Detecting recent positive selection in the human genome from haplotype structure
Abstract
The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.
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Sabeti et al. and Voight et al. developed computationally efficient methods for detecting evidence of selection in whole genomes and applied them to the HapMap populations.
“Recently, Sabeti et al.99,100 and Voight et al.101 developed computationally efficient methods for detecting evidence of selection in whole genomes and have applied those methods to the HapMap populations.”
From Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. (2008) · cites this paper as [99]
Cites
The Structure of Haplotype Blocks in the Human Genome
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., Higgins, J., DeFelice, M., Lochner, A., Faggart, M., et al. (2002) · Science · doi:10.1126/science.1069424 · Cited by 5,863 · see citing works
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A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858 · see citing works
A second generation human haplotype map of over 3.1 million SNPs
The International HapMap Consortium (2007) · Nature · doi:10.1038/nature06258 · Cited by 4,438 · see citing works
Genome-wide detection and characterization of positive selection in human populations
The International HapMap Consortium, Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., et al. (2007) · Nature · doi:10.1038/nature06250 · Cited by 2,131 · see citing works
Self-citationAssociation of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans
Genovese, G., Friedman, D. J., Ross, M. D., Lecordier, L., Uzureau, P., Freedman, B. I., Bowden, D. W., Langefeld, C. D., Oleksyk, T. K., Uscinski Knob, A. L., et al. (2010) · Science · doi:10.1126/science.1193032 · Cited by 2,028 · see citing works
Linkage disequilibrium--understanding the evolutionary past and mapping the medical future.
Slatkin, M. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2361 · Cited by 1,614 · see citing works
Convergent adaptation of human lactase persistence in Africa and Europe
Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., Powell, K., Mortensen, H. M., Hirbo, J. B., Osman, M., et al. (2007) · Nature Genetics · doi:10.1038/ng1946 · Cited by 1,615 · see citing works
Approximate Bayesian Computation (ABC) in practice
Csilléry, K., Blum, M. G. B., Gaggiotti, O. E., & François, O. (2010) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2010.04.001 · Cited by 1,302 · see citing works
Positive Natural Selection in the Human Lineage
Sabeti, P. C., Schaffner, S. F., Fry, B., Lohmueller, J., Varilly, P., Shamovsky, O., Palma, A., Mikkelsen, T. S., Altshuler, D., & Lander, E. S. (2006) · Science · doi:10.1126/science.1124309 · Cited by 1,157 · see citing works
Self-citationSNPs in ecology, evolution and conservation
Morin, P. A., Luikart, G., Wayne, R. K., & the SNP workshop group (2004) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2004.01.009 · Cited by 1,080 · see citing works
Initial impact of the sequencing of the human genome
Lander, E. S. (2011) · Nature · doi:10.1038/nature09792 · Cited by 1,044 · see citing works
Self-citationA HapMap harvest of insights into the genetics of common disease
Manolio, T. A., Brooks, L. D., & Collins, F. S. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34772 · Cited by 889 · see citing works
Signals of recent positive selection in a worldwide sample of human populations
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) · Genome Research · doi:10.1101/gr.087577.108 · Cited by 717 · see citing works
Genetic determinants of hair, eye and skin pigmentation in Europeans
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.13 · Cited by 750 · see citing works
Haplotype blocks and linkage disequilibrium in the human genome
Wall, J. D., & Pritchard, J. K. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1123 · Cited by 642 · see citing works
Calibrating a coalescent simulation of human genome sequence variation
Schaffner, S. F., Foo, C., Gabriel, S., Reich, D., Daly, M. J., & Altshuler, D. (2005) · Genome Research · doi:10.1101/gr.3709305 · Cited by 616 · see citing works
Self-citationFumagalli, M., Sironi, M., Pozzoli, U., Ferrer-Admettla, A., Pattini, L., & Nielsen, R. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002355 · Cited by 600 · see citing works
Natural selection has driven population differentiation in modern humans
Barreiro, L. B., Laval, G., Quach, H., Patin, E., & Quintana-Murci, L. (2008) · Nature Genetics · doi:10.1038/ng.78 · Cited by 605 · see citing works
Localizing Recent Adaptive Evolution in the Human Genome.
