Revisiting the false positive rate in detecting recent positive selection

Abstract

There is increasing interest in studying the molecular mechanisms of recent adaptations caused by positive selection in the genomics era. Such endeavors to detect recent positive selection, however, have been severely handicapped by false positives due to the confounding impact of demography and the population structure. To reduce false positives, it is critical to conduct a functional analysis to identify the true candidate genes/mutations from those that are filtered through neutrality tests. However, the extremely high cost of such functional analysis may restrict studies within a small number of model species. In particular, when the false positive rate of neutrality tests is high, the efficiency of the functional analysis will also be very low. Therefore, although the recent improvements have been made in the (joint) inference of demography and selection, our ultimate goal, which is to understand the mechanism of adaptation generally in a wide variety of natural populations, may not be achieved using the currently available approaches. More attention should thus be spent on the development of more reliable tests that could not only free themselves from the confounding impact of demography and the population structure but also have reasonable power to detect selection.

Graphical abstract

Keywords

recent positive selection / selective sweep / demography / population structure / false positive

References

[1] Pulvers, J. N., Journiac, N., Arai, Y., and Nardelli, J (2015) MCPH1: a window into brain development and evolution. Front. Cell. Neurosci., 10.3389/fncel.2015.00092

[2] Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S. L., Wiebe, V., Kitano, T., Monaco, A. P. and Pääbo, S. (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature, 418, 869–872

[3] Swallow, D. M. (2003) Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet., 37, 197–219

[4] Poulter, M., Hollox, E., Harvey, C. B., Mulcare, C., Peuhkuri, K., Kajander, K., Sarner, M., Korpela, R. and Swallow, D. M. (2003) The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann. Hum. Genet., 67, 298–311

[5] Bersaglieri, T., Sabeti, P. C., Patterson, N., Vanderploeg, T., Schaffner, S. F., Drake, J. A., Rhodes, M., Reich, D. E. and Hirschhorn, J. N. (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet., 74, 1111–1120

[6] Nielsen, R. (2009) Adaptionism-30 years after Gould and Lewontin. Evolution, 63, 2487–2490

[7] Hurst, L. D. (2009) Fundamental concepts in genetics: genetics and the understanding of selection. Nat. Rev. Genet., 10, 83–93

[8] Tajima, F. (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics, 123, 585–595

[9] Fu, Y.-X. (1997) Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection. Genetics, 147, 915–925

[10] Fay, J. C. and Wu, C.-I. (2000) Hitchhiking under positive Darwinian selection. Genetics, 155, 1405–1413

[11] Smith, J. M. and Haigh, J. (1974) The hitch-hiking effect of a favourable gene. Genet. Res., 23, 23–35

[12] Galtier, N., Depaulis, F. and Barton, N. H. (2000) Detecting bottlenecks and selective sweeps from DNA sequence polymorphism. Genetics, 155, 981–987

[13] Kim, Y. and Stephan, W. (2002) Detecting a local signature of genetic hitchhiking along a recombining chromosome. Genetics, 160, 765–777

[14] Nielsen, R., Williamson, S., Kim, Y., Hubisz, M. J., Clark, A. G. and Bustamante, C. (2005) Genomic scans for selective sweeps using SNP data. Genome Res., 15, 1566–1575

[15] Li, H. and Stephan, W. (2005) Maximum-likelihood methods for detecting recent positive selection and localizing the selected site in the genome. Genetics, 171, 377–384

[16] Fu, Y.-X. and Li, W.-H. (1993) Statistical tests of neutrality of mutations. Genetics, 133, 693–709

[17] Sabeti, P. C., Reich, D. E., Higgins, J. M., Levine, H. Z. P., Richter, D. J., Schaffner, S. F., Gabriel, S. B., Platko, J. V., Patterson, N. J., McDonald, G. J., (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature, 419, 832–837

[18] Zeng, K., Fu, Y.-X., Shi, S. and Wu, C.-I. (2006) Statistical tests for detecting positive selection by utilizing high-frequency variants. Genetics, 174, 1431–1439

[19] MacCallum, C. and Hill, E. (2006) Being positive about selection. PLoS Biol., 4, e87

