Sequencing the chimpanzee genome: insights into human evolution and disease

Key Points

  • The sequencing of the chimpanzee genome is now under way. Substantial data are expected to be available by the summer of 2003.

  • Because the last common ancestor of chimpanzees and humans lived only 5 million years ago, the comparison of the chimpanzee and human genome sequences provides an unprecedented opportunity to examine the genetic changes that are associated with the rapid evolution of new phenotypic characteristics.

  • Genetic differences between chimpanzees and humans are of significant medical interest as they might help to explain the distinctive set of disease susceptibilities seen in humans.

  • Approximately 95% of the chimpanzee genome seems to align directly with corresponding regions of the human genome and within these aligned segments, sequence divergence is only 1.2%.

  • Comparison of the chimpanzee and human genome sequences offers our best hope of looking back at the genetic changes that shaped modern humans.

  • One hypothesis about the evolution of modern humans emphasizes the importance of regulatory mutations, whereas another predicts that loss-of-function mutations on the human lineage were important in the phenotypic divergence of chimpanzees and humans. The chimpanzee genome sequence will facilitate tests of both hypotheses.

  • Genome sequencing of another great ape, preferably the gorilla, will be necessary to determine whether particular genetic differences occurred on the chimpanzee or the human lineage.

  • Evidence indicates that chimpanzees and humans have significantly different patterns of common disease.

  • Because of ethical constraints on the use of chimpanzees as experimental animals, alternative approaches will be required to develop the comparative biology of chimpanzees and humans. These approaches should include much more comprehensive capture of records of the veterinary care provided to captive chimpanzees.

  • Full use of the chimpanzee genome sequence will depend on greatly expanded studies of great ape phenotypes.

Abstract

Large-scale sequencing of the chimpanzee genome is now imminent. Beyond the inherent fascination of comparing the sequence of the human genome with that of our closest living relative, this project is likely to yield tangible scientific benefits in two areas. First, the discovery of functionally important mutations that are specific to the human lineage offers a new path towards medical benefits. Second, chimpanzee–human comparisons are likely to yield molecular insights into how new biological characteristics evolve — findings that might be relevant throughout the tree of life.

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Figure 1: Sequence-based phylogenetic tree for the human and the great apes.

References

  1. 1

    McConkey, E. H. & Goodman, M. A human genome evolution project is needed. Trends Genet. 13, 350–351 (1997).

    CAS  Article  Google Scholar 

  2. 2

    McConkey, E. H. & Varki, A. A primate genome project deserves high priority. Science 289, 1295–1296 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Normile, D. Genomics: chimp sequencing crawls forward. Science 291, 2297 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Cyranoski, D. Almost human. Nature 418, 910–912 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Goodman, S. & Check, F. The great primate debate. Nature 417, 684–687 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Nutall, G. H. F. Blood Immunity and Blood Relationships (Cambridge Univ. Press, London, 1904).

    Google Scholar 

  7. 7

    Washburn, S. L. (ed.) Classification and Human Evolution (Aldine, Chicago, Illinois, 2002).

    Google Scholar 

  8. 8

    Syner, F. N. & Goodman, M. Differences in the lactic dehydrogenases of primate brains. Nature 209, 426–428 (1966).

    CAS  Article  Google Scholar 

  9. 9

    Sarich, V. M. & Wilson, A. C. Immunological time scale for hominid evolution. Science 158, 1200–1203 (1967).

    CAS  Article  Google Scholar 

  10. 10

    Doolittle, R. F., Wooding, G. L., Lin, Y. & Riley, M. Hominoid evolution as judged by fibrinopeptide structures. J. Mol. Evol. 1, 74–83 (1971).

    CAS  Article  Google Scholar 

  11. 11

    King, M. -C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975). Classic paper that reviews earlier literature on the biochemical similarities between chimpanzee and human, adds new data based on serum proteins and proposes that regulatory changes probably account for the rapid phenotypic divergence of chimpanzees and humans.

    CAS  Article  Google Scholar 

  12. 12

    Eyre-Walker, A. & Keightley, P. D. High genomic deleterious mutation rates in hominids. Nature 397, 344–347 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Varki, A. A chimpanzee genome project is a biomedical imperative. Genome Res. 10, 1065–1070 (2000). Survey of existing knowledge about the biomedical differences between great apes and humans.

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Fujiyama, A. et al. Construction and analysis of a human–chimpanzee comparative clone map. Science 295, 131–134 (2002). Analysis of the first large set of genomic DNA sequences from the chimpanzee.

