Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Evolution of genetic and genomic features unique to the human lineage

Key Points

  • 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.

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genome positions of human-lineage-specific gene changes.

Similar content being viewed by others

References

  1. McLean, C. Y. et al. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471, 216–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Reich, D. et al. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468, 1053–1060 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Enard, W. & Paabo, S. Comparative primate genomics. Annu. Rev. Genom. Hum. Genet. 5, 351–378 (2004).

    Article  CAS  Google Scholar 

  8. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yunis, J. J. & Prakash, O. The origin of man: a chromosomal pictorial legacy. Science 215, 1525–1530 (1982).

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Linardopoulou, E. V. et al. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437, 94–100 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mikkelsen, T. S. et al. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

    Article  CAS  Google Scholar 

  18. Clark, A. G., et al. Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios. Science 302, 1960–1963 (2003).

    CAS  PubMed  Google Scholar 

  19. Berglund, J., Pollard, K. S. & Webster, M. T. Hotspots of biased nucleotide substitutions in human genes. PLoS Biol. 7, e26 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Grossman, S. R. et al. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327, 883–886 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marques-Bonet, T. et al. A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457, 877–881 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alkan, C. et al. Personalized copy number and segmental duplication maps using next-generation sequencing. Nature Genet. 41, 1061–1067 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Sudmant, P. H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Treangen, T. J. & Salzberg, S. L. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nature Rev. Genet. 13, 36–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Khodosevich, K., Lebedev, Y. & Sverdlov, E. Endogenous retroviruses and human evolution. Comp. Funct. Genomics. 3, 494–498 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nature Rev. Genet. 10, 691–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Lee, J. et al. Different evolutionary fates of recently integrated human and chimpanzee LINE-1 retrotransposons. Gene 390, 18–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature. 460, 1127–1131 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Singer, T. et al. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes. Trends Neurosci. 33, 345–354 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. Genet. 11, 446–450 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Lin, L., et al. Evolution of alternative splicing in primate brain transcriptomes. Hum. Mol. Genet. 19, 2958–2973 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim, D. S. & Hahn, Y. Identification of human-specific transcript variants induced by DNA insertions in the human genome. Bioinformatics 27, 14–21 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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.

  40. Li, W. H. Molecular Evolution (Sinauer Associates, 1997).

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. O'Bleness, M. S. et al. Evolutionary history and genome organization of DUF1220 protein domains. G3 2, 977–986 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Andries, V., Vandepoele, L. & van Roy, F. in Neuroblastoma — Present and Future Ch. 9 (ed. Shimada, H.) (InTech Publishing, 2012).

    Google Scholar 

  45. Dumas, L. & Sikela, J. M. DUF1220 domains, cognitive disease, and human brain evolution. Cold Spring Harb. Symp. Quant. Biol. 74, 375–382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. Uddin, M. et al. Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates. BMC Evol. Biol. 8, 8 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cioffi, F., Lanni, A. & Goglia, F. Thyroid hormones, mitochondrial bioenergetics and lipid handling. Curr. Opin. Endocrinol. Diabetes Obes. 17, 402–407 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Enard, W. et al. A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell 137, 961–971 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pastorcic, M., Birnbaum, S. & Hixson, J. E. Baboon apolipoprotein C-I: cDNA and gene structure and evolution. Genomics 13, 368–374 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Puppione, D. L. et al. Detection of two distinct forms of apoC-I in great apes. Comp. Biochem. Physiol. 5, 73–79 (2010).

    Google Scholar 

  56. 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).

    Article  CAS  PubMed  Google Scholar 

  57. Berbée, J. F. et al. Apolipoprotein CI knock-out mice display impaired memory functions. J. Alzheimers Dis. 23, 737–747 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  61. 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.

    Article  CAS  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Varki, A. Uniquely human evolution of sialic acid genetics and biology. Proc. Natl Acad. Sci. USA 107, 8939–8946 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stedmann, H. H. et al. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428, 415–418 (2004).

