 (2010).
Arnold, S., Goglia, F. & Kadenbach, B. 3,5-diiodothyronine binds to subunit Va of cytochrome-c oxidase and abolishes the allosteric inhibition of respiration by ATP. Eur. J. Biochem. 252, 325–330 (1998).
Enard, W. et al. A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell 137, 961–971 (2009).
Kim, H. L., Igawa, T., Kawashima, A., Satta, Y. & Takahata, N. Divergence, demography and gene loss along the human lineage. Phil. Trans. R. Soc. B 365, 2451–2457 (2010).
Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).
Pastorcic, M., Birnbaum, S. & Hixson, J. E. Baboon apolipoprotein C-I: cDNA and gene structure and evolution. Genomics 13, 368–374 (1992).
Puppione, D. L. et al. Detection of two distinct forms of apoC-I in great apes. Comp. Biochem. Physiol. 5, 73–79 (2010).
Lucatelli, J. F. et al. Genetic influences on Alzheimer's disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil. Neurochem. Res. 36, 1533–1539 (2011).
Berbée, J. F. et al. Apolipoprotein CI knock-out mice display impaired memory functions. J. Alzheimers Dis. 23, 737–747 (2011).
Hansen, J. B. et al. The apolipoprotein C-I content of very-low-density lipoproteins is associated with fasting triglycerides, postprandial lipemia, and carotid atherosclerosis. J. Lipids 2011, 271062 (2011).
Grallert, H. et al. Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. Eur. Heart J. 33, 238–251 (2012).
Varki, N. M. et al. Heart disease is common in humans and chimpanzees, but is caused by different pathological processes. Evol. Appl. 2, 101–112 (2009).
Varki, N. M., Strobert, E., Dick E. J. Jr, Benirschke, K. & Varki, A. Biomedical differences between humans and nonhuman hominids; potential roles for uniquely human aspects of sialic acid biology. Annu. Rev. Pathol. Mech. 6, 365–393 (2011). This review emphasizes that many human diseases are uniquely human and relates some of the differences in evidence that genes involved in the biology of sialic acids constitute a 'hotspot' in human evolution.
Hayakawa, T., Aki, I., Varki, A., Satta, Y. & Takahata, N. Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution. Genetics 172, 1139–1146 (2006).
Varki, A. Uniquely human evolution of sialic acid genetics and biology. Proc. Natl Acad. Sci. USA 107, 8939–8946 (2010).
Stedmann, H. H. et al. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428, 415–418 (2004).
Wang, X. et al. Evolution of Siglec-11 and Siglec-16 genes in hominins. Mol. Biol. Evol. 29, 2073–2086 (2012). The first examples of genes inactivated in relation to the timing of origin of modern humans are presented in this paper. The data suggest that infectious agents may have played a part in selection.
Wang, Y. & Neumann, H. Alleviation of neurotoxicity by microglial human Siglec-11. J. Neurosci. 30, 3482–3488 (2010).
Wang, X. et al. Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology. Glycobiology 21, 1038–1048 (2011).
Schmidt, J., Kirsch, S., Rappoid, G. A. & Schempp, W. Complex evolution of a Y-chromosomal double homeobox 4 (DUX4)-related gene family in hominoids. PLoS ONE 4, e5288 (2009).
Crocker, P. R. Siglecs in innate immunity. Curr. Opin. Pharmacol. 5, 431–437 (2005).
Wang, X. et al. Specific inactivation of two immunomodulatory SIGLEC genes during human evolution. Proc. Natl Acad. Sci. USA 109, 9935–9940 (2012).
Dennis, M. Y. et al. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149, 912–922 (2012).
Charrier, C. et al. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149, 923–935 (2012).
Walker, C. G., Holness, M. J., Gibbons, G. F. & Sugden, M. C. Fasting-induced increases in aquaporin 7 and adipose triglyceride lipase mRNA expression in adipose tissue are attenuated by peroxisome proliferator-activated receptor alpha deficiency. Int. J. Obes. 31, 1165–1171 (2007).