[20] Bamshad, M. and Wooding, S. P. (2003) Signatures of natural selection in the human genome. Nat. Rev. Genet., 4, 99–111

[21] Kauer, M. O., Dieringer, D. and Schlötterer, C. (2003) A microsatellite variability screen for positive selection associated with the “out of Africa” habitat expansion of Drosophila melanogaster. Genetics, 165, 1137–1148

[22] Sabeti, P. C., Schaffner, S. F., Fry, B., Lohmueller, J., Varilly, P., Shamovsky, O., Palma, A., Mikkelsen, T. S., Altshuler, D. and Lander, E. S. (2006) Positive natural selection in the human lineage. Science, 312, 1614–1620

[23] Pavlidis, P., Hutter, S. and Stephan, W. (2008) A population genomic approach to map recent positive selection in model species. Mol. Ecol., 17, 3585–3598

[24] Nielsen, R., Hellmann, I., Hubisz, M., Bustamante, C. and Clark, A. G. (2007) Recent and ongoing selection in the human genome. Nat. Rev. Genet., 8, 857–868

[25] Vitti, J. J., Grossman, S. R. and Sabeti, P. C. (2013) Detecting natural selection in genomic data. Annu. Rev. Genet., 47, 97–120

[26] Bank, C., Ewing, G. B., Ferrer-Admettla, A., Foll, M. and Jensen, J. D. (2014) Thinking too positive? Revisiting current methods of population genetic selection inference. Trends Genet., 30, 540–546

[27] Pool, J. E., Hellmann, I., Jensen, J. D. and Nielsen, R. (2010) Population genetic inference from genomic sequence variation. Genome Res., 20, 291–300

[28] Chen, H., Patterson, N. and Reich, D. (2010) Population differentiation as a test for selective sweeps. Genome Res., 20, 393–402

[29] Karlsson, E. K., Kwiatkowski, D. P. and Sabeti, P. C. (2014) Natural selection and infectious disease in human populations. Nat. Rev. Genet., 15, 379–393

[30] Mathieson, I., Lazaridis, I., Rohland, N., Mallick, S., Patterson, N., Roodenberg, S. A., Harney, E., Stewardson, K., Fernandes, D., Novak, M., (2015) Genome-wide patterns of selection in 230 ancient Eurasians. Nature, 528, 499–503

[31] Tajima, F. (1989) The effect of change in population size on DNA polymorphism. Genetics, 123, 597–601

[32] Jensen, J. D., Kim, Y., DuMont, V. B., Aquadro, C. F. and Bustamante, C. D. (2005) Distinguishing between selective sweeps and demography using DNA polymorphism data. Genetics, 170, 1401–1410

[33] Przeworski, M. (2002) The signature of positive selection at randomly chosen loci. Genetics, 160, 1179–1189

[34] Hudson, R. R. (1990) Gene genealogies and the coalescent process. In Oxford Surveys in Evolutionary Biology. Vol. 7, D. Futuyma and J. Antonovics, Editors. 1–44 New York: Oxford University Press

[35] Hudson, R. R. (2002) Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics, 18, 337–338

[36] Achaz, G. (2009) Frequency spectrum neutrality tests: one for all and all for one. Genetics, 183, 249–258

[37] Li, H. (2011) A new test for detecting recent positive selection that is free from the confounding impacts of demography. Mol. Biol. Evol., 28, 365–375

[38] Cornuet, J. M. and Luikart, G. (1996) Description and power analysis of two tests for detecting recent population bottlenecks from allele frequency data. Genetics, 144, 2001–2014

[39] Schlötterer, C., Kauer, M. and Dieringer, D. (2004) Allele excess at neutrally evolving microsatellites and the implications for tests of neutrality. Proc. Biol. Sci., 271, 869–874

[40] Li, H. and Wiehe, T. (2013) Coalescent tree imbalance and a simple test for selective sweeps based on microsatellite variation. PLoS Comput. Biol., 9, e1003060

[41] Thornton, K. R. and Jensen, J. D. (2007) Controlling the false-positive rate in multilocus genome scans for selection. Genetics, 175, 737–750

