How well do we understand the basis of classic selective sweeps in humans?

Classic selective sweeps occur when positive selection increases a variant's frequency from low to high in a population, and underlie some long‐studied human characteristics such as variation in skin, hair or eye colour. In such well‐studied ‘gold standard’ examples, a known variant has been associated with a plausible phenotype and underlying selective force. Signatures of classic sweeps have more recently been detected in population‐genetic data independently of any prior information about the corresponding phenotype or selective force, and usually without suggesting any insights into these. Motivated by the need to understand such candidates, we first review the gold standards and show that our understanding of them is often incomplete or unconvincing; only two of the examples we consider are compellingly explained. We assess approaches for large‐scale association of classic sweep candidate variants to phenotypes and selective forces, test these on the gold standards, and discuss the standards of evidence needed to adequately understand a selective sweep.

[1]  George Q. Daley,et al.  Induced pluripotent stem cells in disease modelling and drug discovery , 2019, Nature Reviews Genetics.

[2]  D. Rujescu,et al.  A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia , 2019, Molecular Psychiatry.

[3]  Helen E. Parkinson,et al.  The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 , 2018, Nucleic Acids Res..

[4]  K. Rawlik,et al.  Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability , 2018, Nature Communications.

[5]  N. Kamatani,et al.  Genome-wide association study in Japanese females identifies fifteen novel skin-related trait associations , 2018, Scientific Reports.

[6]  Asan,et al.  Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations , 2018, Molecular biology and evolution.

[7]  M. Dabert,et al.  Analysis of LCT-13910 genotypes and bone mineral density in ancient skeletal materials , 2018, PloS one.

[8]  D. O’Rourke,et al.  Environmental selection during the last ice age on the mother-to-infant transmission of vitamin D and fatty acids through breast milk , 2018, Proceedings of the National Academy of Sciences.

[9]  S. Rasmussen,et al.  Physiological and Genetic Adaptations to Diving in Sea Nomads , 2018, Cell.

[10]  M. P. Concas,et al.  Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability , 2018, Nature Genetics.

[11]  Takafumi Hara,et al.  The Role of the Slc39a Family of Zinc Transporters in Zinc Homeostasis in Skin , 2018, Nutrients.

[12]  Ivor Karavanić,et al.  The Genomic History of Southeastern Europe , 2017, Nature.

[13]  C. Tyler-Smith,et al.  FineMAV: prioritizing candidate genetic variants driving local adaptations in human populations , 2018, Genome Biology.

[14]  A. Auton,et al.  Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment , 2017, American journal of human genetics.

[15]  Jessica C. Thompson,et al.  Reconstructing Prehistoric African Population Structure , 2017, Cell.

[16]  G. Perry,et al.  Harnessing ancient genomes to study the history of human adaptation , 2017, Nature Reviews Genetics.

[17]  P. Visscher,et al.  10 Years of GWAS Discovery: Biology, Function, and Translation. , 2017, American journal of human genetics.

[18]  Pavlos Pavlidis,et al.  A survey of methods and tools to detect recent and strong positive selection , 2017, Journal of Biological Research-Thessaloniki.

[19]  L. Hood,et al.  Evolutionary history of Tibetans inferred from whole-genome sequencing , 2017, PLoS genetics.

[20]  Mattias Jakobsson,et al.  Tracing the peopling of the world through genomics , 2017, Nature.

[21]  C. Giuliani,et al.  Positive selection of lactase persistence among people of Southern Arabia. , 2016, American journal of physical anthropology.

[22]  Pardis C Sabeti,et al.  Genome-wide scans reveal variants at EDAR predominantly affecting hair straightness in Han Chinese and Uyghur populations , 2016, Human Genetics.

[23]  Fred H. Gage,et al.  Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility , 2016, Nature.

[24]  Rolando González-José,et al.  A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation , 2016, Nature Communications.

[25]  Joseph K. Pickrell,et al.  Detection and interpretation of shared genetic influences on 42 human traits , 2015, Nature Genetics.