Kondo, H. et al. Human aquaporin adipose (AQPap) gene. Genomic structure, promoter analysis and functional mutation. Eur. J. Biochem. 269, 1814–1826 (2002).
Bramble, D. M. & Lieberman, D. E. Endurance running and the evolution of Homo. Nature 432, 345–352 (2004). This provides a well-reasoned argument based on anatomical and physiological evidence that endurance running had a major role in human evolution at the origin of the genus Homo.
Knowles, D. G. & McLysaght, A. Recent de novo origin of human protein-coding genes. Genome Res. 19, 1752–1759 (2009).
Li, C. Y. et al. A human-specific de novo protein-coding gene associated with human brain functions. PLoS Comput. Biol. 6, e1000734 (2010).
Wu, D. D., Irwin, D. M. & Zhang, Y. P. De novo origin of human protein-coding genes. PLoS Genet. 7, e1002379 (2011).
Buhl, A. M. et al. Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia. Blood 107, 2904–2911 (2006).
Romero, I. G., Ruvinsky, I. & Gilad, Y. Comparative studies of gene expression and the evolution of gene regulation. Nature Rev. Genet. 13, 505–516 (2012).
Ross, N. L. J. et al. Methylation of two Homo sapiens-specific X-Y homologous genes in Klinefelter's syndrome (XXY). Am. J. Med. Genet. B 141, 544–548 (2006).
Yoshida, K. & Sugano, S. Identification of a novel protocadherin gene (PCDH11) on the human XY homology region in Xq21.3. Genomics 62, 540–543 (1999).
Kalmady, S. V. & Venkatasubramanian, G. Evidence for positive selection on protocadherin Y gene in Homo sapiens: implications for schizophrenia. Schizophr. Res. 108, 299–300 (2009).
Crow, T. J. Handedness, language lateralisation and anatomical asymmetry: relevance of protocadherin XY to hominid speciation and the aetiology of psychosis. Point of view. Br. J. Psychiatry 181, 295–297 (2002).
Speevak, M. D. & Farrell, S. A. Non-syndromic language delay in a child with disruption in the Protocadherin11X/Y gene pair. Am. J. Med. Genet. B 156, 484–489 (2011).
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).
Brinkman-Van der Linden, E. C. et al. Human-specific expression of Siglec-6 in the placenta. Glycobiology 17, 922–931 (2007).
Winn, V. D. et al. Severe preeclampsia-related changes in gene expression at the maternal-fetal interface include sialic acid-binding immunoglobulin-like lectin-6 and pappalysin-2. Endocrinology 150, 452–462 (2009).
Cooper, D. N. & Kehrer-Sawatzki, H. Exploring the potential relevance of human-specific genes to complex disease. Hum. Gen. 5, 99–107 (2011).
Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002). This is an important paper that discusses the connection between complex genomic architecture and recurrent disease. The authors put forth the idea that these regions may have an important role in primate speciation.
Olson, M. V. & Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nature Rev. Genet. 4, 20–28 (2003).
Soto, P. C., Stein, L. L., Hurtado-Ziola, N., Hedrick, S. M. & Varki, A. Relative over-reactivity of human versus chimpanzee lymphocytes: implications for the human diseases associated with immune activation. J. Immunol. 184, 4185–4195 (2010).
Carrasquillo, M. M. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nature Genet. 41, 192–198 (2009).
Evans, P. D. et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum. Mol. Genet. 13, 489–494 (2004).
Rimol, L. M. et al. Sex-dependent association of common variants of microcephaly genes with brain structure. Proc. Natl Acad. Sci. USA 107, 384–388 (2010).
Mekel-Bobrov, N. et al. The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence. Hum. Mol. Genet. 16, 600–608 (2007).
Brunetti-Pierri, N. et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genet. 40, 1466–1471 (2008).