Williamson, S. H., Hubisz, M. J., Clark, A. G., Payseur, B. A., Bustamante, C. D., & Nielsen, R. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030090 · Cited by 507 · see citing works
Gazal, S., Finucane, H. K., Furlotte, N. A., Loh, P.-R., Palamara, P. F., Liu, X., Schoech, A., Bulik-Sullivan, B., Neale, B. M., Gusev, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3954 · Cited by 525 · see citing works
Evidence for archaic adaptive introgression in humans
Racimo, F., Sankararaman, S., Nielsen, R., & Huerta-Sánchez, E. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3936 · Cited by 521 · see citing works
Gautier, M., & Vitalis, R. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts115 · Cited by 528 · see citing works
A new approach for using genome scans to detect recent positive selection in the human genome
Tang, K., Thornton, K. R., & Stoneking, M. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050171 · Cited by 489 · see citing works
The role of geography in human adaptation
Coop, G., Pickrell, J. K., Novembre, J., Kudaravalli, S., Li, J., Absher, D., Myers, R. M., Cavalli-Sforza, L. L., Feldman, M. W., & Pritchard, J. K. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000500 · Cited by 412 · see citing works
Genome-wide scans for footprints of natural selection
Oleksyk, T. K., Smith, M. W., & O'Brien, S. J. (2010) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2009.0219 · Cited by 340 · see citing works
Genomic regions exhibiting positive selection identified from dense genotype data
Carlson, C. S., Thomas, D. J., Eberle, M. A., Swanson, J. E., Livingston, R. J., Rieder, M. J., & Nickerson, D. A. (2005) · Genome Research · doi:10.1101/gr.4326505 · Cited by 298 · see citing works
Dannemann, M., Andrés, A. M., & Kelso, J. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.11.015 · Cited by 249 · see citing works
Population genetic study of the brain-derived neurotrophic factor (BDNF) gene
Petryshen, T. L., Sabeti, P. C., Aldinger, K. A., Fry, B., Fan, J. B., Schaffner, S. F., Waggoner, S. G., Tahl, A. R., & Sklar, P. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.24 · Cited by 267 · see citing works
Self-citationGene Losses during Human Origins
Wang, X., Grus, W. E., & Zhang, J. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040052 · Cited by 246 · see citing works
Fujimoto, A., Kimura, R., Ohashi, J., Omi, K., Yuliwulandari, R., Batubara, L., Mustofa, M. S., Samakkarn, U., Settheetham-Ishida, W., Ishida, T., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddm355 · Cited by 231 · see citing works
Lao, O., de Gruijter, J. M., van Duijn, K., Navarro, A., & Kayser, M. (2007) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2006.00341.x · Cited by 231 · see citing works
Classic Selective Sweeps Revealed by Massive Sequencing in Cattle
Qanbari, S., Pausch, H., Jansen, S., Somel, M., Strom, T. M., Fries, R., Nielsen, R., & Simianer, H. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004148 · Cited by 233 · see citing works
Amini, S., Pushkarev, D., Christiansen, L., Kostem, E., Royce, T., Turk, C., Pignatelli, N., Adey, A., Kitzman, J. O., Vijayan, K., et al. (2014) · Nature Genetics · doi:10.1038/ng.3119 · Cited by 189 · see citing works
Zhernakova, A., Elbers, C. C., Ferwerda, B., Romanos, J., Trynka, G., Dubois, P. C., de Kovel, C. G. F., Franke, L., Oosting, M., Barisani, D., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.05.004 · Cited by 195 · see citing works
Genetics of autoimmune diseases: Insights from population genetics
