Background

We are one of the great apes, but differ from orangutans, gorillas, chimpanzees and bonobos in our enormous numbers, distribution all over the world, yet surprisingly low genetic diversity and even distribution of this diversity among populations. All of these human-specific characteristics are explained in a simple way: recent expansion of modern humans from a small population in Africa within the last 100,000 years. All human populations therefore share most of their genetic variants and susceptibilities because these were present in the ancestral population. But populations differ slightly because of a combination of random genetic drift and natural selection affecting them differently during the expansions into new environments over the last 50,000 years.

One view of the expansion of anatomically and behaviourally modern humans out of Africa around 50 thousand years ago (KYA). Times and routes are very uncertain. [The Wellcome Trust Sanger Institute]

With the availability of genomic sequences from humans and apes and accumulation of extensive information about the variation within humans, we can now begin to reconstruct these expansions and search directly for the functional genetic variants that have contributed to the characteristics of modern humans. Most DNA variants are evolutionarily neutral (they have no effect on fitness) but provide information on past population sizes and migrations, and we continue to investigate these, particularly using the Y chromosome and mitochondrial DNA. A few variants increase fitness and are of particular interest. We can recognise these from the patterns of variation in the surrounding DNA, or by carrying out functional studies. We would like to catalogue the positively selected regions in the human genome and understand the basis for their selection.

Disease-associated alleles are generally expected to decrease fitness, so why are they present at all and not eliminated by negative selection? New disease variants arise continually by mutation, and while some are eliminated rapidly, those that confer only a small decrease in fitness may persist in the population for many generations. Indeed, if the disease develops only after an individual has reproduced, the causal variant may be, in evolutionary terms, neutral. Occasionally, a disease-associated allele may actually confer a fitness advantage in certain circumstances and be positively selected, as the sickle allele has been in malaria-endemic regions. An evolutionary perspective can thus help us to understand our disease susceptibilities more fully.

By exploring the genetic signals left in our gene pool in these ways we can reconstruct human evolutionary history and advance our understanding of what makes us human, what makes populations differ from one another, and why we suffer from some diseases.

Selected publications

• Human evolutionary genetics: origins, peoples, and disease (2004) Jobling MA, Hurles ME and Tyler-Smith C: [Book] Garland Science, Abingdon and New York
• Genomic archaeology
• Handbook of Human Molecular Evolution

Research

Current projects

• 1000 Genomes Project
• The Structural Variation Consortium
• The gorilla genome
• The pig X/Y chromosomes
• mtDNA and the Y chromosome
• Positive selection in humans

Previous projects

• Gene number variation and human evolution
• Population differentiation and human evolution
• Y-chromosomal variation and human evolution

Publications

Selected team publications 2009

• Genetic variation in South Asia: assessing the influences of geography, language and ethnicity for understanding history and disease risk.

  Ayub Q and Tyler-Smith C

  Briefings in functional genomics & proteomics 2009;8;5;395-404

  PUBMED: 19535507; DOI: 10.1093/bfgp/elp015

• Genomic complexity of the Y-STR DYS19: inversions, deletions and founder lineages carrying duplications.

  Balaresque P, Parkin EJ, Roewer L, Carvalho-Silva DR, Mitchell RJ, van Oorschot RA, Henke J, Stoneking M, Nasidze I, Wetton J, de Knijff P, Tyler-Smith C and Jobling MA

  International journal of legal medicine 2009;123;1;15-23

  PUBMED: 18553096; DOI: 10.1007/s00414-008-0253-3; PMC: 2680205

• Origins and functional impact of copy number variation in the human genome.

  Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, The Wellcome Trust Case Control Consortium, Tyler-Smith C, Carter NP, Lee C, Scherer SW and Hurles ME

  Nature 2009

  PUBMED: 19812545; DOI: 10.1038/nature08516

• A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia.

  Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards MB, Price AL, Patterson N, Reich D, Singh L, Tyler-Smith C and Thangaraj K

  Nature genetics 2009;41;2;187-91

  PUBMED: 19151713; DOI: 10.1038/ng.309; PMC: 2697598

• Traces of sub-Saharan and Middle Eastern lineages in Indian Muslim populations.

