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Adaptive evolution of interleukin-3 (IL3), a gene associated with brain volume variation in general human populations

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Abstract

Greatly expanded brain volume is one of the most characteristic traits that distinguish humans from other primates. Recent studies have revealed genes responsible for the dramatically enlarged human brain size (i.e., the microcephaly genes), and it has been well documented that many microcephaly genes have undergone accelerated evolution along the human lineage. In addition to being far larger than other primates, human brain volume is also highly variable in general populations. However, the genetic basis underlying human brain volume variation remains elusive and it is not known whether genes regulating human brain volume variation also have experienced positive selection. We have previously shown that genetic variants (near the IL3 gene) on 5q33 were significantly associated with brain volume in Chinese population. Here, we provide further evidence that support the significant association of genetic variants on 5q33 with brain volume. Bioinformatic analyses suggested that rs31480 is likely to be the causal variant among the studied SNPs. Molecular evolutionary analyses suggested that IL3 might have undergone positive selection in primates and humans. Neutrality tests further revealed signatures of positive selection of IL3 in Han Chinese and Europeans. Finally, extended haplotype homozygosity (EHH) and relative EHH analyses showed that the C allele of SNP rs31480 might have experienced recent positive selection in Han Chinese. Our results suggest that IL3 is an important genetic regulator for human brain volume variation and implied that IL3 might have experienced weak or modest positive selection in the evolutionary history of humans, which may be due to its contribution to human brain volume.

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References

  • Aiello L, Dean C (1990) An introduction to human evolutionary anatomy. Academic Press, London

    Google Scholar 

  • Anisimova M, Bielawski JP, Yang Z (2002) Accuracy and power of bayes prediction of amino acid sites under positive selection. Mol Biol Evol 19:950–958

    Article  CAS  PubMed  Google Scholar 

  • Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nat Rev Genet 4:99–111

    Article  CAS  PubMed  Google Scholar 

  • Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11:17–30

    Article  CAS  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed  Google Scholar 

  • Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG (2002) ASPM is a major determinant of cerebral cortical size. Nat Genet 32:316–320

    Article  CAS  PubMed  Google Scholar 

  • Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG (2003) Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet 73:1170–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, Cherry JM, Snyder M (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22:1790–1797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Wang X, Hossain S, O’Neill FA, Walsh D, van den Oord E, Fanous A, Kendler KS (2007) Interleukin 3 and schizophrenia: the impact of sex and family history. Mol Psychiatry 12:273–282

    CAS  PubMed  Google Scholar 

  • Cockayne DA, Bodine DM, Cline A, Nienhuis AW, Dunbar CE (1994) Transgenic mice expressing antisense interleukin-3 RNA develop a B-cell lymphoproliferative syndrome or neurologic dysfunction. Blood 84:2699–2710

    CAS  PubMed  Google Scholar 

  • Dorssers L, Burger H, Bot F, Delwel R, Geurts van Kessel AH, Lowenberg B, Wagemaker G (1987) Characterization of a human multilineage-colony-stimulating factor cDNA clone identified by a conserved noncoding sequence in mouse interleukin-3. Gene 55:115–124

    Article  CAS  PubMed  Google Scholar 

  • Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT (2004) Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119:1027–1040

    Article  CAS  PubMed  Google Scholar 

  • Enard W, Paabo S (2004) Comparative primate genomics. Annu Rev Genomics Hum Genet 5:351–378

    Article  CAS  PubMed  Google Scholar 

  • Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT (2004) Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13:489–494

    Article  CAS  PubMed  Google Scholar 

  • Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frei K, Bodmer S, Schwerdel C, Fontana A (1985) Astrocytes of the brain synthesize interleukin 3-like factors. J Immunol 135:4044–4047

    CAS  PubMed  Google Scholar 

  • Frei K, Bodmer S, Schwerdel C, Fontana A (1986) Astrocyte-derived interleukin 3 as a growth factor for microglia cells and peritoneal macrophages. J Immunol 137:3521–3527