Morrow, E . M. Genomic copy number variation in disorders of cognitive development. J. Am. Acad. Child. Adolesc. Psychiatry 49, 1091–1104 (2010).
Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012).
Scally, A., et al. Insights into hominid evolution from the gorilla genome sequence. Nature 483, 169–175 (2012).
Prüfer, K., et al. The bonobo genome compared with the chimpanzee and human genomes. Nature 486, 527–531 (2012).
Mefford, H. C. & Eichler, E. E. Duplication hotspots, rare genomic disorders, and common disease. Curr. Opin. Genet. Dev. 19, 196–204 (2009).
McConkey, E. H. & Varki, A. Genomics. Thoughts on the future of great ape research. Science 309, 1499–1501 (2005).
Altevogt, B. M., Pankevich, D. E., Pope, A. M. & Kahn, J. P. Research agenda. Guiding limited use of chimpanzees in research. Science 335, 41–42 (2012).
Khaitovich, P. et al. Metabolic changes in schizophrenia and human brain evolution. Genome Biol. 9, R124 (2008).
Gamble, C., Davies, W., Pettitt, P. & Richards, M. Climate change and evolving human diversity in Europe during the last glacial. Phil. Trans. R. Soc. Lond. B 359, 243–253 (2004).
Pfefferle, A. D. et al. Comparative expression analysis of the phosphocreatine circuit in extant primates: implications for human brain evolution. J. Hum. Evol. 60, 205–212 (2011).
Martin, R. D. The evolution of human reproduction: a primatological perspective. Am. J. Phys. Anthropol. Suppl. 45, 59–84 (2007).
Fooladi, M. M. The healing effects of crying. Holist. Nurs. Pract. 19, 248 (2005).
Liu, X. et al. Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res. 22, 611–622 (2012).
Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004).
Chen, J. M., Cooper, D. N., Chuzhanova, N., Férec, C. & Patrinos, G. P. Gene conversion: mechanisms, evolution and human disease. Nature Rev. Genet. 8, 762–775 (2007).
Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006). Using a genome-wide comparison of human and non-human genome sequences, this study identified a dramatically changing microRNA- encoding gene, highly accelerated region 1 forward ( HAR1F ), which showed a highly accelerated HLS change in sequence and is highly expressed in the human fetal brain.
Doggett, N. A. et al. A 360-kb interchromosomal duplication of the human HYDIN locus. Genomics 88, 762–771 (2006).
Lai, C. S., Gerrelli, D., Monaco, A. P., Fisher, S. E. & Copp, A. J. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 126, 2455–2462 (2003).
Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002). This provides the first evidence that the coding sequence of the FOXP2 gene, which is mutated in a family with a speech disorder, underwent human-specific alterations consistent with positive selection.
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).
Evans, P. D., Vallender, E. J. & Lahn, B. T. Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ. Gene 375, 75–79 (2006).
Araud, T. et al. The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function. Biochem. Pharmacol. 82, 904–914 (2011).
Lussiana, C. et al. Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fecundity and molecular biology of FSHR protein and gene. Obstet. Gynecol. Surv. 63, 785–795 (2008).
Plunkett, J. et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet. 7, e1001365 (2011).
Evans, P. D., Anderson, J. R., Vallender, E. J., Choi, S. S. & Lahn, B. T. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum. Mol. Genet. 13, 1139–1145 (2004).
Ciesek, S. et al. Impact of intra- and interspecies variation of occludin on its function as coreceptor for authentic hepatitis C virus particles. J. Virol. 85, 7613–7621 (2011).
Shin, E. Y. et al. Phosphorylation of p85 beta PIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth. J. Biol. Chem. 277, 44417–44430 (2002).
Majava, V. et al. Structural and functional characterization of human peripheral nervous system myelin protein P2. PLoS ONE 5, e10300 (2010).
Hennah, W. & Porteous, D. The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS ONE 4, e4906 (2009).