Ramos, P. S., Shedlock, A. M., & Langefeld, C. D. (2015) · Journal of Human Genetics · doi:10.1038/jhg.2015.94 · Cited by 173 · see citing works
Mondal, M., Casals, F., Xu, T., Dall'Olio, G. M., Pybus, M., Netea, M. G., Comas, D., Laayouni, H., Li, Q., Majumder, P. P., et al. (2016) · Nature Genetics · doi:10.1038/ng.3621 · Cited by 149 · see citing works
Worldwide distribution of NAT2 diversity: Implications for NAT2 evolutionary history
Sabbagh, A., Langaney, A., Darlu, P., Gérard, N., Krishnamoorthy, R., & Poloni, E. S. (2008) · BMC Genetics · doi:10.1186/1471-2156-9-21 · Cited by 147 · see citing works
Red fox genome assembly identifies genomic regions associated with tame and aggressive behaviours
Kukekova, A. V., Johnson, J. L., Xiang, X., Feng, S., Liu, S., Rando, H. M., Kharlamova, A. V., Herbeck, Y., Serdyukova, N. A., Xiong, Z., et al. (2018) · Nature Ecology & Evolution · doi:10.1038/s41559-018-0611-6 · Cited by 145 · see citing works
Sams, A. J., Dumaine, A., Nédélec, Y., Yotova, V., Alfieri, C., Tanner, J. E., Messer, P. W., & Barreiro, L. B. (2016) · Genome Biology · doi:10.1186/s13059-016-1098-6 · Cited by 140 · see citing works
Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection
Ohashi, J., Naka, I., Patarapotikul, J., Hananantachai, H., Brittenham, G., Looareesuwan, S., Clark, A. G., & Tokunaga, K. (2004) · The American Journal of Human Genetics · doi:10.1086/421330 · Cited by 137 · see citing works
Identifying genes underlying skin pigmentation differences among human populations
Myles, S., Somel, M., Tang, K., Kelso, J., & Stoneking, M. (2006) · Human Genetics · doi:10.1007/s00439-006-0256-4 · Cited by 132 · see citing works
Genome-Wide Scan for Selection Signatures in Six Cattle Breeds in South Africa
Makina, S. O., Muchadeyi, F. C., van Marle-Köster, E., Taylor, J. F., Makgahlela, M. L., & Maiwashe, A. (2015) · Genetics Selection Evolution · doi:10.1186/s12711-015-0173-x · Cited by 125 · see citing works
Untangling Oceanic settlement: the edge of the knowable
Hurles, M. E., Matisoo-Smith, E., Gray, R. D., & Penny, D. (2003) · Trends in Ecology & Evolution · doi:10.1016/s0169-5347(03)00245-3 · Cited by 118 · see citing works
A scan for signatures of positive selection in candidate loci for skin pigmentation in humans
Izagirre, N., García, I., Junquera, C., de la Rúa, C., & Alonso, S. (2006) · Molecular Biology and Evolution · doi:10.1093/molbev/msl030 · Cited by 119 · see citing works
Ancestral components of admixed genomes in a Mexican cohort
Johnson, N. A., Coram, M. A., Shriver, M. D., Romieu, I., Barsh, G. S., London, S. J., & Tang, H. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002410 · Cited by 114 · see citing works
Detection of selective sweeps in structured populations: a comparison of recent methods
Vatsiou, A. I., Bazin, E., & Gaggiotti, O. E. (2016) · Molecular Ecology · doi:10.1111/mec.13360 · Cited by 111 · see citing works
Novel genetic loci affecting facial shape variation in humans
Xiong, Z., Dankova, G., Howe, L. J., Lee, M. K., Hysi, P. G., de Jong, M. A., Zhu, G., Adhikari, K., Li, D., Li, Y., et al. (2019) · eLife · doi:10.7554/elife.49898 · Cited by 92 · see citing works
Testing for ancient selection using cross-population allele frequency differentiation
Racimo, F. (2016) · Genetics · doi:10.1534/genetics.115.178095 · Cited by 96 · see citing works
Saravanan, K. A., Panigrahi, M., Kumar, H., Parida, S., Bhushan, B., Gaur, G. K., Dutt, T., Mishra, B. P., & Singh, R. K. (2021) · Genomics · doi:10.1016/j.ygeno.2021.02.009 · Cited by 98 · see citing works
Identifying the favored mutation in a positive selective sweep.