    CAS  PubMed  Google Scholar 

  • Fu YX (1997) Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection. Genetics 147:915–925

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  CAS  PubMed  Google Scholar 

  • Gautier M, Vitalis R (2012) rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure. Bioinformatics 28:1176–1177

    Article  CAS  PubMed  Google Scholar 

  • Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP (1998) Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence. Mol Phylogenet Evol 9:585–598

    Article  CAS  PubMed  Google Scholar 

  • Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prufer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Hober B, Hoffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Z, Gusic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PL, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Paabo S (2010) A draft sequence of the Neandertal genome. Science 328:710–722

    Article  CAS  PubMed  Google Scholar 

  • Hazlett HC, Poe MD, Lightbody AA, Styner M, MacFall JR, Reiss AL, Piven J (2012) Trajectories of early brain volume development in fragile X syndrome and autism. J Am Acad Child Adolesc Psychiatry 51:921–933

    Article  PubMed  PubMed Central  Google Scholar 

  • Henneberg M (1988) Decrease of human skull size in the Holocene. Hum Biol 60:395–405

    CAS  PubMed  Google Scholar 

  • Ikram MA, Fornage M, Smith AV, Seshadri S, Schmidt R, Debette S, Vrooman HA, Sigurdsson S, Ropele S, Taal HR, Mook-Kanamori DO, Coker LH, Longstreth WT Jr, Niessen WJ, DeStefano AL, Beiser A, Zijdenbos AP, Struchalin M, Jack CR Jr, Rivadeneira F, Uitterlinden AG, Knopman DS, Hartikainen AL, Pennell CE, Thiering E, Steegers EA, Hakonarson H, Heinrich J, Palmer LJ, Jarvelin MR, McCarthy MI, Grant SF, St Pourcain B, Timpson NJ, Smith GD, Sovio U, Nalls MA, Au R, Hofman A, Gudnason H, van der Lugt A, Harris TB, Meeks WM, Vernooij MW, van Buchem MA, Catellier D, Jaddoe VW, Gudnason V, Windham BG, Wolf PA, van Duijn CM, Mosley TH Jr, Schmidt H, Launer LJ, Breteler MM, DeCarli C (2012) Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat Genet 44:539–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, Mannan J, Karbani G, Corry P, Levene MI, Mueller RF, Markham AF, Lench NJ, Woods CG (1998) Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 63:541–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamieson CR, Govaerts C, Abramowicz MJ (1999) Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet 65:1465–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamieson CR, Fryns JP, Jacobs J, Matthijs G, Abramowicz MJ (2000) Primary autosomal recessive microcephaly: MCPH5 maps to 1q25-q32. Am J Hum Genet 67:1575–1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamegai M, Niijima K, Kunishita T, Nishizawa M, Ogawa M, Araki M, Ueki A, Konishi Y, Tabira T (1990) Interleukin 3 as a trophic factor for central cholinergic neurons in vitro and in vivo. Neuron 4:429–436

    Article  CAS  PubMed  Google Scholar 

  • Karlsson EK, Kwiatkowski DP, Sabeti PC (2014) Natural selection and infectious disease in human populations. Nat Rev Genet 15:379–393

    Article  CAS  PubMed  Google Scholar 

  • Konishi Y, Kamegai M, Takahashi K, Kunishita T, Tabira T (1994) Production of interleukin-3 by murine central nervous system neurons. Neurosci Lett 182:271–274

    Article  CAS  PubMed  Google Scholar 

  • Kosakovsky Pond SL, Murrell B, Fourment M, Frost SD, Delport W, Scheffler K (2011) A random effects branch-site model for detecting episodic diversifying selection. Mol Biol Evol 28:3033–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kouprina N, Pavlicek A, Mochida GH, Solomon G, Gersch W, Yoon YH, Collura R, Ruvolo M, Barrett JC, Woods CG, Walsh CA, Jurka J, Larionov V (2004) Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol 2:E126

