Methods to Detect Selection on Noncoding DNA

  • Ying Zhen
  • Peter Andolfatto
Part of the Methods in Molecular Biology book series (MIMB, volume 856)


Vast tracts of noncoding DNA contain elements that regulate gene expression in higher eukaryotes. Describing these regulatory elements and understanding how they evolve represent major challenges for biologists. Advances in the ability to survey genome-scale DNA sequence data are providing unprecedented opportunities to use evolutionary models and computational tools to identify functionally important elements and the mode of selection acting on them in multiple species. This chapter reviews some of the current methods that have been developed and applied on noncoding DNA, what they have shown us, and how they are limited. Results of several recent studies reveal that a significantly larger fraction of noncoding DNA in eukaryotic organisms is likely to be functional than previously believed, implying that the functional annotation of most noncoding DNA in these organisms is largely incomplete. In Drosophila, recent studies have further suggested that a large fraction of noncoding DNA divergence observed between species may be the product of recurrent adaptive substitution. Similar studies in humans have revealed a more complex pattern, with signatures of recurrent positive selection being largely concentrated in conserved noncoding DNA elements. Understanding these patterns and the extent to which they generalize to other organisms awaits the analysis of forthcoming genome-scale polymorphism and divergence data from more species.

Key words

Adaptive evolution Neutrality test Selective constraint Deleterious mutations McDonald–Kreitman test Population genetics 



Thanks to Stephen Wright, Molly Przeworski, Kevin Bullaughey, and anonymous reviewers for helpful discussion and comments on the manuscript. This work was supported in part by NIH grant R01-GM083228.


  1. 1.
    Lewin, B. (2007) Genes IX, Oxford University Press. p 892.Google Scholar
  2. 2.
    Stern, D. L., (2010) Evolution, development and the predictable genome. Roberts and Co. Publishing. p 264.Google Scholar
  3. 3.
    Wray, G., Hahn, M., Abouheif, E., Balhoff, J., Pizer, M., Rockman, M., and Romano, L. (2003) The evolution of transcriptional regulation in eukaryotes, Mol Biol Evol 20, 1377–1419.PubMedCrossRefGoogle Scholar
  4. 4.
    Davidson, E. H. (2001) Genomic regulatory systems : development and evolution, Academic Press, San Diego.Google Scholar
  5. 5.
    Carroll, S. B. (2000) Endless forms: the evolution of gene regulation and morphological diversity, Cell 101, 577–580.Google Scholar
  6. 6.
    Sakabe, N. J., and Nobrega, M. A. (2010) Genome-wide maps of transcription regulatory elements, Wiley Interdiscip Rev Syst Biol Med 2, 422–437.PubMedCrossRefGoogle Scholar
  7. 7.
    Charlesworth, B., Betancourt, A. J., Kaiser, V. B., and Gordo, I. (2009) Genetic recombination and molecular evolution, Cold Spring Harb Symp Quant Biol 74, 177–186.PubMedCrossRefGoogle Scholar
  8. 8.
    Wright, S., and Andolfatto, P. (2008) The impact of natural selection on the genome: emerging patterns in drosophila and arabidopsis, Annu Rev Ecol Evol Syst 39, 193–213.Google Scholar
  9. 9.
    Keightley, P. D., and Eyre-Walker, A. (1999) Terumi Mukai and the riddle of deleterious mutation rates, Genetics 153, 515–523.PubMedGoogle Scholar
  10. 10.
    Kondrashov, A. S. (1988) Deleterious mutations and the evolution of sexual reproduction, Nature 336, 435–440.PubMedCrossRefGoogle Scholar
  11. 11.
    Hahn, M. (2007) Detecting natural selection on cis-regulatory DNA, Genetica 129, 7–18.Google Scholar
  12. 12.
    Oleksyk, T. K., Smith, M. W., and O'Brien, S. J. (2010) Genome-wide scans for footprints of natural selection, Phil Trans Roy Soc B 365, 185–205.CrossRefGoogle Scholar
  13. 13.