Saus, E. et al. Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients. J. Psychiatr. Res. 44, 971–978 (2010).
Kouprina, N. et al. The SPANX gene family of cancer-testis specific antigens: rapid evolution, an unusual case of positive selection and amplification in African Great Apes and hominids. Proc. Natl Acad. Sci. USA 101, 3077–3082 (2004).
Westbrook, V. A. et al. Hominoid-specific SPANXA/D genes demonstrate differential expression in individuals and protein localization to a distinct nuclear envelope domain during spermatid morphogenesis. Mol. Hum. Reprod. 12, 703–716 (2006).
We would like to thank S. O'Bleness for editorial comments, M. Dickens for graphics assistance and J. Noonan for access to published images. We also thank the many student and faculty contributors to the Matrix of Comparative Anthropogeny (MOCA) website. Work in our laboratories has been supported by the US National Institutes of Health and by the Mathers Foundation of New York, which also supports the MOCA website.
James M. Sikela is the founder of and a shareholder in GATC Science, LLC. Ajit Varki is a co-founder of and shareholder in Sialix, Inc. Majesta O'Bleness, Veronica Searles and Pascal Gagneux declare no competing financial interests.
- Accelerated evolution
More nucleotide or copy number changes in a particular region or gene than would be expected from background rates of mutation over time (for example, in cytochrome c oxidase subunit Va (COX5A)).
- Copy number changes
Increases or decreases in the number of copies of a gene or segment (for example, in SLIT–ROBO rho GTPase-activating protein 2 (SRGAP2)).
- Fluorescent in situ hybridization
(FISH). A technique used to visualize the location of specific DNA sequences on chromosomes.
- Array-based comparative genomic hybridization
(Array CGH). A microarray- based method for detecting copy number variation in the genome.
- Protein domains
Discrete portions of a protein sequence that may evolve and function independently of the rest of the protein (for example, in the DUF1220 domain).
- Domain amplification
Intragenic copy number increase of a protein domain (for example, in the DUF1220 domain).
- Amino acid change
A DNA change that leads to a change at the protein sequence level (for example, in forkhead box P2 (FOXP2)).
Loss of gene function while most of the gene is retained (for example, in apolipoprotein C1 (APOC1)).
- 'Less-is-more' hypothesis
The hypothesis that gene loss has a major role in evolution.
Allelic genetic variations within a species (for example, in amylase, alpha 1A (AMY1A)).
- Gene conversion
'Pasting' of identity from one homologous gene to another (for example, in sialic-acid-binding Ig superfamily lectin 11 (SIGLEC11)).
- Expression pattern change
Change in timing, level and/or location of gene expression (for example, in protocadherin 11 from the X chromosome to the Y chromosome (PCDH11XY)).
A process by which a genetic change in an allele produces a novel protein function (for example, in double homeobox (DUX) family members).
- De novo human gene
A novel gene arising from formerly non-coding DNA (for example, in chronic lymphocytic leukaemia upregulated 1 (CLLU1)).
- Human-specific disease
A disease that is present only in the human lineage. A number of diseases are thought to be human-specific (such as Alzheimer's disease and myocardial infarction), but proving that such diseases are not present in other species remains a challenging task.
- Gene nurseries
Dynamic regions of the genome that are capable of undergoing rapid evolutionary change owing to a duplication-prone genome architecture and are therefore frequent sites for the production of novel genes by gene duplication.
- Hydatidiform mole
An abnormal form of pregnancy in which a non-viable egg, probably the result of an egg missing a nucleus, is fertilized and becomes a mass on the uterine wall. The resultant growing tissue is haploid in nature owing to it having only a paternal genetic contribution.
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O'Bleness, M., Searles, V., Varki, A. et al. Evolution of genetic and genomic features unique to the human lineage. Nat Rev Genet 13, 853–866 (2012). https://doi.org/10.1038/nrg3336
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