    Article  Google Scholar 

  16. 16

    Yunis, J. J., Sawyer, J. R. & Dunham, K. The striking resemblance of high-resolution G-banded chromosomes of man and chimpanzee. Science 208, 1145–1148 (1980).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Gagneux, P. & Varki, A. Genetic differences between humans and great apes. Mol. Phylogenet. Evol. 18, 2–13 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Hacia, J. G. Genome of the apes. Trends Genet. 17, 637–645 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Wood, B. & Collard, M. Anthropology — the human genus. Science 284, 65–71 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Krings, M. et al. Neandertal DNA sequences and the origin of modern humans. Cell 90, 19–30 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Ovchinnikov, I. V. et al. Molecular analysis of Neanderthal DNA from the northern Caucasus. Nature 404, 490–493 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Hofreiter, M., Serre, D., Poinar, H. N., Kuch, M. & Pääbo, S. Ancient DNA. Nature Rev. Genet. 2, 353–359 (2001).

    CAS  Article  Google Scholar 

  24. 24

    International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 15, 928–933 (2001).

  25. 25

    Harpending, H. C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Lewis, E. B. The bithorax complex: the first fifty years. Int. J. Dev. Biol. 42, 403–415 (1998).

    CAS  PubMed  Google Scholar 

  27. 27

    International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  28. 28

    Enard, W. et al. Intra- and interspecific variation in primate gene expression patterns. Science 296, 340–343 (2002).

    CAS  Article  Google Scholar 

  29. 29

    Gagneux, P. et al. Proteomic comparison of human and great ape blood plasma reveals conserved glycosylation and differences in thyroid hormone metabolism. Am. J. Phys. Anthropol. 115, 99–109 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999). Short review outlining the argument that gene loss is likely to be an important mechanism of rapid evolutionary change.

    CAS  Article  Google Scholar 

  31. 31

    Muchmore, E. A., Diaz, S. & Varki, A. A structural difference between the cell surfaces of humans and the great apes. Am. J. Phys. Anthropol. 107, 187–198 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Chou, H. H. et al. A mutation in human CMP-sialic acid hydroxylase occurred after the HomoPan divergence. Proc. Natl Acad. Sci. USA 95, 11751–11756 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Irie, A., Koyama, S., Kozutsumi, Y., Kawasaki, T. & Suzuki, A. The molecular basis for the absence of N-glycolylneuraminic acid in humans. J. Biol. Chem. 273, 15866–15871 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Hayakawa, T., Satta, Y., Gagneux, P., Varki, A. & Takahata, N. Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene. Proc. Natl Acad. Sci. USA 98, 11399–11404 (2001).

    CAS  Article  Google Scholar 

  35. 35

    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). Reviews the discovery that humans are unable to synthesize a sialic acid found in great apes and other primates due to an inactivating mutation in the gene for an enzyme that modifies a precursor; also, estimates the timing of this mutation relative to other steps in human evolution.

    CAS  Article  Google Scholar 

  36. 36

    Varki, A. Loss of N-glycolylneuraminic acid in humans: mechanisms, consequences and implications for hominid evolution. Yb. Phys. Anthropol. 44, 54–69 (2002).

    Google Scholar 

  37. 37

    Zhang, X. M., Cathala, G., Soua, Z., Lefranc, M. P. & Huck, S. The human T-cell receptor γ variable pseudogene V10 is a distinctive marker of human speciation. Immunogenetics 43, 196–203 (1996).

    CAS  PubMed  Google Scholar 

  38. 38

    Rouquier, S. et al. A gene recently inactivated in human defines a new olfactory receptor family in mammals. Hum. Mol. Genet. 7, 1337–1345 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Winter, H. et al. Human type I hair keratin pseudogene phihHaA has functional orthologs in the chimpanzee and gorilla: evidence for recent inactivation of the human gene after the PanHomo divergence. Hum. Genet. 108, 37–42 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Jinnah, H. A., De Gregorio, L., Harris, J. C., Nyhan, W. L. & O'Neill, J. P. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat. Res. 463, 309–326 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Samonte, R. V. & Eichler, E. E. Segmental duplications and the evolution of the primate genome. Nature Rev. Genet. 3, 65–72 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Trask, B. J. et al. Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes. Hum. Mol. Genet. 7, 13–26 (1998).

    CAS  Article  Google Scholar 

  44. 44

    Crow, T. J. Handedness, language lateralisation and anatomical asymmetry: relevance of protocadherin XY to hominid speciation and the aetiology of psychosis. Br. J. Psychiatry 181, 295–297 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Nicholson, T. R., Yang, J., DeLisi, L. E. & Crow, T. J. Allele sharing for schizophrenia and schizo-affective disorder within a region of Homo sapiens specific XY homology. Am. J. Med. Genet. 114, 637–640 (2002).

    Article  Google Scholar 

  46. 46

    Angata, T., Varki, N. M. & Varki, A. A second uniquely human mutation affecting sialic acid biology. J. Biol. Chem. 276, 40282–40287 (2001).

    CAS  Article  Google Scholar 

  47. 47

    Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002).