    Charlesworth, B., and Charlesworth, D. (2010) Elements of evolutionary genetics, Roberts and Co. Publishers.Google Scholar
  14. 14.
    Park, P. J. (2009) ChIP-seq: advantages and challenges of a maturing technology, Nat Rev Genet 10, 669–680.PubMedCrossRefGoogle Scholar
  15. 15.
    Wang, Z., Gerstein, M., and Snyder, M. (2009) RNA-Seq: a revolutionary tool for transcriptomics, Nat Rev Genet 10, 57–63.PubMedCrossRefGoogle Scholar
  16. 16.
    Shibata, Y., and Crawford, G. E. (2009) Mapping regulatory elements by DNaseI hypersensitivity chip (DNase-Chip), Methods Mol Biol 556, 177–190.PubMedCrossRefGoogle Scholar
  17. 17.
    Kimura, M. (1983) The neutral theory of molecular evolution, Cambridge University Press, Cambridge.Google Scholar
  18. 18.
    Kondrashov, A. S., and Crow, J. F. (1993) A molecular approach to estimating the human deleterious mutation rate, Hum Mutat 2, 229–234.PubMedCrossRefGoogle Scholar
  19. 19.
    Shabalina, S., and Kondrashov, A. (1999) Pattern of selective constraint in C-elegans and C-briggsae genomes, Genet Res 74, 23–30.PubMedCrossRefGoogle Scholar
  20. 20.
    Shabalina, S., Ogurtsov, A., Kondrashov, V., and Kondrashov, A. (2001) Selective constraint in intergenic regions of human and mouse genomes, Trends in Genetics 17, 373–376.PubMedCrossRefGoogle Scholar
  21. 21.
    Bergman, C., and Kreitman, M. (2001) Analysis of conserved noncoding DNA in Drosophila reveals similar constraints in intergenic and intronic sequences, Genome Res 11, 1335–1345.CrossRefGoogle Scholar
  22. 22.
    Andolfatto, P. (2005) Adaptive evolution of non-coding DNA Drosophila, Nature, 437, 1149–1152.Google Scholar
  23. 23.
    Siepel, A., Bejerano, G., Pedersen, J., Hinrichs, A., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L., Richards, S., Weinstock, G., Wilson, R., Gibbs, R., Kent, W., Miller, W., and Haussler, D. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes, Genome Res 15, 1034–1050.PubMedCrossRefGoogle Scholar
  24. 24.
    Halligan, D. L., and Keightley, P. D. (2006) Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison, Genome Res 16, 875–884.CrossRefGoogle Scholar
  25. 25.
    Gaffney, D. J., and Keightley, P. D. (2006) Genomic selective constraints in murid noncoding DNA, PLoS Genetics 2, 1912–1923.CrossRefGoogle Scholar
  26. 26.
    Eory, L., Halligan, D. L., and Keightley, P. D. (2010) Distributions of Selectively Constrained Sites and Deleterious Mutation Rates in the Hominid and Murid Genomes, Mol Biol Evol 27, 177–192.PubMedCrossRefGoogle Scholar
  27. 27.
    Consortium. (2007) Evolution of genes and genomes on the Drosophila phylogeny, Nature 450, 203–218.Google Scholar
  28. 28.
    Cooper, G., Stone, E., Asimenos, G., Green, E., Batzoglou, S., and Sidow, A. (2005) Distribution and intensity of constraint in mammalian genomic sequence, Genome Res 15, 901–913.PubMedCrossRefGoogle Scholar
  29. 29.
    Duret, L., and Bucher, P. (1997) Searching for regulatory elements in human noncoding sequences, Curr Opin Struc Biol 7, 399–406.CrossRefGoogle Scholar
  30. 30.
