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Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution

Nature Genetics 39, 1140–1144 (2007) | Download Citation

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Abstract

Surveys of protein-coding sequences for evidence of positive selection in humans or chimpanzees have flagged only a few genes known to function in neural or nutritional processes1,2,3,4,5, despite pronounced differences between humans and chimpanzees in behavior, cognition and diet6,7,8. It may be that most such differences are due to changes in gene regulation rather than protein structure9. Here, we present the first survey of promoter (5′-flanking) regions, which are rich in cis-regulatory sequences, for evidence of positive selection in humans. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly in glucose metabolism.

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References

  1. 1.

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

  2. 2.

    et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005).

  3. 3.

    Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

  4. 4.

    et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005) (doi:10.1371/journal.pbio.0030170).

  5. 5.

    , , , & Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup. Genomics 88, 745–751 (2006).

  6. 6.

    What's so special about human tool use? Neuron 39, 201–204 (2003).

  7. 7.

    Language evolution: What do chimpanzees have to say? Curr. Biol. 15, R884–R886 (2005).

  8. 8.

    (ed.). Evolution of the Human Diet: the Known, the Unknown, and the Unknowable (Oxford Univ. Press, Oxford, 2007).

  9. 9.

    & Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).

  10. 10.

    & Positive selection on the human genome. Hum. Mol. Genet. 13, R245–R254 (2004).

  11. 11.

    et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).

  12. 12.

    et al. The evolution of transcriptional regulation in eukaryotes. Mol. Biol. Evol. 20, 1377–1419 (2003).

  13. 13.

    et al. Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol. 3, e387 (2005) (doi:10.1371/journal.pbio.0030387).

  14. 14.

    et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat. Genet. 39, 31–40 (2007).

  15. 15.

    , , & A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006) (doi:10.1371/journal.pbio.0040072).

  16. 16.

    , , & Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc. Natl. Acad. Sci. USA 103, 135–140 (2006).

  17. 17.

    et al. Forces shaping the fastest evolving regions in the human genome. PLoS Genet. 2, e168 (2006) (doi:10.1371/journal.pgen.0020168).

  18. 18.

    , , & Accelerated evolution of conserved noncoding sequences in humans. Science 314, 786 (2006).

  19. 19.

    et al. Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression. Genome Res. 16, 656–668 (2006).

  20. 20.

    et al. Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res. 16, 123–131 (2006).

  21. 21.

    & Distribution and characterization of regulatory elements in the human genome. Genome Res. 12, 1827–1836 (2002).

  22. 22.

    & Intronic sequences flanking alternatively spliced exons are conserved between human and mouse. Genome Res. 13, 1631–1637 (2003).

  23. 23.

    et al. Selection on human genes as revealed by comparisons to chimpanzee cDNA. Genome Res. 13, 831–837 (2003).

  24. 24.

    , & Evidence for widespread degradation of gene control regions in hominid genomes. PloS Biol. 3, e42 (2005) (doi:10.1371/journal.pbio.0030042).

  25. 25.

    & Detecting selection in noncoding regions of nucleotide sequences. Genetics 167, 949–958 (2004).

  26. 26.

    , & Evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level. Mol. Biol. Evol. 22, 2472–2479 (2005).

  27. 27.

    & Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

  28. 28.

    & Sequencing the chimpanzee genome: insights into human evolution and disease. Nat. Rev. Genet. 4, 20–28 (2003).

  29. 29.

    et al. Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. PLoS Genet. 1, e38 (2005) (doi:10.1371/journal.pgen.0010038).

  30. 30.

    et al. Toward a neutral evolutionary model of gene expression. Science 309, 1850–1854 (2005).

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Acknowledgements

We thank J. Pavisic and T. Severson for assistance with gene annotations; G. Barber, M. Diekhans, W. Kent, S. Kosakovsky Pond and W. Miller for advice about their software; F. Hsu, K. Rosenbloom and A. Zweig for advice about UCSC resources and J. Horvath, J. Pritchard, M. Turelli, H. Willard and members of the G. Wray laboratory for comments on the manuscript. Most of the computations were performed on the Duke Shared Cluster Resource, which is maintained by the Duke Center for Computational Science, Engineering and Medicine. This research was supported by the Duke Institute for Genome Sciences and Policy and a US National Science Foundation Postdoctoral Fellowship in Biological Informatics to R.H. (grant number 0434655).

Author information

    • Ralph Haygood
    •  & Olivier Fedrigo

    These authors contributed equally to this work.

Affiliations

  1. Biology Department, Duke University, Durham, North Carolina 27708, USA.

    • Ralph Haygood
    • , Olivier Fedrigo
    • , Brian Hanson
    • , Ken-Daigoro Yokoyama
    •  & Gregory A Wray

  2. Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA.

    • Olivier Fedrigo
    •  & Gregory A Wray

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ralph Haygood.

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    A fuller presentation of our models.

  2. 2.

    Supplementary Table 2

    Basic results, human lineage, passing cutoffs.

  3. 3.

    Supplementary Table 3

    Basic results, human lineage, failing cutoffs.

  4. 4.

    Supplementary Table 4

    Basic results, chimpanzee lineage, passing cutoffs.

  5. 5.

    Supplementary Table 5

    Basic results, chimpanzee lineage, failing cutoffs.

  6. 6.

    Supplementary Table 6

    Further analyses of PANTHER biological process categories.

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    Supplementary Text and Figures

    Supplementary Discussion

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DOI

https://doi.org/10.1038/ng2104

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