    Article  CAS  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang, Y. & Neumann, H. Alleviation of neurotoxicity by microglial human Siglec-11. J. Neurosci. 30, 3482–3488 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Crocker, P. R. Siglecs in innate immunity. Curr. Opin. Pharmacol. 5, 431–437 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Wang, X. et al. Specific inactivation of two immunomodulatory SIGLEC genes during human evolution. Proc. Natl Acad. Sci. USA 109, 9935–9940 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dennis, M. Y. et al. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149, 912–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Charrier, C. et al. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149, 923–935 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  Google Scholar 

  74. Kondo, H. et al. Human aquaporin adipose (AQPap) gene. Genomic structure, promoter analysis and functional mutation. Eur. J. Biochem. 269, 1814–1826 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  Google Scholar 

  76. Knowles, D. G. & McLysaght, A. Recent de novo origin of human protein-coding genes. Genome Res. 19, 1752–1759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li, C. Y. et al. A human-specific de novo protein-coding gene associated with human brain functions. PLoS Comput. Biol. 6, e1000734 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu, D. D., Irwin, D. M. & Zhang, Y. P. De novo origin of human protein-coding genes. PLoS Genet. 7, e1002379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Buhl, A. M. et al. Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia. Blood 107, 2904–2911 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. 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).

    Article  CAS  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  PubMed  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  Google Scholar 

  86. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brinkman-Van der Linden, E. C. et al. Human-specific expression of Siglec-6 in the placenta. Glycobiology 17, 922–931 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. Cooper, D. N. & Kehrer-Sawatzki, H. Exploring the potential relevance of human-specific genes to complex disease. Hum. Gen. 5, 99–107 (2011).

    Article  CAS  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. Olson, M. V. & Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nature Rev. Genet. 4, 20–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

  96. 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).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. Morrow, E . M. Genomic copy number variation in disorders of cognitive development. J. Am. Acad. Child. Adolesc. Psychiatry 49, 1091–1104 (2010).

    PubMed  PubMed Central  Google Scholar 

  99. Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Scally, A., et al. Insights into hominid evolution from the gorilla genome sequence. Nature 483, 169–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Prüfer, K., et al. The bonobo genome compared with the chimpanzee and human genomes. Nature 486, 527–531 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mefford, H. C. & Eichler, E. E. Duplication hotspots, rare genomic disorders, and common disease. Curr. Opin. Genet. Dev. 19, 196–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. McConkey, E. H. & Varki, A. Genomics. Thoughts on the future of great ape research. Science 309, 1499–1501 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. Khaitovich, P. et al. Metabolic changes in schizophrenia and human brain evolution. Genome Biol. 9, R124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  Google Scholar 

  107. 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).

    Article  PubMed  Google Scholar 

  108. Martin, R. D. The evolution of human reproduction: a primatological perspective. Am. J. Phys. Anthropol. Suppl. 45, 59–84 (2007).

    Article  Google Scholar 

  109. Fooladi, M. M. The healing effects of crying. Holist. Nurs. Pract. 19, 248 (2005).

    Article  PubMed  Google Scholar 

  110. Liu, X. et al. Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res. 22, 611–622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  Google Scholar 

  113. 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.

    Article  CAS  PubMed  Google Scholar 

  114. Doggett, N. A. et al. A 360-kb interchromosomal duplication of the human HYDIN locus. Genomics 88, 762–771 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  PubMed  Google Scholar 

  116. 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.

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  PubMed  Google Scholar 

  121. Plunkett, J. et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet. 7, e1001365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. Majava, V. et al. Structural and functional characterization of human peripheral nervous system myelin protein P2. PLoS ONE 5, e10300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hennah, W. & Porteous, D. The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS ONE 4, e4906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  PubMed  Google Scholar 

  128. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James M. Sikela.

Ethics declarations

Competing interests

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.

Related links

Related links

FURTHER INFORMATION

Ajit Varki's homepage

James M. Sikela's homepage

Center for Academic Training and Research in Anthropogeny (CARTA)

Matrix of Comparative Anthropogeny (MOCA)

OMIM — Online Mendelian Inheritance in Man

Glossary

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)).

Pseudogenization

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.

Polymorphisms

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)).

Neofunctionalization

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3336

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research