    Boffelli, D., McAuliffe, J., Ovcharenko, D., Lewis, K., Ovcharenko, I., Pachter, L., and Rubin, E. (2003) Phylogenetic shadowing of primate sequences to find functional regions of the human genome, Science 299, 1391–1394.PubMedCrossRefGoogle Scholar
  31. 31.
    DeRose-Wilson, L. J., and Gaut, B. S. (2007) Transcription-related mutations and GC content drive variation in nucleotide substitution rates across the genomes of Arabidopsis thaliana and Arabidopsis lyrata, BMC Evol Biol, 7, 66.PubMedCrossRefGoogle Scholar
  32. 32.
    Britten, R. (1996) Cases of ancient mobile element DNA insertions that now affect gene regulation, Mol Phylogenet Evol 5, 13–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Nishihara, H., Smit, A. F. A., and Okada, N. (2006) Functional noncoding sequences derived from SINEs in the mammalian genome, Genome Res 16, 864–874.CrossRefGoogle Scholar
  34. 34.
    Haddrill, P., Charlesworth, B., Halligan, D., and Andolfatto, P. (2005) Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content, Genome Biology 6, r67.PubMedCrossRefGoogle Scholar
  35. 35.
    Tajima, F. (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism, Genetics 123, 585–595.PubMedGoogle Scholar
  36. 36.
    Hahn, M., Stajich, J., and Wray, G. (2003) The effects of selection against spurious transcription factor binding sites, Mol Biol Evol 20, 901–906.PubMedCrossRefGoogle Scholar
  37. 37.
    Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibe, B., Bouix, J., Caiment, F., Elsen, J., Eychenne, F., Larzul, C., Laville, E., Meish, F., Milenkovic, D., Tobin, J., Charlier, C., and Georges, M. (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep, Nature Genetics 38, 813–818.PubMedCrossRefGoogle Scholar
  38. 38.
    Bullaughey, K. (2011) Changes in selective effects over time facilitate turnover of enhancer sequences, Genetics 187, 567–82.Google Scholar
  39. 39.
    Blow, M. J., McCulley, D. J., Li, Z., Zhang, T., Akiyama, J. A., Holt, A., Plajzer-Frick, I., Shoukry, M., Wright, C., Chen, F., Afzal, V., Bristow, J., Ren, B., Black, B. L., Rubin, E. M., Visel, A., and Pennacchio, L. A. (2010) ChIP-Seq identification of weakly conserved heart enhancers, Nat Genet 42, 806–810.PubMedCrossRefGoogle Scholar
  40. 40.
    Pollard, K. S., Salama, S. R., King, B., Kern, A. D., Dreszer, T., Katzman, S., Siepel, A., Pedersen, J. S., Bejerano, G., Baertsch, R., Rosenbloom, K. R., Kent, J., and Haussler, D. (2006) Forces shaping the fastest evolving regions in the human genome, PLos Genetics 2, 1599–1611.Google Scholar
  41. 41.
    Prabhakar, S., Noonan, J. P., Paabo, S., and Rubin, E. M. (2006) Accelerated evolution of conserved noncoding sequences in humans, Science 314, 786–786.PubMedCrossRefGoogle Scholar
  42. 42.
    Bird, C., Stranger, B., Liu, M., Thomas, D., Ingle, C., Beazley, C., Miller, O, W., Hurles, M., and Dermitzakis, E. (2007) Fast-evolving noncoding sequences in the human genome, Genome Biol, 8, R118.Google Scholar
  43. 43.
    Haygood, R., Fedrigo, O., Hanson, B., Yokoyama, K.-D., and Awray, G. (2007) Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution, Nature Genetics 39, 1140–1144.PubMedCrossRefGoogle Scholar
  44. 44.
    Kim, S. Y., and Pritchard, J. K. (2007) Adaptive evolution of conserved noncoding elements in mammals, PLos Genetics 3, 1572–1586.PubMedGoogle Scholar
  45. 45.