    Article  PubMed  PubMed Central  Google Scholar 

  • Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948

    Article  CAS  PubMed  Google Scholar 

  • Li WH (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:96–99

    Article  CAS  PubMed  Google Scholar 

  • Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452

    Article  CAS  PubMed  Google Scholar 

  • Liew FY, Millott S, Li Y, Lelchuk R, Chan WL, Ziltener H (1989) Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol 19:1227–1232

    Article  CAS  PubMed  Google Scholar 

  • Luo XJ, Li M, Huang L, Nho K, Deng M, Chen Q, Weinberger DR, Vasquez AA, Rijpkema M, Mattay VS, Saykin AJ, Shen L, Fernandez G, Franke B, Chen JC, Chen XN, Wang JK, Xiao X, Qi XB, Xiang K, Peng YM, Cao XY, Li Y, Shi XD, Gan L, Su B (2012) The interleukin 3 gene (IL3) contributes to human brain volume variation by regulating proliferation and survival of neural progenitors. PLoS One 7:e50375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Moczygemba M, Huston DP (2003) Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol 112:653–665 (quiz 666)

    Article  CAS  PubMed  Google Scholar 

  • Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA, Lahn BT (2005) Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science 309:1720–1722

    Article  CAS  PubMed  Google Scholar 

  • Mochida GH, Walsh CA (2001) Molecular genetics of human microcephaly. Curr Opin Neurol 14:151–156

    Article  CAS  PubMed  Google Scholar 

  • Montgomery SH, Capellini I, Venditti C, Barton RA, Mundy NI (2011) Adaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates. Mol Biol Evol 28:625–638

    Article  CAS  PubMed  Google Scholar 

  • Moroni SC, Rossi A (1995) Enhanced survival and differentiation in vitro of different neuronal populations by some interleukins. Int J Dev Neurosci 13:41–49

    Article  CAS  PubMed  Google Scholar 

  • Moynihan L, Jackson AP, Roberts E, Karbani G, Lewis I, Corry P, Turner G, Mueller RF, Lench NJ, Woods CG (2000) A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Am J Hum Genet 66:724–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen R, Yang Z (1998) Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nishinakamura R, Nakayama N, Hirabayashi Y, Inoue T, Aud D, McNeil T, Azuma S, Yoshida S, Toyoda Y, Arai K et al (1995) Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal. Immunity 2:211–222

    Article  CAS  PubMed  Google Scholar 

  • Nordahl CW, Lange N, Li DD, Barnett LA, Lee A, Buonocore MH, Simon TJ, Rogers S, Ozonoff S, Amaral DG (2011) Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders. Proc Natl Acad Sci USA 108:20195–20200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pamilo P, Bianchi NO (1993) Evolution of the Zfx and Zfy genes: rates and interdependence between the genes. Mol Biol Evol 10:271–281

    CAS  PubMed  Google Scholar 

  • Pattison L, Crow YJ, Deeble VJ, Jackson AP, Jafri H, Rashid Y, Roberts E, Woods CG (2000) A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31. Am J Hum Genet 67:1578–1580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE (2007) Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp 28:464–473

    Article  PubMed  Google Scholar 

  • Posthuma D, De Geus EJ, Baare WF, Hulshoff Pol HE, Kahn RS, Boomsma DI (2002) The association between brain volume and intelligence is of genetic origin. Nat Neurosci 5:83–84

    Article  CAS  PubMed  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ritchie GR, Dunham I, Zeggini E, Flicek P (2014) Functional annotation of noncoding sequence variants. Nat Methods 11:294–296

    Article  CAS  PubMed  Google Scholar 

  • Roberts E, Jackson AP, Carradice AC, Deeble VJ, Mannan J, Rashid Y, Jafri H, McHale DP, Markham AF, Lench NJ, Woods CG (1999) The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1-13.2. Eur J Hum Genet 7:815–820