[42] Li, H. and Stephan, W. (2006) Inferring the demographic history and rate of adaptive substitution in Drosophila. PLoS Genet., 2, e166

[43] Parsch, J., Meiklejohn, C. D. and Hartl, D. L. (2001) Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans. Genetics, 159, 647–657

[44] Stephan, W., Song, Y. S. and Langley, C. H. (2006) The hitchhiking effect on linkage disequilibrium between linked neutral loci. Genetics, 172, 2647–2663

[45] McVean, G. (2007) The structure of linkage disequilibrium around a selective sweep. Genetics, 175, 1395–1406

[46] Kim, Y. and Nielsen, R. (2004) Linkage disequilibrium as a signature of selective sweeps. Genetics, 167, 1513–1524

[47] Jensen, J. D., Thornton, K. R., Bustamante, C. D. and Aquadro, C. F. (2007) On the utility of linkage disequilibrium as a statistic for identifying targets of positive selection in nonequilibrium populations. Genetics, 176, 2371–2379

[48] Akey, J. M., Zhang, G., Zhang, K., Jin, L. and Shriver, M. D. (2002) Interrogating a high-density SNP map for signatures of natural selection. Genome Res., 12, 1805–1814

[49] Pickrell, J. K., Coop, G., Novembre, J., Kudaravalli, S., Li, J. Z., Absher, D., Srinivasan, B. S., Barsh, G. S., Myers, R. M., Feldman, M. W., (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res., 19, 826–837

[50] Kayser, M., Brauer, S. and Stoneking, M. (2003) A genome scan to detect candidate regions influenced by local natural selection in human populations. Mol. Biol. Evol., 20, 893–900

[51] Storz, J. F., Payseur, B. A. and Nachman, M. W. (2004) Genome scans of DNA variability in humans reveal evidence for selective sweeps outside of Africa. Mol. Biol. Evol., 21, 1800–1811

[52] Carlson, C. S., Thomas, D. J., Eberle, M. A., Swanson, J. E., Livingston, R. J., Rieder, M. J. and Nickerson, D. A. (2005) Genomic regions exhibiting positive selection identified from dense genotype data. Genome Res., 15, 1553–1565

[53] Voight, B. F., Kudaravalli, S., Wen, X. and Pritchard, J. K. (2006) A map of recent positive selection in the human genome. PLoS Biol., 4, e72

[54] Tang, K., Thornton, K. R. and Stoneking, M. (2007) A new approach for using genome scans to detect recent positive selection in the human genome. PLoS Biol., 5, e171

[55] Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., , (2007) Genome-wide detection and characterization of positive selection in human populations. Nature, 449, 913–918

[56] Li, J. Z., Absher, D. M., Tang, H., Southwick, A. M., Casto, A. M., Ramachandran, S., Cann, H. M., Barsh, G. S., Feldman, M., Cavalli-Sforza, L. L., (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science, 319, 1100–1104

[57] Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H. Y., (2010) A draft sequence of the Neandertal genome. Science, 328, 710–722

[58] Reich, D., Green, R. E., Kircher, M., Krause, J., Patterson, N., Durand, E. Y., Viola, B., Briggs, A. W., Stenzel, U., Johnson, P. L. F., (2010) Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature, 468, 1053–1060

[59] Akey, J. M. (2009) Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res., 19, 711–722

[60] Fu, W. Q. and Akey, J. M. (2013) Selection and adaptation in the human genome. Annu. Rev. Genom. Hum. G.,14,467-489

[61] Huerta-Sánchez, E., Jin, X., Asan, , Bianba, Z., Peter, B. M., Vinckenbosch, N., Liang, Y., Yi, X., He, M., SomelM., (2014) Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature, 512, 194–197

[62] Teschke, M., Mukabayire, O., Wiehe, T. and Tautz, D. (2008) Identification of selective sweeps in closely related populations of the house mouse based on microsatellite scans. Genetics, 180, 1537–1545

[63] Glinka, S., Ometto, L., Mousset, S., Stephan, W. and De Lorenzo, D. (2003) Demography and natural selection have shaped genetic variation in Drosophila melanogaster: a multi-locus approach. Genetics, 165, 1269–1278