    Wong, W., and Nielsen, R. (2004) Detecting selection in noncoding regions of nucleotide sequences, Genetics 167, 949–958.PubMedCrossRefGoogle Scholar
  46. 46.
    Holloway, A. K., Begun, D. J., Siepel, A., and Pollard, K. S. (2008) Accelerated sequence divergence of conserved genomic elements in Drosophila melanogaster, Genome Res 18, 1592–1601.CrossRefGoogle Scholar
  47. 47.
    Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R., and Siepel, A. (2010) Detection of nonneutral substitution rates on mammalian phylogenies, Genome Res 20, 110–121.PubMedCrossRefGoogle Scholar
  48. 48.
    Hurst, L. (2002) The Ka/Ks ratio: diagnosing the form of sequence evolution, 18, 486–487.Google Scholar
  49. 49.
    Hahn, M., Rockman, M., Soranzo, N., Goldstein, D., and Wray, G. (2004) Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the Factor VII locus in humans, Genetics 167, 867–877.PubMedCrossRefGoogle Scholar
  50. 50.
    Lunter, G., Ponting, C. P., and Hein, J. (2006) Genome-wide identification of human functional DNA using a neutral in-del model, PLoS Comp BIol 2, 2–12.CrossRefGoogle Scholar
  51. 51.
    Presgraves, D. C. (2006) Intron length evolution in drosophila, Mol Biol Evol 23, 2203–2213.PubMedCrossRefGoogle Scholar
  52. 52.
    Parsch, J., Novozhilov, S., Saminadin-Peter, S., Wong, K., and Andolfatto, P. (2010) On the utility of short intron sequences as a reference for the detection of positive and negative Selection in Drosophila, Mol Biol Evol, 27, 1226–1234.Google Scholar
  53. 53.
    Moses, A. M. (2009) Statistical tests for natural selection on regulatory regions based on the strength of transcription factor binding sites, BMC Evol Biol 9, 286.PubMedCrossRefGoogle Scholar
  54. 54.
    Satija, R., Pachter, L., and Hein, J. (2008) Combining statistical alignment and phylogenetic footprinting to detect regulatory elements, Bioinformatics 24, 1236–1242.PubMedCrossRefGoogle Scholar
  55. 55.
    Lunter, G., Rocco, A., Mimouni, N., Heger, A., Caldeira, A., and Hein, J. (2008) Uncertainty in homology inferences: assessing and improving genomic sequence alignment, Genome Res 18, 298–309.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang, J., Keightley, P. D., and Johnson, T. (2006) MCALIGN2: faster, accurate global pairwise alignment of non-coding DNA sequences based on explicit models of in-del evolution, BMC Bioinformatics 7, 292.PubMedCrossRefGoogle Scholar
  57. 57.
    Keightley, P. D., and Johnson, T. (2004) MCALIGN: stochastic alignment of noncoding DNA sequences based on an evolutionary model of sequence evolution, Genome Res 14, 442–450.PubMedCrossRefGoogle Scholar
  58. 58.
    Pollard, D. A., Bergman, C. M., Stoye, J., Celniker, S. E., and Eisen, M. B. (2004) Benchmarking tools for the alignment of functional noncoding DNA, BMC Bioinformatics 5, 6.PubMedCrossRefGoogle Scholar
  59. 59.
    Landan, G., and Graur, D. (2007) Heads or tails: a simple reliability check for multiple sequence alignments, Mol Biol Evol 24, 1380–1383.PubMedCrossRefGoogle Scholar
  60. 60.
    Satija, R., Hein, J., and Lunter, G. A. (2010) Genome-wide functional element detection using pairwise statistical alignment outperforms multiple genome footprinting techniques, Bioinformatics 26, 2116–2120.PubMedCrossRefGoogle Scholar
  61. 61.
    Liu, K., Raghavan, S., Nelesen, S., Linder, C. R., and Warnow, T. (2009) Rapid and accurate large-scale coestimation of sequence alignments and phylogenetic trees, Science 324, 1561–1564.PubMedCrossRefGoogle Scholar
  62. 62.