  Eaaswarkhanth M, Haque I, Ravesh Z, Romero IG, Meganathan PR, Dubey B, Khan FA, Chaubey G, Kivisild T, Tyler-Smith C, Singh L and Thangaraj K

  European journal of human genetics : EJHG 2010;18;3;354-63

  PUBMED: 19809480; DOI: 10.1038/ejhg.2009.168

• Geographical structure of the Y-chromosomal genetic landscape of the Levant: a coastal-inland contrast.

  El-Sibai M, Platt DE, Haber M, Xue Y, Youhanna SC, Wells RS, Izaabel H, Sanyoura MF, Harmanani H, Bonab MA, Behbehani J, Hashwa F, Tyler-Smith C, Zalloua PA and Genographic Consortium

  Annals of human genetics 2009;73;Pt 6;568-81

  PUBMED: 19686289; DOI: 10.1111/j.1469-1809.2009.00538.x

• TSPY1 copy number variation influences spermatogenesis and shows differences among Y lineages.

  Giachini C, Nuti F, Turner DJ, Laface I, Xue Y, Daguin F, Forti G, Tyler-Smith C and Krausz C

  The Journal of clinical endocrinology and metabolism 2009;94;10;4016-22

  PUBMED: 19773397; DOI: 10.1210/jc.2009-1029

• Geographical affinities of the HapMap samples.

  He M, Gitschier J, Zerjal T, de Knijff P, Tyler-Smith C and Xue Y

  PloS one 2009;4;3;e4684

  PUBMED: 19259268; DOI: 10.1371/journal.pone.0004684; PMC: 2649532

• The peopling of Korea revealed by analyses of mitochondrial DNA and Y-chromosomal markers.

  Jin HJ, Tyler-Smith C and Kim W

  PloS one 2009;4;1;e4210

  PUBMED: 19148289; DOI: 10.1371/journal.pone.0004210; PMC: 2615218

• Phenotypic variation within European carriers of the Y-chromosomal gr/gr deletion is independent of Y-chromosomal background.

  Krausz C, Giachini C, Xue Y, O'Bryan MK, Gromoll J, Rajpert-de Meyts E, Oliva R, Aknin-Seifer I, Erdei E, Jorgensen N, Simoni M, Ballescà JL, Levy R, Balercia G, Piomboni P, Nieschlag E, Forti G, McLachlan R and Tyler-Smith C

  Journal of medical genetics 2009;46;1;21-31

  PUBMED: 18782837; DOI: 10.1136/jmg.2008.059915; PMC: 2698292

• HI: haplotype improver using paired-end short reads.

  Long Q, MacArthur D, Ning Z and Tyler-Smith C

  Bioinformatics (Oxford, England) 2009;25;18;2436-7

  PUBMED: 19570807; DOI: 10.1093/bioinformatics/btp412; PMC: 2735667

• Genetic structure of nomadic Bedouin from Kuwait.

  Mohammad T, Xue Y, Evison M and Tyler-Smith C

  Heredity 2009;103;5;425-33

  PUBMED: 19639002; DOI: 10.1038/hdy.2009.72

• A worldwide survey of human male demographic history based on Y-SNP and Y-STR data from the HGDP-CEPH populations.

  Shi W, Ayub Q, Vermeulen M, Shao RG, Zuniga S, van der Gaag K, de Knijff P, Kayser M, Xue Y and Tyler-Smith C

  Molecular biology and evolution 2010;27;2;385-93

  PUBMED: 19822636; DOI: 10.1093/molbev/msp243; PMC: 2806244

• A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

  Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M, Salo P, Voight BF, Burns P, Laskowski RA, Xue Y, Menzel S, Altshuler D, Bradley JR, Bumpstead S, Burnett MS, Devaney J, Döring A, Elosua R, Epstein SE, Erber W, Falchi M, Garner SF, Ghori MJ, Goodall AH, Gwilliam R, Hakonarson HH, Hall AS, Hammond N, Hengstenberg C, Illig T, König IR, Knouff CW, McPherson R, Melander O, Mooser V, Nauck M, Nieminen MS, O'Donnell CJ, Peltonen L, Potter SC, Prokisch H, Rader DJ, Rice CM, Roberts R, Salomaa V, Sambrook J, Schreiber S, Schunkert H, Schwartz SM, Serbanovic-Canic J, Sinisalo J, Siscovick DS, Stark K, Surakka I, Stephens J, Thompson JR, Völker U, Völzke H, Watkins NA, Wells GA, Wichmann HE, Van Heel DA, Tyler-Smith C, Thein SL, Kathiresan S, Perola M, Reilly MP, Stewart AF, Erdmann J, Samani NJ, Meisinger C, Greinacher A, Deloukas P, Ouwehand WH and Gieger C

  Nature genetics 2009;41;11;1182-90

  PUBMED: 19820697; DOI: 10.1038/ng.467

• A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.

  Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA and Stratton MR

  Nature genetics 2009;41;5;535-43

  PUBMED: 19377476; DOI: 10.1038/ng.367

• The will-o'-the-wisp of genetics--hunting for the azoospermia factor gene.

  Tyler-Smith C and Krausz C

  The New England journal of medicine 2009;360;9;925-7

  PUBMED: 19246366; DOI: 10.1056/NEJMe0900301; PMC: 2700876

• Improving global and regional resolution of male lineage differentiation by simple single-copy Y-chromosomal short tandem repeat polymorphisms.

  Vermeulen M, Wollstein A, van der Gaag K, Lao O, Xue Y, Wang Q, Roewer L, Knoblauch H, Tyler-Smith C, de Knijff P and Kayser M

  Forensic science international. Genetics 2009;3;4;205-13

  PUBMED: 19647704; DOI: 10.1016/j.fsigen.2009.01.009

• Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree.

  Xue Y, Wang Q, Long Q, Ng BL, Swerdlow H, Burton J, Skuce C, Taylor R, Abdellah Z, Zhao Y, Asan, MacArthur DG, Quail MA, Carter NP, Yang H and Tyler-Smith C

  Current biology : CB 2009;19;17;1453-7

  PUBMED: 19716302; DOI: 10.1016/j.cub.2009.07.032; PMC: 2748900

• Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation.

  Xue Y, Zhang X, Huang N, Daly A, Gillson CJ, Macarthur DG, Yngvadottir B, Nica AC, Woodwark C, Chen Y, Conrad DF, Ayub Q, Mehdi SQ, Li P and Tyler-Smith C

  Genetics 2009;183;3;1065-77

  PUBMED: 19737746; DOI: 10.1534/genetics.109.107722; PMC: 2778960

• A genome-wide survey of the prevalence and evolutionary forces acting on human nonsense SNPs.

  Yngvadottir B, Xue Y, Searle S, Hunt S, Delgado M, Morrison J, Whittaker P, Deloukas P and Tyler-Smith C

  American journal of human genetics 2009;84;2;224-34

  PUBMED: 19200524; DOI: 10.1016/j.ajhg.2009.01.008; PMC: 2668024

• The promise and reality of personal genomics.

  Yngvadottir B, Macarthur DG, Jin H and Tyler-Smith C

  Genome biology 2009;10;9;237

  PUBMED: 19723346; DOI: 10.1186/gb-2009-10-9-237; PMC: 2768970

Selected team publications 2008

• Dynamic nature of the proximal AZFc region of the human Y chromosome: multiple independent deletion and duplication events revealed by microsatellite analysis.

  Balaresque P, Bowden GR, Parkin EJ, Omran GA, Heyer E, Quintana-Murci L, Roewer L, Stoneking M, Nasidze I, Carvalho-Silva DR, Tyler-Smith C, de Knijff P and Jobling MA

  Human mutation 2008;29;10;1171-80

  PUBMED: 18470947; DOI: 10.1002/humu.20757; PMC: 2689608

• A novel 154-bp deletion in the human mitochondrial DNA control region in healthy individuals.

  Behar DM, Blue-Smith J, Soria-Hernanz DF, Tzur S, Hadid Y, Bormans C, Moen A, Tyler-Smith C, Quintana-Murci L, Wells RS and Genographic Consortium

  Human mutation 2008;29;12;1387-91

  PUBMED: 18629826; DOI: 10.1002/humu.20835; PMC: 2697596

• The dawn of human matrilineal diversity.

  Behar DM, Villems R, Soodyall H, Blue-Smith J, Pereira L, Metspalu E, Scozzari R, Makkan H, Tzur S, Comas D, Bertranpetit J, Quintana-Murci L, Tyler-Smith C, Wells RS, Rosset S and Genographic Consortium

  American journal of human genetics 2008;82;5;1130-40

  PUBMED: 18439549; DOI: 10.1016/j.ajhg.2008.04.002; PMC: 2427203

• The functional impact of structural variation in humans.