[64] Ometto, L., Glinka, S., De Lorenzo, D. and Stephan, W. (2005) Inferring the effects of demography and selection on Drosophila melanogaster populations from a chromosome-wide scan of DNA variation. Mol. Biol. Evol., 22, 2119–2130

[65] Emerson, J. J., Cardoso-Moreira, M., Borevitz, J. O. and Long, M. (2008) Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster. Science, 320, 1629–1631

[66] Pavlidis, P., Jensen, J. D., Stephan, W. and Stamatakis, A. (2012) A critical assessment of storytelling: gene ontology categories and the importance of validating genomic scans. Mol. Biol. Evol., 29, 3237–3248

[67] Schmid, K. J., Ramos-Onsins, S., Ringys-Beckstein, H., Weisshaar, B. and Mitchell-Olds, T. (2005) A multilocus sequence survey in Arabidopsis thaliana reveals a genome-wide departure from a neutral model of DNA sequence polymorphism. Genetics, 169, 1601–1615

[68] Borevitz, J. O., Hazen, S. P., Michael, T. P., Morris, G. P., Baxter, I. R., Hu, T. T., Chen, H., Werner, J. D., Nordborg, M., Salt, D. E., (2007) Genome-wide patterns of single-feature polymorphism in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA, 104, 12057–12062

[69] Stajich, J. E. and Hahn, M. W. (2005) Disentangling the effects of demography and selection in human history. Mol. Biol. Evol., 22, 63–73

[70] Wang, E. T., Kodama, G., Baldi, P. and Moyzis, R. K. (2006) Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc. Natl. Acad. Sci. USA, 103, 135–140

[71] Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., Watkins, P. B., Daly, A., Wrighton, S. A., Hall, S. D., (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet., 27, 383–391

[72] Lamason, R. L., Mohideen, M. A., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., (2005) SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science, 310, 1782–1786

[73] Lewontin, R. C. and Krakauer, J. (1973) Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics, 74, 175–195

[74] Beaumont, M. and Nichols, R. A. (1996) Evaluating loci for use in the genetic analysis of population structure. Proc. R. Soc. Lond. B Biol. Sci., 263, 1619–1626

[75] Beaumont, M. A. and Balding, D. J. (2004) Identifying adaptive genetic divergence among populations from genome scans. Mol. Ecol., 13, 969–980

[76] Nei, M. and Maruyama, T. (1975) Letters to the editors: Lewontin-Krakauer test for neutral genes. Genetics, 80, 395

[77] Charlesworth, B., Nordborg, M. and Charlesworth, D. (1997) The effects of local selection, balanced polymorphism and background selection on equilibrium patterns of genetic diversity in subdivided populations. Genet. Res., 70, 155–174

[78] Stephan, W., Xing, L., Kirby, D. A. and Braverman, J. M. (1998) A test of the background selection hypothesis based on nucleotide data from Drosophila ananassae. Proc. Natl. Acad. Sci. USA, 95, 5649–5654

[79] Weir, B. S., Cardon, L. R., Anderson, A. D., Nielsen, D. M. and Hill, W. G. (2005) Measures of human population structure show heterogeneity among genomic regions. Genome Res., 15, 1468–1476

[80] Di Rienzo, A., Donnelly, P., Toomajian, C., Sisk, B., Hill, A., Petzl-Erler, M. L., Haines, G. K. and Barch, D. H. (1998) Heterogeneity of microsatellite mutations within and between loci, and implications for human demographic histories. Genetics, 148, 1269–1284

[81] Harr, B., Zangerl, B., Brem, G. and Schlötterer, C. (1998) Conservation of locus-specific microsatellite variability across species: a comparison of two Drosophila sibling species, D. melanogaster and D. simulans. Mol. Biol. Evol., 15, 176–184

[82] Schlötterer, C. (2002) A microsatellite-based multilocus screen for the identification of local selective sweeps. Genetics, 160, 753–763

[83] Wiehe, T., Nolte, V., Zivkovic, D. and Schlötterer, C. (2007) Identification of selective sweeps using a dynamically adjusted number of linked microsatellites. Genetics, 175, 207–218