    Article  CAS  PubMed  Google Scholar 

  • Roth G, Dicke U (2005) Evolution of the brain and intelligence. Trends Cogn Sci 9:250–257

    Article  PubMed  Google Scholar 

  • Ruff CB, Trinkaus E, Holliday TW (1997) Body mass and encephalization in Pleistocene Homo. Nature 387:173–176

    Article  CAS  PubMed  Google Scholar 

  • Rushton JP (1992) Cranial capacity related to sex, rank, and race in a stratified random sample of 6,325 U.S. Military personnel. Intelligence 16:401–413

    Article  Google Scholar 

  • Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837

    Article  CAS  PubMed  Google Scholar 

  • Schaffner SF, Foo C, Gabriel S, Reich D, Daly MJ, Altshuler D (2005) Calibrating a coalescent simulation of human genome sequence variation. Genome Res 15:1576–1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheet P, Stephens M (2006) A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78:629–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siepel A (2009) Phylogenomics of primates and their ancestral populations. Genome Res 19:1929–1941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann O, Bernard M, Brown AA, Cannon DM, Chakravarty MM, Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ, Homuth G, Hottenga JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G, Lee PH, Liu X, Loth E, Lourdusamy A, Mattingsdal M, Mohnke S, Maniega SM, Nho K, Nugent AC, O’Brien C, Papmeyer M, Putz B, Ramasamy A, Rasmussen J, Rijpkema M, Risacher SL, Roddey JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E, Teumer A, Trabzuni D, Turner J, van Eijk K, van Erp TG, van Tol MJ, Wittfeld K, Wolf C, Woudstra S, Aleman A, Alhusaini S, Almasy L, Binder EB, Brohawn DG, Cantor RM, Carless MA, Corvin A, Czisch M, Curran JE, Davies G, de Almeida MA, Delanty N, Depondt C, Duggirala R, Dyer TD, Erk S, Fagerness J, Fox PT, Freimer NB, Gill M, Goring HH, Hagler DJ, Hoehn D, Holsboer F, Hoogman M, Hosten N, Jahanshad N, Johnson MP, Kasperaviciute D, Kent JW Jr, Kochunov P, Lancaster JL, Lawrie SM, Liewald DC, Mandl R, Matarin M, Mattheisen M, Meisenzahl E, Melle I, Moses EK, Muhleisen TW et al (2012) Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet 44:552–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stomski FC, Sun Q, Bagley CJ, Woodcock J, Goodall G, Andrews RK, Berndt MC, Lopez AF (1996) Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding. Mol Cell Biol 16:3035–3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taal HR, St Pourcain B, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Moller E, Bradfield JP, Freathy RM, Geller F, Guxens M, Cousminer DL, Kerkhof M, Timpson NJ, Ikram MA, Beilin LJ, Bonnelykke K, Buxton JL, Charoen P, Chawes BL, Eriksson J, Evans DM, Hofman A, Kemp JP, Kim CE, Klopp N, Lahti J, Lye SJ, McMahon G, Mentch FD, Muller-Nurasyid M, O’Reilly PF, Prokopenko I, Rivadeneira F, Steegers EA, Sunyer J, Tiesler C, Yaghootkar H, Breteler MM, Decarli C, Debette S, Fornage M, Gudnason V, Launer LJ, van der Lugt A, Mosley TH Jr, Seshadri S, Smith AV, Vernooij MW, Blakemore AI, Chiavacci RM, Feenstra B, Fernandez-Banet J, Grant SF, Hartikainen AL, van der Heijden AJ, Iniguez C, Lathrop M, McArdle WL, Molgaard A, Newnham JP, Palmer LJ, Palotie A, Pouta A, Ring SM, Sovio U, Standl M, Uitterlinden AG, Wichmann HE, Vissing NH, van Duijn CM, McCarthy MI, Koppelman GH, Estivill X, Hattersley AT, Melbye M, Bisgaard H, Pennell CE, Widen E, Hakonarson H, Smith GD, Heinrich J, Jarvelin MR, Jaddoe VW (2012) Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat Genet 44:532–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabira T, Chui DH, Fan JP, Shirabe T, Konishi Y (1998) Interleukin-3 and interleukin-3 receptors in the brain. Ann N Y Acad Sci 840:107–116