    Loytynoja, A., and Goldman, N. (2010) webPRANK: a phylogeny-aware multiple sequence aligner with interactive alignment browser, BMC Bioinformatics 11, 579.PubMedCrossRefGoogle Scholar
  63. 63.
    Sawyer, S. A., Dykhuizen, D. E., and Hartl, D. L. (1987) Confidence interval for the number of selectively neutral amino acid polymorphisms, Proc Natl Acad Sci U S A 84, 6225–6228.PubMedCrossRefGoogle Scholar
  64. 64.
    Akashi, H., and Schaeffer, S. (1997) Natural selection and the frequency distributions of ''silent'' DNA polymorphism in Drosophila, Genetics 146, 295–307.PubMedGoogle Scholar
  65. 65.
    Keightley, P. D., and Eyre-Walker, A. (2007) Joint inference of the distribution of fitness effects of deleterious mutations and population demography based on nucleotide polymorphism frequencies, Genetics 177, 2251–2261.PubMedCrossRefGoogle Scholar
  66. 66.
    Boyko, A. R., Williamson, S. H., Indap, A. R., Degenhardt, J. D., Hernandez, R. D., Lohmueller, K. E., Adams, M. D., Schmidt, S., Sninsky, J. J., Sunyaev, S. R., White, T. J., Nielsen, R., Clark, A. G., and Bustamante, C. D. (2008) Assessing the evolutionary impact of amino acid mutations in the human genome, PLoS Genetics, 30, e1000083Google Scholar
  67. 67.
    Hernandez, R. D., Williamson, S. H., and Bustamante, C. D. (2007) Context dependence, ancestral misidentification, and spurious signatures of natural selection, Mol Biol Evol 24, 1792–1800.Google Scholar
  68. 68.
    Baudry, E., and Depaulis, F. (2003) Effect of misoriented sites on neutrality tests with outgroup, Genetics 165, 1619–1622.Google Scholar
  69. 69.
    Kryukov, G., Schmidt, S., and Sunyaev, S. (2005) Small fitness effect of mutations in highly conserved non-coding regions, Human Molecular Genetics 14, 2221–2229.PubMedCrossRefGoogle Scholar
  70. 70.
    Foxe, J. P., Dar, V.-u.-N., Zheng, H., Nordborg, M., Gaut, B. S., and Wright, S. I. (2008) Selection on amino acid substitutions in Arabidopsis, Mol Biol Evol 25, 1375–1383.PubMedCrossRefGoogle Scholar
  71. 71.
    Doniger, S. W., Kim, H. S., Swain, D., Corcuera, D., Williams, M., Yang, S. P., and Fay, J. C. (2008) A catalog of neutral and deleterious polymorphism in yeast, PLoS Genet 4, e1000183.PubMedCrossRefGoogle Scholar
  72. 72.
    Kim, S., Plagnol, V., Hu, T. T., Toomajian, C., Clark, R. M., Ossowski, S., Ecker, J. R., Weigel, D., and Nordborg, M. (2007) Recombination and linkage disequilibrium in Arabidopsis thaliana, Nat Genet 39, 1151–1155.PubMedCrossRefGoogle Scholar
  73. 73.
    Zeng, K., and Charlesworth, B. (2010) Studying patterns of recent evolution at synonymous sites and intronic sites in Drosophila melanogaster, J Mol Evol 70, 116–128.Google Scholar
  74. 74.
    Bachtrog, D., and Andolfatto, P. (2006) Selection, recombination and demographic history in Drosophila miranda, Genetics 174, 2045–2059.Google Scholar
  75. 75.
    Haddrill, P., Bachtrog, D., and Andolfatto, P. (2008) Positive and negative selection on noncoding DNA in Drosophila simulans, Mol Biol Evol 25, 1825–1834.Google Scholar
  76. 76.