[26]  Omar E. Cornejo,et al.  Population genetic analysis of the DARC locus (Duffy) reveals adaptation from standing variation associated with malaria resistance in humans , 2016, bioRxiv.

[27]  D. Reich,et al.  The genetic history of Ice Age Europe , 2016, Nature.

[28]  D. Balding,et al.  A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features , 2016, Nature Communications.

[29]  Asan,et al.  Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas , 2016, Human Genetics.

[30]  C. Richards,et al.  Evidence for an Association Between Infant Mortality and Homozygosity For the Arctic Variant of Carnitine Palmitoyltransferase 1A , 2015, Genetics in Medicine.

[31]  Harry Hemingway,et al.  Health and population effects of rare gene knockouts in adult humans with related parents , 2015, Science.

[32]  Giovanni Marco Dall'Olio,et al.  Hierarchical boosting: a machine-learning framework to detect and classify hard selective sweeps in human populations , 2015, Bioinform..

[33]  Paul M. Matthews,et al.  The UK Biobank. , 2015, Brain : a journal of neurology.

[34]  D. Reich,et al.  Genome-wide patterns of selection in 230 ancient Eurasians , 2015, Nature.

[35]  Anders Eriksson,et al.  Upper Palaeolithic genomes reveal deep roots of modern Eurasians , 2015, Nature Communications.

[36]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[37]  David Balding,et al.  A genome-wide association study identifies multiple loci for variation in human ear morphology , 2015, Nature Communications.

[38]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[39]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[40]  A. Di Rienzo,et al.  Adaptations to local environments in modern human populations. , 2014, Current opinion in genetics & development.

[41]  W. Enard Mouse models of human evolution. , 2014, Current opinion in genetics & development.

[42]  Sreeurpa Ray Human Evolutionary Genetics , 2014, The Yale Journal of Biology and Medicine.

[43]  R. Mägi,et al.  A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. , 2014, American journal of human genetics.

[44]  M. Kayser,et al.  Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene. , 2014, Human molecular genetics.

[45]  Heng Li,et al.  Genome sequence of a 45,000-year-old modern human from western Siberia , 2014, Nature.

[46]  C. Tyler-Smith,et al.  Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences , 2014, Genome Biology.

[47]  Asan,et al.  Altitude adaptation in Tibet caused by introgression of Denisovan-like DNA , 2014, Nature.

[48]  C. Tyler-Smith,et al.  Genome-Wide Analysis of Cold Adaptation in Indigenous Siberian Populations , 2014, PloS one.

[49]  Joshua M. Akey,et al.  Resurrecting Surviving Neandertal Lineages from Modern Human Genomes , 2014, Science.

[50]  Mattias Jakobsson,et al.  The genome of a Late Pleistocene human from a Clovis burial site in western Montana , 2014, Nature.

[51]  C. Rooryck,et al.  SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. , 2014, The Journal of investigative dermatology.

[52]  David Comas,et al.  Extreme Population Differences in the Human Zinc Transporter ZIP4 (SLC39A4) Are Explained by Positive Selection in Sub-Saharan Africa , 2014, PLoS genetics.

[53]  D. Reich,et al.  The landscape of Neandertal ancestry in present-day humans , 2014, Nature.

[54]  E. Grice,et al.  Ethnic/Racial and Genetic Influences on Cerumen Odorant Profiles , 2014, Journal of Chemical Ecology.

[55]  B. Gessner,et al.  Association of a genetic variant of carnitine palmitoyltransferase 1A with infections in Alaska Native children. , 2013, The Journal of pediatrics.

[56]  Sharon R Grossman,et al.  Detecting natural selection in genomic data. , 2013, Annual review of genetics.

[57]  N. Bradman,et al.  Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep. , 2013, American journal of human genetics.

[58]  Damian Smedley,et al.  Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes , 2013, Cell.

[59]  Y. Kudva,et al.  Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy , 2013, Disease Models & Mechanisms.

