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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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
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
Swallow, D. M. (2003) Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet., 37, 197–219
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
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
Nielsen, R. (2009) Adaptionism-30 years after Gould and Lewontin. Evolution, 63, 2487–2490
Hurst, L. D. (2009) Fundamental concepts in genetics: genetics and the understanding of selection. Nat. Rev. Genet., 10, 83–93
Tajima, F. (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics, 123, 585–595
Fu, Y.-X. (1997) Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection. Genetics, 147, 915–925
Fay, J. C. and Wu, C.-I. (2000) Hitchhiking under positive Darwinian selection. Genetics, 155, 1405–1413
Smith, J. M. and Haigh, J. (1974) The hitch-hiking effect of a favourable gene. Genet. Res., 23, 23–35
Galtier, N., Depaulis, F. and Barton, N. H. (2000) Detecting bottlenecks and selective sweeps from DNA sequence polymorphism. Genetics, 155, 981–987
Kim, Y. and Stephan, W. (2002) Detecting a local signature of genetic hitchhiking along a recombining chromosome. Genetics, 160, 765–777
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
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
Fu, Y.-X. and Li, W.-H. (1993) Statistical tests of neutrality of mutations. Genetics, 133, 693–709
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., et al. (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature, 419, 832–837
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
MacCallum, C. and Hill, E. (2006) Being positive about selection. PLoS Biol., 4, e87
Bamshad, M. and Wooding, S. P. (2003) Signatures of natural selection in the human genome. Nat. Rev. Genet., 4, 99–111
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
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
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
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
Vitti, J. J., Grossman, S. R. and Sabeti, P. C. (2013) Detecting natural selection in genomic data. Annu. Rev. Genet., 47, 97–120
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
Pool, J. E., Hellmann, I., Jensen, J. D. and Nielsen, R. (2010) Population genetic inference from genomic sequence variation. Genome Res., 20, 291–300
Chen, H., Patterson, N. and Reich, D. (2010) Population differentiation as a test for selective sweeps. Genome Res., 20, 393–402
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
Mathieson, I., Lazaridis, I., Rohland, N., Mallick, S., Patterson, N., Roodenberg, S. A., Harney, E., Stewardson, K., Fernandes, D., Novak, M., et al. (2015) Genome-wide patterns of selection in 230 ancient Eurasians. Nature, 528, 499–503
Tajima, F. (1989) The effect of change in population size on DNA polymorphism. Genetics, 123, 597–601
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
Przeworski, M. (2002) The signature of positive selection at randomly chosen loci. Genetics, 160, 1179–1189
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
Hudson, R. R. (2002) Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics, 18, 337–338
Achaz, G. (2009) Frequency spectrum neutrality tests: one for all and all for one. Genetics, 183, 249–258
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
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
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
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
Thornton, K. R. and Jensen, J. D. (2007) Controlling the falsepositive rate in multilocus genome scans for selection. Genetics, 175, 737–750
Li, H. and Stephan, W. (2006) Inferring the demographic history and rate of adaptive substitution in Drosophila. PLoS Genet., 2, e166
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
Stephan, W., Song, Y. S. and Langley, C. H. (2006) The hitchhiking effect on linkage disequilibrium between linked neutral loci. Genetics, 172, 2647–2663
McVean, G. (2007) The structure of linkage disequilibrium around a selective sweep. Genetics, 175, 1395–1406
Kim, Y. and Nielsen, R. (2004) Linkage disequilibrium as a signature of selective sweeps. Genetics, 167, 1513–1524
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
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
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., et al. (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res., 19, 826–837
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
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
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
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
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
Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., et al., (2007) Genome-wide detection and characterization of positive selection in human populations. Nature, 449, 913–918
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., et al. (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science, 319, 1100–1104
Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H. Y., et al. (2010) A draft sequence of the Neandertal genome. Science, 328, 710–722
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., et al. (2010) Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature, 468, 1053–1060
Akey, J. M. (2009) Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res., 19, 711–722
Fu, W. Q. and Akey, J. M. (2013) Selection and adaptation in the human genome. Annu. Rev. Genom. Hum. G., 14, 467–489
Huerta-Sánchez, E., Jin, X., Asan, X., Bianba, Z., Peter, B. M., Vinckenbosch, N., Liang, Y., Yi, X., He, M., Somel M., et al. (2014) Altitude adaptation in Tibetans caused by introgression of Denisovanlike DNA. Nature, 512, 194–197
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
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
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
Emerson, J. J., Cardoso-Moreira, M., Borevitz, J. O. and Long, M. (2008) Natural selection shapes genome-wide patterns of copynumber polymorphism in Drosophila melanogaster. Science, 320, 1629–1631
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
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
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., et al. (2007) Genome-wide patterns of single-feature polymorphism in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA, 104, 12057–12062
Stajich, J. E. and Hahn, M. W. (2005) Disentangling the effects of demography and selection in human history. Mol. Biol. Evol., 22, 63–73
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
Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., Watkins, P. B., Daly, A., Wrighton, S. A., Hall, S. D., et al. (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet., 27, 383–391
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., et al. (2005) SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science, 310, 1782–1786
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
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
Beaumont, M. A. and Balding, D. J. (2004) Identifying adaptive genetic divergence among populations from genome scans. Mol. Ecol., 13, 969–980
Nei, M. and Maruyama, T. (1975) Letters to the editors: Lewontin- Krakauer test for neutral genes. Genetics, 80, 395
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
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
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
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
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
Schlötterer, C. (2002) A microsatellite-based multilocus screen for the identification of local selective sweeps. Genetics, 160, 753–763
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
Grossman, S. R., Shlyakhter, I., Karlsson, E. K., Byrne, E. H., Morales, S., Frieden, G., Hostetter, E., Angelino, E., Garber, M., Zuk, O., et al. (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science, 327, 883–886
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., et al. (2013) Identifying recent adaptations in large-scale genomic data. Cell, 152, 703–713
Lin, K., Li, H., Schlö tterer, C. and Futschik, A. (2011) Distinguishing positive selection from neutral evolution: boosting the performance of summary statistics. Genetics, 187, 229–244
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.
Markovtsova, L., Marjoram, P. and Tavaré, S. (2000) The effects of rate variation on ancestral inference in the coalescent. Genetics, 156, 1427–1436
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
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
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
Reed, F. A. and Tishkoff, S. A. (2006) Positive selection can create false hotspots of recombination. Genetics, 172, 2011–2014
Li, J., Li, H., Jakobsson, M., Li, S., Sjö din, 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
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
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
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
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
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
Nielsen, R., Hubisz, M. J., Hellmann, I., Torgerson, D., Andrés, A. M., Albrechtsen, A., Gutenkunst, R., Adams, M. D., Cargill, M., Boyko, A., et al. (2009) Darwinian and demographic forces affecting human protein coding genes. Genome Res., 19, 838–849
Fijarczyk, A. and Babik, W. (2015) Detecting balancing selection in genomes: limits and prospects. Mol. Ecol., 24, 3529–3545
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is dedicated to the Special Collection of Recent Advances in Next-Generation Bioinformatics (Ed. Xuegong Zhang).
Rights and permissions
About this article
Cite this article
Xiang-Yu, J., Yang, Z., Tang, K. et al. Revisiting the false positive rate in detecting recent positive selection. Quant Biol 4, 207–216 (2016). https://doi.org/10.1007/s40484-016-0077-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40484-016-0077-y