    Casillas, S., Barbadilla, A., and Bergman, C. (2007) Purifying selection maintains highly conserved Noncoding sequences in Drosophila, Mol Biol Evol 24, 2222–2234.Google Scholar
  77. 77.
    Eyre-Walker, A., and Keightley, P. D. (2009) Estimating the rate of adaptive molecular evolution in the presence of slightly deleterious mutations and population size change, Mol Biol Evol 26, 2097–2108.PubMedCrossRefGoogle Scholar
  78. 78.
    Drake, J., Bird, C., Nemesh, J., Thomas, D., Newton-Cheh, C., Reymond, A., Excoffier, L., Attar, H., Antonarakis, S., Dermitzakis, E., and Hirschhorn, J. (2006) Conserved noncoding sequences are selectively constrained and not mutation cold spots, Nature Genetics 38, 223–227.Google Scholar
  79. 79.
    Asthana, S., Noble, W., Kryukov, G., Grantt, C., Sunyaev, S., and Stamatoyannopoulos, J. (2007) Widely distributed noncoding purifying selection in the human genome, Proc Natl Acad Sci USA 104, 12410–12415.Google Scholar
  80. 80.
    Katzman, S., Kern, A. D., Bejerano, G., Fewell, G., Fulton, L., Wilson, R. K., Salama, S. R., and Haussler, D. (2007) Human genome ultraconserved elements are ultraselected, Science 317, 915.PubMedCrossRefGoogle Scholar
  81. 81.
    Chen, K., and Rajewsky, N. (2006) Natural selection on human microRNA binding sites inferred from SNP data, Nat Genet 38, 1452–1456.PubMedCrossRefGoogle Scholar
  82. 82.
    Ronald, J., and Akey, J. M. (2007) The evolution of gene expression QTL in Saccharomyces cerevisiae, PLoS One 2, e678.PubMedCrossRefGoogle Scholar
  83. 83.
    Emerson, J. J., Hsieh, L. C., Sung, H. M., Wang, T. Y., Huang, C. J., Lu, H. H., Lu, M. Y., Wu, S. H., and Li, W. H. (2010) Natural selection on cis and trans regulation in yeasts, Genome Res 20, 826–836.PubMedCrossRefGoogle Scholar
  84. 84.
    Kern, A., and Haussler, D. (2010) A population genetic Hidden Markov Model for detecting genomic regions under selection, Mol Biol Evol 27, 1673–85Google Scholar
  85. 85.
    Hudson, R. R. (2002) Generating samples under a Wright-Fisher neutral model of genetic variation, Bioinformatics 18, 337–338.PubMedCrossRefGoogle Scholar
  86. 86.
    McDonald, J. H., and Kreitman, M. (1991) Adaptive Protein Evolution at the Adh Locus in Drosophila, Nature 351, 652–654.PubMedCrossRefGoogle Scholar
  87. 87.
    Sawyer, S. A., and Hartl, D. L. (1992) Population genetics of polymorphism and divergence, Genetics 132, 1161–1176.PubMedGoogle Scholar
  88. 88.
    Ohta, T. (1993) Amino acid substitution at the Adh locus of Drosophila is facilitated by small population size, Proc Natl Acad Sci U S A 90, 4548–4551.PubMedCrossRefGoogle Scholar
  89. 89.
    Sawyer, S. A., Parsch, J., Zhang, Z., and Hartl, D. L. (2007) Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila, Proc Natl Acad Sci U S A 104, 6504–6510.PubMedCrossRefGoogle Scholar
  90. 90.
    Bustamante, C. D., Wakeley, J., Sawyer, S., and Hartl, D. L. (2001) Directional selection and the site-frequency spectrum, Genetics 159, 1779–1788.PubMedGoogle Scholar
  91. 91.
    Fay, J. C., Wyckoff, G. J., and Wu, C. I. (2001) Positive and negative selection on the human genome, Genetics 158, 1227–1234.PubMedGoogle Scholar
  92. 92.