Akbari, A., Vitti, J. J., Iranmehr, A., Bakhtiari, M., Sabeti, P. C., Mirarab, S., & Bafna, V. (2018) · Nature Methods · doi:10.1038/nmeth.4606 · Cited by 95 · see citing works
Self-citationEvidence for recent positive selection at the human AIM1 locus in a European population
Soejima, M., Tachida, H., Ishida, T., Sano, A., & Koda, Y. (2006) · Molecular Biology and Evolution · doi:10.1093/molbev/msj018 · Cited by 84 · see citing works
Understanding the accuracy of statistical haplotype inference with sequence data of known phase
Andrés, A. M., Clark, A. G., Shimmin, L., Boerwinkle, E., Sing, C. F., & Hixson, J. E. (2007) · Genetic Epidemiology · doi:10.1002/gepi.20185 · Cited by 68 · see citing works
Kiezun, A., Pulit, S. L., Francioli, L. C., van Dijk, F., Swertz, M., Boomsma, D. I., van Duijn, C. M., Slagboom, P. E., van Ommen, G. J. B., Wijmenga, C., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003301 · Cited by 72 · see citing works
Nezer, C., Collette, C., Moreau, L., Brouwers, B., Kim, J.-J., Giuffra, E., Buys, N., Andersson, L., & Georges, M. (2003) · Genetics · doi:10.1093/genetics/165.1.277 · Cited by 69 · see citing works
Understanding the evolution of human pigmentation: recent contributions from population genetics
Rees, J. L., & Harding, R. M. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2011.358 · Cited by 50 · see citing works
Mohajeri, K., Cantsilieris, S., Huddleston, J., Nelson, B. J., Coe, B. P., Campbell, C. D., Baker, C., Harshman, L., Munson, K. M., Kronenberg, Z. N., et al. (2016) · Genome Research · doi:10.1101/gr.211284.116 · Cited by 42 · see citing works
Bomba, L., Nicolazzi, E. L., Milanesi, M., Negrini, R., Mancini, G., Biscarini, F., Stella, A., Valentini, A., & Ajmone-Marsan, P. (2015) · Genetics Selection Evolution · doi:10.1186/s12711-015-0113-9 · Cited by 42 · see citing works
Mekonnen, Y. A., Gültas, M., Effa, K., Hanotte, O., & Schmitt, A. O. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01095 · Cited by 37 · see citing works
PopHuman: the human population genomics browser
Casillas, S., Mulet, R., Villegas-Mirón, P., Hervas, S., Sanz, E., Velasco, D., Bertranpetit, J., Laayouni, H., & Barbadilla, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx943 · Cited by 29 · see citing works
A test for ancient selective sweeps and an application to candidate sites in modern humans
Racimo, F., Kuhlwilm, M., & Slatkin, M. (2014) · Molecular Biology and Evolution · doi:10.1093/molbev/msu255 · Cited by 30 · see citing works
Zhang, C., Li, J., Tian, L., Lu, D., Yuan, K., Yuan, Y., & Xu, S. (2015) · Scientific Reports · doi:10.1038/srep09658 · Cited by 27 · see citing works
Seo, D., Lee, D. H., Jin, S., Won, J. I., Lim, D., Park, M., Kim, T. H., Lee, H. K., Kim, S., Choi, I., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-09425-0 · Cited by 25 · see citing works
Non-random mate choice in humans: Insights from a genome scan
LAURENT, R., TOUPANCE, B., & CHAIX, R. (2012) · Molecular Ecology · doi:10.1111/j.1365-294x.2011.05376.x · Cited by 21 · see citing works
Beissinger, T. M., Gholami, M., Erbe, M., Weigend, S., Weigend, A., de Leon, N., Gianola, D., & Simianer, H. (2016) · Heredity · doi:10.1038/hdy.2015.81 · Cited by 14 · see citing works
Yao, Y., Yang, J., Xie, Y., Liao, H., Yang, B., Xu, Q., & Rao, S. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbz048 · Cited by 10 · see citing works
- Authors
- 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., Ackerman, H. C., Campbell, S. J., Altshuler, D., Cooper, R., Kwiatkowski, D., Ward, R., & Lander, E. S.
- Affiliations
- Massachusetts Institute of Technology (US)
- Centre for Human Genetics (GB)
- Harvard University (US)
- Loyola University Medical Center (US)
- University of Oxford (GB)
- Corresponding author
- Lander, Eric S.
- ORCID
- Venue
- Nature
- Published
- 2002-10
- Volume
- 419
- Issue
- 6909
- Pages
- 832-837
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2055543630
- Cited by
- 2,106
- References
- 1
- Citations by year
- 2026: 44 · 2025: 73 · 2024: 109 · 2023: 82 · 2022: 83 · 2021: 122 · 2020: 101 · 2019: 70 · 2018: 83 · 2017: 95 · 2016: 106 · 2015: 117 · 2014: 98 · 2013: 94 · 2012: 84
- FWCI
- 32.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- extended haplotype homozygosity, glucose-6-phosphate dehydrogenase, CD40 ligand, malaria resistance, human population genetics, selection detection
- MeSH terms
- Africa, Alleles, Animals, Computer Simulation, Gene Pool, Glucosephosphate Dehydrogenase, Haplotypes, Homozygote, Humans, Malaria, Male, Mutation, Plasmodium falciparum, Selection, Genetic, Time Factors, Genetic Variation, Genome, Human, Evolution, Molecular, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, CD40 Ligand
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