  Hurles ME, Dermitzakis ET and Tyler-Smith C

  Trends in genetics : TIG 2008;24;5;238-45

  PUBMED: 18378036; DOI: 10.1016/j.tig.2008.03.001

• Copy number variation and evolution in humans and chimpanzees.

  Perry GH, Yang F, Marques-Bonet T, Murphy C, Fitzgerald T, Lee AS, Hyland C, Stone AC, Hurles ME, Tyler-Smith C, Eichler EE, Carter NP, Lee C and Redon R

  Genome research 2008;18;11;1698-710

  PUBMED: 18775914; DOI: 10.1101/gr.082016.108; PMC: 2577862

• Maximum-likelihood estimation of site-specific mutation rates in human mitochondrial DNA from partial phylogenetic classification.

  Rosset S, Wells RS, Soria-Hernanz DF, Tyler-Smith C, Royyuru AK, Behar DM and Genographic Consortium

  Genetics 2008;180;3;1511-24

  PUBMED: 18791242; DOI: 10.1534/genetics.108.091116; PMC: 2581953

• Maternal footprints of Southeast Asians in North India.

  Thangaraj K, Chaubey G, Kivisild T, Selvi Rani D, Singh VK, Ismail T, Carvalho-Silva D, Metspalu M, Bhaskar LV, Reddy AG, Chandra S, Pande V, Prathap Naidu B, Adarsh N, Verma A, Jyothi IA, Mallick CB, Shrivastava N, Devasena R, Kumari B, Singh AK, Dwivedi SK, Singh S, Rao G, Gupta P, Sonvane V, Kumari K, Basha A, Bhargavi KR, Lalremruata A, Gupta AK, Kaur G, Reddy KK, Rao AP, Villems R, Tyler-Smith C and Singh L

  Human heredity 2008;66;1;1-9

  PUBMED: 18223312; DOI: 10.1159/000114160; PMC: 2588665

• Long-range, high-throughput haplotype determination via haplotype-fusion PCR and ligation haplotyping.

  Turner DJ, Tyler-Smith C and Hurles ME

  Nucleic acids research 2008;36;13;e82

  PUBMED: 18562465; DOI: 10.1093/nar/gkn373; PMC: 2490767

• An evolutionary perspective on Y-chromosomal variation and male infertility.

  Tyler-Smith C

  International journal of andrology 2008;31;4;376-82

  PUBMED: 18399979; DOI: 10.1111/j.1365-2605.2008.00889.x; PMC: 2628431

• Variation of the oxytocin/neurophysin I (OXT) gene in four human populations.

  Xu Y, Xue Y, Asan , Daly A, Wu L and Tyler-Smith C

  Journal of human genetics 2008;53;7;637-43

  PUBMED: 18566739; DOI: 10.1007/s10038-008-0292-0; PMC: 2680061

• Adaptive evolution of UGT2B17 copy-number variation.

  Xue Y, Sun D, Daly A, Yang F, Zhou X, Zhao M, Huang N, Zerjal T, Lee C, Carter NP, Hurles ME and Tyler-Smith C

  American journal of human genetics 2008;83;3;337-46

  PUBMED: 18760392; DOI: 10.1016/j.ajhg.2008.08.004; PMC: 2556428

• Identifying genetic traces of historical expansions: Phoenician footprints in the Mediterranean.

  Zalloua PA, Platt DE, El Sibai M, Khalife J, Makhoul N, Haber M, Xue Y, Izaabel H, Bosch E, Adams SM, Arroyo E, López-Parra AM, Aler M, Picornell A, Ramon M, Jobling MA, Comas D, Bertranpetit J, Wells RS, Tyler-Smith C and Genographic Consortium

  American journal of human genetics 2008;83;5;633-42

  PUBMED: 18976729; DOI: 10.1016/j.ajhg.2008.10.012; PMC: 2668035

• Y-chromosomal diversity in Lebanon is structured by recent historical events.

  Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE, Royyuru AK, Herrera RJ, Hernanz DF, Blue-Smith J, Wells RS, Comas D, Bertranpetit J, Tyler-Smith C and Genographic Consortium

  American journal of human genetics 2008;82;4;873-82

  PUBMED: 18374297; DOI: 10.1016/j.ajhg.2008.01.020; PMC: 2427286