    Eyre-Walker, A., Keightley, P. D., Smith, N. G., and Gaffney, D. (2002) Quantifying the slightly deleterious mutation model of molecular evolution, Mol Biol Evol 19, 2142–2149.PubMedCrossRefGoogle Scholar
  93. 93.
    Bierne, N., and Eyre-Walker, A. (2004) The genomic rate of adaptive amino acid substitution in Drosophila, Mol Biol Evol 21, 1350–1360.PubMedCrossRefGoogle Scholar
  94. 94.
    Welch, J. J. (2006) Estimating the genomewide rate of adaptive protein evolution in Drosophila, Genetics 173, 821–837.PubMedCrossRefGoogle Scholar
  95. 95.
    Jenkins, D. L., Ortori, C. A., and Brookfield, J. F. (1995) A test for adaptive change in DNA sequences controlling transcription, Proc Biol Sci 261, 203–207.PubMedCrossRefGoogle Scholar
  96. 96.
    Ludwig, M. Z., and Kreitman, M. (1995) Evolutionary dynamics of the enhancer region of even-skipped in Drosophila, Mol Biol Evol 12, 1002–1011.PubMedGoogle Scholar
  97. 97.
    Holloway, A., Lawniczak, M., Mezey, J., Begun, D., and Jones, C. (2007) Adaptive gene expression divergence inferred from population genomics, PLoS Genetics 3, 2007–2013.Google Scholar
  98. 98.
    Kohn, M., Fang, S., and Wu, C. (2004) Inference of positive and negative selection on the 5 ' regulatory regions of Drosophila genes, Mol Biol Evol 21, 374–383.PubMedCrossRefGoogle Scholar
  99. 99.
    Torgerson, D., Boyko, A., Hernandez, R., Indap, A., Hu, X., White, T., Sninsky, J., Cargill, M., Adams, M., Bustamante, C., and Clark, A. (2009) Evolutionary Processes Acting on Candidate cis-Regulatory Regions in Humans Inferred from Patterns of Polymorphism and Divergence, PLoS Genetics 5, e1000592.Google Scholar
  100. 100.
    Kousathanas, A., Oliver, F., Halligan, D. L., and Keightley, P. D. (2010) Positive and negative selection on non-coding DNA close to protein-coding genes in wild house mice, Mol Biol Evol 28, 1183–91.Google Scholar
  101. 101.
    Elyashiv, E., Bullaughey, K., Sattath, S., Rinott, Y., Przeworski, M., and Sella, G. (2010) Shifts in the intensity of purifying selection: An analysis of genome-wide polymorphism data from two closely related yeast species, Genome Res, 20, 1558–1573.Google Scholar
  102. 102.
    Akashi, H. (1995) Inferring Weak Selection from Patterns of Polymorphism and Divergence at Silent Sites in Drosophila DNA, Genetics 139, 1067–1076.PubMedGoogle Scholar
  103. 103.
    Templeton, A. R. (1996) Contingency tests of neutrality using intra/interspecific gene trees: the rejection of neutrality for the evolution of the mitochondrial cytochrome oxidase II gene in the hominoid primates, Genetics 144, 1263–1270.PubMedGoogle Scholar
  104. 104.
    Charlesworth, J., and Eyre-Walker, A. (2006) The rate of adaptive evolution in enteric bacteria, Mol Biol Evol 23, 1348–1356.PubMedCrossRefGoogle Scholar
  105. 105.
    Sawyer, S. A., Kulathinal, R. J., Bustamante, C. D., and Hartl, D. L. (2003) Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection, J Mol Evol 57 Suppl 1, S154-164.PubMedCrossRefGoogle Scholar
  106. 106.
    Andolfatto, P. (2008) Controlling type-I error of the McDonald-Kreitman test in genome wide scans for selection on noncoding DNA, Genetics 180, 1767–1771Google Scholar
  107. 107.
    Smith, N. G., and Eyre-Walker, A. (2002) Adaptive protein evolution in Drosophila, Nature 415, 1022–1024.PubMedCrossRefGoogle Scholar
  108. 108.