    Article  CAS  PubMed  Google Scholar 

  • Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • The 1000 Genomes Project Consortium (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073

    Article  PubMed Central  Google Scholar 

  • Thompson PM, Cannon TD, Narr KL, van Erp T, Poutanen VP, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam CG, Kaprio J, Khaledy M, Dail R, Zoumalan CI, Toga AW (2001) Genetic influences on brain structure. Nat Neurosci 4:1253–1258

    Article  CAS  PubMed  Google Scholar 

  • Thompson P, Cannon TD, Toga AW (2002) Mapping genetic influences on human brain structure. Ann Med 34:523–536

    Article  CAS  PubMed  Google Scholar 

  • Wang YQ, Su B (2004) Molecular evolution of microcephalin, a gene determining human brain size. Hum Mol Genet 13:1131–1137

    Article  CAS  PubMed  Google Scholar 

  • Wang JK, Li Y, Su B (2008) A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Hum Mol Genet 17:1329–1335

    Article  CAS  PubMed  Google Scholar 

  • Weber GF, Chousterman BG, He S, Fenn AM, Nairz M, Anzai A, Brenner T, Uhle F, Iwamoto Y, Robbins CS, Noiret L, Maier SL, Zonnchen T, Rahbari NN, Scholch S, Klotzsche-von Ameln A, Chavakis T, Weitz J, Hofer S, Weigand MA, Nahrendorf M, Weissleder R, Swirski FK (2015) Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347:1260–1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen TC, Tanaka J, Peng H, Desaki J, Matsuda S, Maeda N, Fujita H, Sato K, Sakanaka M (1998) Interleukin 3 prevents delayed neuronal death in the hippocampal CA1 field. J Exp Med 188:635–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, Auerbach W, Eynon EE, Stevens S, Manz MG, Flavell RA (2011) Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci USA 108:2390–2395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76:717–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Z, Taylor JA (2009) SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res 37:W600–W605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556

    CAS  PubMed  Google Scholar 

  • Yang Z (1998) Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol Biol Evol 15:568–573

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Swanson WJ (2002) Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes. Mol Biol Evol 19:49–57

    Article  PubMed  Google Scholar 

  • Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG et al (1986) Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell 47:3–10

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Wong WS, Nielsen R (2005) Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118

    Article  CAS  PubMed  Google Scholar 

  • Zambrano A, Otth C, Mujica L, Concha II, Maccioni RB (2007) Interleukin-3 prevents neuronal death induced by amyloid peptide. BMC Neurosci 8:82

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J (2003) Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165:2063–2070

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

XJL was supported by the 100 Talents Program (BaiRenJiHua) of the Kunming Institute of Zoology, Chinese Academy of Sciences, and Project of Thousand Youth Talents of China. YGY was supported by the Ministry of Science and Technology of China (2011CB910900) and the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020300). Chunhui Chen was supported by the National Natural Science Foundation of China (31100807). QD and Chuansheng Chen were supported by the 111 Project of the Ministry of Education of China (B07008).

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Correspondence to Xiong-jian Luo.

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Ming Li, Liang Huang, Kaiqin Li and Yongxia Huo contributed equally to this work.

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Li, M., Huang, L., Li, K. et al. Adaptive evolution of interleukin-3 (IL3), a gene associated with brain volume variation in general human populations. Hum Genet 135, 377–392 (2016). https://doi.org/10.1007/s00439-016-1644-z

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  • DOI: https://doi.org/10.1007/s00439-016-1644-z

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