    CAS  Article  Google Scholar 

  48. 48

    Chen, F. C. & Li, W. H. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am. J. Hum. Genet. 68, 444–456 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Varki, A. et al. Great ape phenome project? Science 282, 239–240 (1998).

    CAS  Article  Google Scholar 

  50. 50

    Committee on Long-Term Care of Chimpanzees, National Research Council. Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use (National Academy Press, Washington, DC, 1997).

  51. 51

    Knoppers, B. M., Avard, D., Cardinal, G. & Glass, K. C. Children and incompetent adults in genetic research: consent and safeguards. Nature Rev. Genet. 3, 221–225 (2002).

    CAS  Article  Google Scholar 

  52. 52

    Goodman, M. The genomic record of humankind's evolutionary roots. Am. J. Hum. Genet. 64, 31–39 (1999).

    CAS  Article  Google Scholar 

  53. 53

    Gagneux, P. et al. Mitochondrial sequences show diverse evolutionary histories of African hominoids. Proc. Natl Acad. Sci. USA 96, 5077–5082 (1999).

    CAS  Article  Google Scholar 

  54. 54

    de Waal, F. & Lanting, F. Bonobo: The Forgotten Ape (Univ. of California Press, Berkeley, California, 1997).

    Google Scholar 

  55. 55

    Takahata, N. & Satta, Y. Evolution of the primate lineage leading to modern humans: phylogenetic and demographic inferences from DNA sequences. Proc. Natl Acad. Sci. USA 94, 4811–4815 (1997).

    CAS  Article  Google Scholar 

  56. 56

    Kumar, S. & Hedges, S. B. A molecular timescale for vertebrate evolution. Nature 392, 917–920 (1998).

    CAS  Article  Google Scholar 

  57. 57

    Brunet, M. et al. A new hominid from the Upper Miocene of Chad, Central Africa. Nature 418, 145–151 (2002).

    CAS  Article  Google Scholar 

  58. 58

    Olson, M. V. The maps: clone by clone by clone. Nature 409, 816–818 (2001).

    CAS  Article  Google Scholar 

  59. 59

    Bailey, W. J. et al. Re-examination of the African hominoid trichotomy with additional sequences from the primate β-globin gene cluster. Mol. Phylogenet. Evol. 1, 97–135 (1992).

    CAS  Article  Google Scholar 

  60. 60

    Novembre, F. J. et al. Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1. J. Virol. 71, 4086–4091 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Krawczynski, K., Prince, A. M. & Nowoslawski, A. Immunopathologic aspects of the HBsAg carrier state in chimpanzees. J. Med. Primatol. 8, 222–232 (1979).

    CAS  Article  Google Scholar 

  62. 62

    Shouval, D. et al. Chronic hepatitis in chimpanzee carriers of hepatitis B virus: morphologic, immunologic, and viral DNA studies. Proc. Natl Acad. Sci. USA 77, 6147–6151 (1980).

    CAS  Article  Google Scholar 

  63. 63

    Dienes, H. P., Purcell, R. H., Popper, H. & Ponzetto, A. The significance of infections with two types of viral hepatitis demonstrated by histologic features in chimpanzees. J. Hepatol. 10, 77–84 (1990).

    CAS  Article  Google Scholar 

  64. 64

    Gagneux, P. & Muchmore, E. A. in HBV Protocols (ed. Hamatake, R.) (Humana Press, Totowa, New Jersey, in the press).

  65. 65

    Escalante, A. A., Barrio, E. & Ayala, F. J. Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene. Mol. Biol. Evol. 12, 616–626 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Ollomo, B. et al. Lack of malaria parasite transmission between apes and humans in Gabon. Am. J. Trop. Med. Hyg. 56, 440–445 (1997).

    CAS  Article  Google Scholar 

  67. 67

    Graham, C. E. Reproductive function in aged female chimpanzees. Am. J. Phys. Anthropol. 50, 291–300 (1979).

    CAS  Article  Google Scholar 

  68. 68

    Murphy B. R. et al. in Chimpanzee Conservation and Public Health: Environments for the Future 21–27 (Diagnon/Bioqual, Inc., Rockville, Maryland, 1992).

    Google Scholar 

  69. 69

    Subbarao, K., Webster, R. G., Kawaoka, Y. & Murphy, B. R. Are there alternative avian influenza viruses for generation of stable attenuated avian–human influenza A reassortant viruses? Virus Res. 39, 105–118 (1995).

    CAS  Article  Google Scholar 

  70. 70

    Gearing, M., Rebeck, G. W., Hyman, B. T., Tigges, J. & Mirra, S. S. Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 9382–9386 (1994).

    CAS  Article  Google Scholar 

  71. 71

    Gearing, M., Tigges, J., Mori, H. & Mirra, S. S. β-Amyloid (A β) deposition in the brains of aged orangutans. Neurobiol. Aging 18, 139–146 (1997).