    Shapiro, J. A., Huang, W., Zhang, C., Hubisz, M. J., Lu, J., Turissini, D. A., Fang, S., Wang, H. Y., Hudson, R. R., Nielsen, R., Chen, Z., and Wu, C. I. (2007) Adaptive genic evolution in the Drosophila genomes,Proc Natl Acad Sci U S A 104, 2271–2276.PubMedCrossRefGoogle Scholar
  109. 109.
    Andolfatto, P. (2007) Hitchhiking effects of recurrent beneficial amino acid substitutions in the Drosophila melanogaster genome, Genome Res 17, 1755–1762.Google Scholar
  110. 110.
    Macpherson, J., Sella, G., Davis, J., and Petrov, D. (2007) Genomewide spatial correspondence between nonsynonymous divergence and neutral polymorphism reveals extensive adaptation in drosophila, Genetics 177, 2083–2099.Google Scholar
  111. 111.
    Bachtrog, D. (2008) Similar rates of protein adaptation in Drosophila miranda and D. melanogaster, two species with different current effective population sizes, BMC Evol Biol 8, 334.PubMedCrossRefGoogle Scholar
  112. 112.
    Cai, J., Macpherson, J., Sella, G., and Petrov, D. (2009) Pervasive Hitchhiking at Coding and Regulatory Sites in Humans, PLoS Genetics 5, e1000336Google Scholar
  113. 113.
    Ingvarsson, P. K. (2009) Natural selection on synonymous and nonsynonymous mutations shapes patterns of polymorphism in Populus tremula, Mol Biol Evol 27, 650–660.PubMedCrossRefGoogle Scholar
  114. 114.
    Fay, J. C., and Wu, C. I. (2001) The neutral theory in the genomic era, Curr Opin Genet Dev 11, 642–646.PubMedCrossRefGoogle Scholar
  115. 115.
    Eyre-Walker, A., and Keightley, P. D. (2007) The distribution of fitness effects of new mutations, Nature Reviews Genetics 8, 610–618.PubMedCrossRefGoogle Scholar
  116. 116.
    Eyre-Walker, A. (2002) Changing effective population size and the McDonald-Kreitman test, Genetics 162, 2017–2024.PubMedGoogle Scholar
  117. 117.
    Andolfatto, P., Wong, K. M., and Bachtrog, D. (2011) Effective population size and the efficacy of selection on the X chromosomes of two closely related Drosophila species, Genome Biol Evol 3, 114–128.PubMedCrossRefGoogle Scholar
  118. 118.
    Hanada, K., Zhang, X., Borevitz, J. O., Li, W. H., and Shiu, S. H. (2007) A large number of novel coding small open reading frames in the intergenic regions of the Arabidopsis thaliana genome are transcribed and/or under purifying selection, Genome Res 17, 632–640.PubMedCrossRefGoogle Scholar
  119. 119.
    Pickrell, J. K., Marioni, J. C., Pai, A. A., Degner, J. F., Engelhardt, B. E., Nkadori, E., Veyrieras, J. B., Stephens, M., Gilad, Y., and Pritchard, J. K. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing, Nature 464, 768–772.PubMedCrossRefGoogle Scholar
  120. 120.
    Sella, G., Petrov, D., Przeworski, M., and Andolfatto, P. (2009) Pervasive Natural Selection in the Drosophila Genome?, PLoS Genetics 5, e1000495.Google Scholar
  121. 121.
    Kudaravalli, S., Veyrieras, J. B., Stranger, B. E., Dermitzakis, E. T., and Pritchard, J. K. (2009) Gene expression levels are a target of recent natural selection in the human genome, Mol Biol Evol 26, 649–658.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Ecology and Evolutionary Biology, The Lewis-Sigler Institute for Integrative GenomicsPrinceton UniversityPrincetonUSA

Personalised recommendations