[60]  Li Jin,et al.  Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant , 2013, Cell.

[61]  Eric S. Lander,et al.  Identifying Recent Adaptations in Large-Scale Genomic Data , 2013, Cell.

[62]  Mark D Shriver,et al.  The timing of pigmentation lightening in Europeans. , 2013, Molecular biology and evolution.

[63]  Albert Hofman,et al.  Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans , 2012, Human Genetics.

[64]  K. Ray,et al.  Molecular basis of albinism in India: evaluation of seven potential candidate genes and some new findings. , 2012, Gene.

[65]  L. Arbour,et al.  Causes and risk factors for infant mortality in Nunavut, Canada 1999–2011 , 2012, BMC Pediatrics.

[66]  H. Vallance,et al.  Carnitine Palmitoyltransferase I and Sudden Unexpected Infant Death in British Columbia First Nations , 2012, Pediatrics.

[67]  P. Hedrick Resistance to malaria in humans: the impact of strong, recent selection , 2012, Malaria Journal.

[68]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[69]  T. Hanihara,et al.  Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits , 2012, Journal of Human Genetics.

[70]  W. Stephan,et al.  A critical assessment of storytelling: gene ontology categories and the importance of validating genomic scans. , 2012, Molecular biology and evolution.

[71]  Joseph K. Pickrell,et al.  A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes , 2012, Science.

[72]  D. Allison,et al.  Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos[S] , 2012, Journal of Lipid Research.

[73]  H. Hoekstra,et al.  Molecular spandrels: tests of adaptation at the genetic level , 2011, Nature Reviews Genetics.

[74]  D. Matern,et al.  Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant. , 2011, Molecular genetics and metabolism.

[75]  Adam Powell,et al.  Evolution of lactase persistence: an example of human niche construction , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[76]  Ryan D. Hernandez,et al.  Classic Selective Sweeps Were Rare in Recent Human Evolution , 2011, Science.

[77]  F. Bamforth,et al.  Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut. , 2010, Molecular genetics and metabolism.

[78]  Christian Gieger,et al.  Genome-wide association analysis identifies three psoriasis susceptibility loci , 2010, Nature Genetics.

[79]  Asan,et al.  Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude , 2010, Science.

[80]  Brian T. Naughton,et al.  Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits , 2010, PLoS genetics.

[81]  N. Jablonski,et al.  Human skin pigmentation as an adaptation to UV radiation , 2010, Proceedings of the National Academy of Sciences.

[82]  Joseph K. Pickrell,et al.  The Genetics of Human Adaptation: Hard Sweeps, Soft Sweeps, and Polygenic Adaptation , 2010, Current Biology.

[83]  Or Zuk,et al.  A Composite of Multiple Signals Distinguishes Causal Variants in Regions of Positive Selection , 2010, Science.

[84]  Andreas Natsch,et al.  A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. , 2010, The Journal of investigative dermatology.

[85]  Stephen J. O'Brien,et al.  Genome-wide scans for footprints of natural selection , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[86]  C. Gieger,et al.  European lactase persistence genotype shows evidence of association with increase in body mass index , 2009, Human molecular genetics.

[87]  D. Conrad,et al.  Population Differentiation as an Indicator of Recent Positive Selection in Humans: An Empirical Evaluation , 2009, Genetics.

[88]  John Novembre,et al.  Spatial patterns of variation due to natural selection in humans , 2009, Nature Reviews Genetics.

[89]  Stephen L. Johnson,et al.  Basonuclin-2 Requirements for Zebrafish Adult Pigment Pattern Development and Female Fertility , 2009, PLoS genetics.

[90]  D. Headon,et al.  Enhanced Edar Signalling Has Pleiotropic Effects on Craniofacial and Cutaneous Glands , 2009, PloS one.

[91]  T. Hanihara,et al.  A common variation in EDAR is a genetic determinant of shovel-shaped incisors. , 2009, American journal of human genetics.