    CAS  Article  Google Scholar 

  72. 72

    Schmidt, R. E. Systemic pathology of chimpanzees. J. Med. Primatol. 7, 274–318 (1978).

    Article  Google Scholar 

  73. 73

    Bieniasz, P. D. et al. A comparative study of higher primate foamy viruses, including a new virus from a gorilla. Virology 207, 217–228 (1995).

    CAS  Article  Google Scholar 

  74. 74

    Schweizer, M. et al. Markers of foamy virus infections in monkeys, apes, and accidentally infected humans: appropriate testing fails to confirm suspected foamy virus prevalence in humans. AIDS Res. Hum. Retroviruses 11, 161–170 (1995).

    CAS  Article  Google Scholar 

  75. 75

    Goepfert, P. A. et al. Analysis of west African hunters for foamy virus infections. AIDS Res. Hum. Retroviruses 12, 1725–1730 (1996).

    CAS  Article  Google Scholar 

  76. 76

    Sandstrom, P. A. et al. Simian foamy virus infection among zoo keepers. Lancet 12, 551–552 (2000).

    Article  Google Scholar 

  77. 77

    McClure, H. M. Tumors in nonhuman primates: observations during a six-year period in the Yerkes primate center colony. Am. J. Phys. Anthropol. 38, 425–429 (1973).

    CAS  Article  Google Scholar 

  78. 78

    Seibold, H. R. & Wolf, R. H. Neoplasms and proliferative lesions in 1065 nonhuman primate necropsies. Lab. Anim. Sci. 23, 533–539 (1973).

    CAS  PubMed  Google Scholar 

  79. 79

    Willemsen, P. T. J. & de Graaf, F. K. Multivalent binding of K99 fimbriae to the N-glycolyl-GM3 ganglioside receptor. Infect. Immun. 61, 4518–4522 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Maynard V. Olson.

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DATABASES

LocusLink

BRCA1

BRCA2

CMAH

FOXP2

SIGLECL1

V10

OMIM

breast cancer

cystic fibrosis

multiple sclerosis

phenylketonuria

rheumatoid arthritis

systemic lupus

type II diabetes

FURTHER INFORMATION

Ajit Varki's laboratory

University of Washington Genome Center

Glossary

GREAT APES

Orang-utans, gorillas, chimpanzees and bonobos.

HETEROCHROMATIN

The densely staining regions of the nucleus that generally contain condensed, transcriptionally inactive regions of the genome.

EUCHROMATIN

The lightly staining regions of the nucleus that generally contain decondensed, transcriptionally active regions of the genome.

FIXATION

The process whereby a genetic variant arises by mutation and then increases in frequency in a population until it is the only variant present.

TRANSTHYRETIN

A protein that is a key transporter of the thyroid hormones in the blood and cerebrospinal fluid. Thyroid hormones stimulate an increase in the metabolic rate of many cell types and have effects on embryonic brain development.

MOLECULAR CLOCK

The steady accumulation of mutations during evolution, which provides a basis for dating the point at which two contemporary species diverged from a common ancestor.

PURIFYING SELECTION

The elimination of deleterious mutations through natural selection.

SIALIC ACID

An acidic sugar that is commonly found at the ends of the glycan chains of cell-surface glycoproteins and glycolipids. They are negatively charged under physiological conditions, contribute to biophysical characteristics of cell surfaces and can be recognized by many receptors of endogenous and exogenous origin.

ALU

A dispersed, intermediatly repetitive, 300-bp DNA sequence present in the human genome.

FRAMESHIFT MUTATION

A mutation that results in a change in the reading frame of a protein-encoding region. Frameshift mutations frequently cause such marked changes in a protein sequence that the protein is completely inactivated.

NONSENSE MUTATION

A mutation that results in the introduction of a stop codon to cause the premature termination of a protein. Nonsense mutations often completely inactivate a protein.

NON-SYNONYMOUS SUBSTITUTION

A mutation in the coding region of a gene that changes the amino acid inserted at a particular position in a protein.

OLD WORLD MONKEYS

Monkeys that are native to Africa and Asia.

CARCINOMA

A type of cancer that originates from epithelial cells. Most human cancers other than leukaemias or lymphomas are carcinomas.

HYDATIDIFORM MOLAR PREGNANCY

A pregnancy resulting from an abnormal fertilization event whose product can expand through successive cell divisions but cannot undergo normal development.

ELECTROPHEROGRAMS

Raw data that are produced during DNA sequencing. An electropherogram displays the fluorescence produced by DNA molecules that have been electrophoretically separated during the DNA sequencing process.

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Olson, M., Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nat Rev Genet 4, 20–28 (2003). https://doi.org/10.1038/nrg981

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