[84] Grossman, S. R., Shlyakhter, I., Karlsson, E. K., Byrne, E. H., Morales, S., Frieden, G., Hostetter, E., Angelino, E., Garber, M., Zuk, O., (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science, 327, 883–886

[85] Grossman, S. R., Andersen, K. G., Shlyakhter, I., Tabrizi, S., Winnicki, S., Yen, A., Park, D. J., Griesemer, D., Karlsson, E. K., Wong, S. H., (2013) Identifying recent adaptations in large-scale genomic data. Cell, 152, 703–713

[86] Lin, K., Li, H., Schlötterer, C. and Futschik, A. (2011) Distinguishing positive selection from neutral evolution: boosting the performance of summary statistics. Genetics, 187, 229–244

[87] Pybus, M., Luisi, P., Dall'Olio, G., Uzkudun, M., Laayouni, H., Bertranpetit, J. and Engelken, J. (2015) Hierarchical boosting: a machine-learning framework to detect and classify hard selective sweeps in human populations. Bioinformatics, 31, 3946–3952

[88] Markovtsova, L., Marjoram, P. and Tavaré, S. (2000) The effects of rate variation on ancestral inference in the coalescent. Genetics, 156, 1427–1436

[89] Aris-Brosou, S. and Excoffier, L. (1996) The impact of population expansion and mutation rate heterogeneity on DNA sequence polymorphism. Mol. Biol. Evol., 13, 494–504

[90] Huber, C. D., DeGiorgio, M., Hellmann, I. and Nielsen, R. (2016) Detecting recent selective sweeps while controlling for mutation rate and background selection. Mol. Ecol., 25, 142–156

[91] O’Reilly, P. F., Birney, E. and Balding, D. J. (2008) Confounding between recombination and selection, and the Ped/Pop method for detecting selection. Genome Res., 18, 1304–1313

[92] Reed, F. A. and Tishkoff, S. A. (2006) Positive selection can create false hotspots of recombination. Genetics, 172, 2011–2014

[93] Li, J., Li, H., Jakobsson, M., Li, S., Sjödin, P. and Lascoux, M. (2012) Joint analysis of demography and selection in population genetics: where do we stand and where could we go? Mol. Ecol., 21, 28–44

[94] Stephan, W. (2016) Signatures of positive selection: from selective sweeps at individual loci to subtle allele frequency changes in polygenic adaptation. Mol. Ecol., 25, 79–88

[95] Kelley, J. L. and Swanson, W. J. (2008) Positive selection in the human genome: from genome scans to biological significance. Annu. Rev. Genomics Hum. Genet., 9, 143–160

[96] Zhai, W., Nielsen, R. and Slatkin, M. (2009) An investigation of the statistical power of neutrality tests based on comparative and population genetic data. Mol. Biol. Evol., 26, 273–283

[97] Gutenkunst, R. N., Hernandez, R. D., Williamson, S. H. and Bustamante, C. D. (2009) Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data. PLoS Genet., 5, e1000695

[98] Excoffier, L., Dupanloup, I., Huerta-Sánchez, E., Sousa, V. C. and Foll, M. (2013) Robust demographic inference from genomic and SNP data. PLoS Genet., 9, e1003905

[99] Nielsen, R., Hubisz, M. J., Hellmann, I., Torgerson, D., Andrés, A. M., Albrechtsen, A., Gutenkunst, R., Adams, M. D., Cargill, M., Boyko, A., (2009) Darwinian and demographic forces affecting human protein coding genes. Genome Res., 19, 838–849

[100] Fijarczyk, A. and Babik, W. (2015) Detecting balancing selection in genomes: limits and prospects. Mol. Ecol., 24, 3529–3545

ACKNOWLEDGEMENTS

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13040800), the National Natural Science Foundation of China (No.91531306) and the 973 project (No.2012CB316505). We thank three anonymous reviewers for their insightful suggestions to improve the manuscript.

COMPLIANCE WITH ETHICS GUIDELINES

The authors Jinggong Xiang-Yu, Zongfeng Yang, Kun Tang and Haipeng Li declare that they have no conflict of interests.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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2016 Higher Education Press and Springer-Verlag Berlin Heidelberg