[92]  Adam Powell,et al.  The Origins of Lactase Persistence in Europe , 2009, PLoS Comput. Biol..

[93]  J. Girard,et al.  Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. , 2009, The Biochemical journal.

[94]  Joshua M Akey,et al.  Where do we go from here? Constructing genomic maps of positive selection in humans: , 2009 .

[95]  R. Sturm,et al.  Molecular genetics of human pigmentation diversity. , 2009, Human molecular genetics.

[96]  R. Wanders,et al.  The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations. , 2009, Molecular genetics and metabolism.

[97]  R. Hegele,et al.  patient-oriented and epidemiological research Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I , 2009 .

[98]  M. Dixon,et al.  Enhanced ectodysplasin‐A receptor (EDAR) signaling alters multiple fiber characteristics to produce the East Asian hair form , 2008, Human mutation.

[99]  T. Tsunoda,et al.  A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia , 2008, Human Genetics.

[100]  A. Norman,et al.  From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. , 2008, The American journal of clinical nutrition.

[101]  H. Konishi,et al.  Contribution of peroxisome-specific isoform of Lon protease in sorting PTS1 proteins to peroxisomes. , 2008, Journal of biochemistry.

[102]  Katsushi Tokunaga,et al.  A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness. , 2008, Human molecular genetics.

[103]  M. Feldman,et al.  Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation , 2008 .

[104]  David Comas,et al.  Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. , 2008, American journal of human genetics.

[105]  Mark G. Thomas,et al.  Lactose digestion and the evolutionary genetics of lactase persistence , 2008, Human Genetics.

[106]  D. Cox,et al.  A genomewide association study of skin pigmentation in a South Asian population. , 2007, American journal of human genetics.

[107]  A. Clark,et al.  Recent and ongoing selection in the human genome , 2007, Nature Reviews Genetics.

[108]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[109]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[110]  C. López-Otín,et al.  Expanding the complexity of the human degradome: polyserases and their tandem serine protease domains. , 2007, Frontiers in bioscience : a journal and virtual library.

[111]  N. Niikawa,et al.  A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland , 2007, Human Genetics.

[112]  Holly M. Mortensen,et al.  Convergent adaptation of human lactase persistence in Africa and Europe , 2007, Nature Genetics.

[113]  Mark G. Thomas,et al.  A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence? , 2006, Human Genetics.

[114]  A. Karsan,et al.  Notch and Minichromosome Maintenance (MCM) Proteins: Integration of Two Ancestral Pathways in Cell Cycle Control , 2006, Cell cycle.

[115]  Joshua M Akey,et al.  Genomic signatures of positive selection in humans and the limits of outlier approaches. , 2006, Genome research.

[116]  Shameek Biswas,et al.  Genomic insights into positive selection. , 2006, Trends in genetics : TIG.

[117]  Pardis C Sabeti,et al.  Positive Natural Selection in the Human Lineage , 2006, Science.

[118]  Pardis Sabeti,et al.  Spread of an inactive form of caspase-12 in humans is due to recent positive selection. , 2006, American journal of human genetics.

[119]  V. Quesada,et al.  Identification and characterization of human polyserase-3, a novel protein with tandem serine-protease domains in the same polypeptide chain , 2006, BMC Biochemistry.

[120]  Jane Loveland,et al.  Genomic anatomy of the Tyrp1 (brown) deletion complex. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[121]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[122]  L. Peltonen,et al.  Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. , 2006, American journal of human genetics.

[123]  Yusuke Nakamura,et al.  A SNP in the ABCC11 gene is the determinant of human earwax type , 2006, Nature Genetics.

[124]  Keith C. Cheng,et al.  SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans , 2005, Science.

[125]  R. Nielsen Molecular signatures of natural selection. , 2005, Annual review of genetics.

[126]  L. Seeb,et al.  Use of sequence data from rainbow trout and Atlantic salmon for SNP detection in Pacific salmon , 2005, Molecular ecology.

[127]  D. Kwiatkowski How malaria has affected the human genome and what human genetics can teach us about malaria. , 2005, American journal of human genetics.

[128]  Geoffrey B. Nilsen,et al.  Whole-Genome Patterns of Common DNA Variation in Three Human Populations , 2005, Science.

[129]  The International HapMap Consortium A haplotype map of the human genome , 2005 .

[130]  D. Bramble,et al.  Endurance running and the evolution of Homo , 2004, Nature.

[131]  G. Chaplin Geographic distribution of environmental factors influencing human skin coloration. , 2004, American journal of physical anthropology.

[132]  Pardis C Sabeti,et al.  Genetic signatures of strong recent positive selection at the lactase gene. , 2004, American journal of human genetics.

[133]  M. Holick,et al.  Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. , 2004, The American journal of clinical nutrition.

[134]  O. Oftedal The Mammary Gland and Its Origin During Synapsid Evolution , 2002, Journal of Mammary Gland Biology and Neoplasia.

[135]  L. Olds,et al.  Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. , 2003, Human molecular genetics.

[136]  Zemin Zhang,et al.  Identification of a Novel Death Domain-Containing Adaptor Molecule for Ectodysplasin-A Receptor that Is Mutated in crinkled Mice , 2002, Current Biology.

[137]  A. Di Rienzo,et al.  Complex signatures of natural selection at the Duffy blood group locus. , 2002, American journal of human genetics.

[138]  Leena Peltonen,et al.  Identification of a variant associated with adult-type hypolactasia , 2002, Nature Genetics.

[139]  M. Justice,et al.  Gene defect in ectodermal dysplasia implicates a death domain adapter in development , 2001, Nature.

[140]  I. Pastan,et al.  MRP8, A New Member of ABC Transporter Superfamily, Identified by EST Database Mining and Gene Prediction Program, Is Highly Expressed in Breast Cancer , 2001, Molecular medicine.

[141]  M. Bennett,et al.  Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. , 2001, Journal of lipid research.

[142]  N. Jablonski,et al.  The evolution of human skin coloration. , 2000, Journal of human evolution.

[143]  A. Pogo,et al.  The Duffy protein: a malarial and chemokine receptor. , 2000, Seminars in hematology.

[144]  S Iwamoto,et al.  Characterization of the Duffy gene promoter: evidence for tissue-specific abolishment of expression in Fy(a-b-) of black individuals. , 1996, Biochemical and biophysical research communications.

[145]  T. Omi,et al.  Identification of a novel exon and spliced form of Duffy mRNA that is the predominant transcript in both erythroid and postcapillary venule endothelium. , 1996, Blood.

[146]  P. Metcalf,et al.  Serum 25-hydroxyvitamin D3 is related to physical activity and ethnicity but not obesity in a multicultural workforce. , 1995, Australian and New Zealand journal of medicine.

[147]  C. Tournamille,et al.  Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy–negative individuals , 1995, Nature Genetics.

[148]  H. Naim,et al.  The polymorphic expression of lactase in adults is regulated at the messenger RNA level. , 1994, Gastroenterology.

[149]  P. V. D. Berghe,et al.  Skin color preference, sexual dimorphism and sexual selection: A case of gene culture co‐evolution?* , 1986 .

[150]  David R. Carrier,et al.  The Energetic Paradox of Human Running and Hominid Evolution [and Comments and Reply] , 1984, Current Anthropology.

[151]  P. Philippe,et al.  The Reproductive Role of the Human Breast [and Comments and Reply] , 1983, Current Anthropology.

[152]  P. Anderson The reproductive role of the human breast. , 1983 .

[153]  L. Miller,et al.  The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. , 1976, The New England journal of medicine.

[154]  G. Cook,et al.  High intestinal lactase concentrations in adult Arbs in Saudi Arabia. , 1975, British medical journal.

[155]  J. M. Smith,et al.  The hitch-hiking effect of a favourable gene. , 1974, Genetical research.

[156]  G Flatz,et al.  Lactose nutrition and natural selection. , 1973, Lancet.