Human Genetics

, Volume 135, Issue 4, pp 377–392 | Cite as

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

  • Ming Li
  • Liang Huang
  • Kaiqin Li
  • Yongxia Huo
  • Chunhui Chen
  • Jinkai Wang
  • Jiewei Liu
  • Zhenwu Luo
  • Chuansheng Chen
  • Qi Dong
  • Yong-gang Yao
  • Bing Su
  • Xiong-jian Luo
Original Investigation


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.


Chinese Population Brain Volume Amino Acid Site Human Lineage Coalescent Simulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

439_2016_1644_MOESM1_ESM.doc (260 kb)
Supplementary material 1 (DOC 259 kb)


  1. Aiello L, Dean C (1990) An introduction to human evolutionary anatomy. Academic Press, LondonGoogle Scholar
  2. Anisimova M, Bielawski JP, Yang Z (2002) Accuracy and power of bayes prediction of amino acid sites under positive selection. Mol Biol Evol 19:950–958CrossRefPubMedGoogle Scholar
  3. Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nat Rev Genet 4:99–111CrossRefPubMedGoogle Scholar
  4. Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11:17–30CrossRefPubMedGoogle Scholar
  5. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  6. 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 32:316–320CrossRefPubMedGoogle Scholar
  7. 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 73:1170–1177CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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 22:1790–1797CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 12:273–282PubMedGoogle Scholar
  10. 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 84:2699–2710PubMedGoogle Scholar
  11. 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 55:115–124CrossRefPubMedGoogle Scholar
  12. 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 119:1027–1040CrossRefPubMedGoogle Scholar
  13. Enard W, Paabo S (2004) Comparative primate genomics. Annu Rev Genomics Hum Genet 5:351–378CrossRefPubMedGoogle Scholar
  14. 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 13:489–494CrossRefPubMedGoogle Scholar
  15. Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413PubMedPubMedCentralGoogle Scholar
  16. Frei K, Bodmer S, Schwerdel C, Fontana A (1985) Astrocytes of the brain synthesize interleukin 3-like factors. J Immunol 135:4044–4047PubMedGoogle Scholar
  17. 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 137:3521–3527PubMedGoogle Scholar
  18. Fu YX (1997) Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection. Genetics 147:915–925PubMedPubMedCentralGoogle Scholar
  19. Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709PubMedPubMedCentralGoogle Scholar
  20. 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 296:2225–2229CrossRefPubMedGoogle Scholar
  21. Gautier M, Vitalis R (2012) rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure. Bioinformatics 28:1176–1177CrossRefPubMedGoogle Scholar
  22. 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 9:585–598CrossRefPubMedGoogle Scholar
  23. 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 328:710–722CrossRefPubMedGoogle Scholar
  24. 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 51:921–933CrossRefPubMedPubMedCentralGoogle Scholar
  25. Henneberg M (1988) Decrease of human skull size in the Holocene. Hum Biol 60:395–405PubMedGoogle Scholar
  26. 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 44:539–544CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 63:541–546CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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 71:136–142CrossRefPubMedPubMedCentralGoogle Scholar
  29. Jamieson CR, Govaerts C, Abramowicz MJ (1999) Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet 65:1465–1469CrossRefPubMedPubMedCentralGoogle Scholar
  30. Jamieson CR, Fryns JP, Jacobs J, Matthijs G, Abramowicz MJ (2000) Primary autosomal recessive microcephaly: MCPH5 maps to 1q25-q32. Am J Hum Genet 67:1575–1577CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 4:429–436CrossRefPubMedGoogle Scholar
  32. Karlsson EK, Kwiatkowski DP, Sabeti PC (2014) Natural selection and infectious disease in human populations. Nat Rev Genet 15:379–393CrossRefPubMedGoogle Scholar
  33. Konishi Y, Kamegai M, Takahashi K, Kunishita T, Tabira T (1994) Production of interleukin-3 by murine central nervous system neurons. Neurosci Lett 182:271–274CrossRefPubMedGoogle Scholar
  34. 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 28:3033–3043CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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:E126CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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 23:2947–2948CrossRefPubMedGoogle Scholar
  37. Li WH (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:96–99CrossRefPubMedGoogle Scholar
  38. Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452CrossRefPubMedGoogle Scholar
  39. 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 19:1227–1232CrossRefPubMedGoogle Scholar
  40. 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:e50375CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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) CrossRefPubMedGoogle Scholar
  42. 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 309:1720–1722CrossRefPubMedGoogle Scholar
  43. Mochida GH, Walsh CA (2001) Molecular genetics of human microcephaly. Curr Opin Neurol 14:151–156CrossRefPubMedGoogle Scholar
  44. 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 28:625–638CrossRefPubMedGoogle Scholar
  45. Moroni SC, Rossi A (1995) Enhanced survival and differentiation in vitro of different neuronal populations by some interleukins. Int J Dev Neurosci 13:41–49CrossRefPubMedGoogle Scholar
  46. 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 66:724–727CrossRefPubMedPubMedCentralGoogle Scholar
  47. Nielsen R, Yang Z (1998) Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936PubMedPubMedCentralGoogle Scholar
  48. 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 2:211–222CrossRefPubMedGoogle Scholar
  49. 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 108:20195–20200CrossRefPubMedPubMedCentralGoogle Scholar
  50. Pamilo P, Bianchi NO (1993) Evolution of the Zfx and Zfy genes: rates and interdependence between the genes. Mol Biol Evol 10:271–281PubMedGoogle Scholar
  51. 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 67:1578–1580CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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 28:464–473CrossRefPubMedGoogle Scholar
  53. 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 5:83–84CrossRefPubMedGoogle Scholar
  54. 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 81:559–575CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ritchie GR, Dunham I, Zeggini E, Flicek P (2014) Functional annotation of noncoding sequence variants. Nat Methods 11:294–296CrossRefPubMedGoogle Scholar
  56. 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 7:815–820CrossRefPubMedGoogle Scholar
  57. Roth G, Dicke U (2005) Evolution of the brain and intelligence. Trends Cogn Sci 9:250–257CrossRefPubMedGoogle Scholar
  58. Ruff CB, Trinkaus E, Holliday TW (1997) Body mass and encephalization in Pleistocene Homo. Nature 387:173–176CrossRefPubMedGoogle Scholar
  59. Rushton JP (1992) Cranial capacity related to sex, rank, and race in a stratified random sample of 6,325 U.S. Military personnel. Intelligence 16:401–413CrossRefGoogle Scholar
  60. 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 419:832–837CrossRefPubMedGoogle Scholar
  61. Schaffner SF, Foo C, Gabriel S, Reich D, Daly MJ, Altshuler D (2005) Calibrating a coalescent simulation of human genome sequence variation. Genome Res 15:1576–1583CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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 78:629–644CrossRefPubMedPubMedCentralGoogle Scholar
  63. Siepel A (2009) Phylogenomics of primates and their ancestral populations. Genome Res 19:1929–1941CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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 44:552–561CrossRefPubMedPubMedCentralGoogle Scholar
  65. 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 16:3035–3046CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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 44:532–538CrossRefPubMedPubMedCentralGoogle Scholar
  67. 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 840:107–116CrossRefPubMedGoogle Scholar
  68. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595PubMedPubMedCentralGoogle Scholar
  69. 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 28:2731–2739CrossRefPubMedPubMedCentralGoogle Scholar
  70. The 1000 Genomes Project Consortium (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073CrossRefPubMedCentralGoogle Scholar
  71. 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 4:1253–1258CrossRefPubMedGoogle Scholar
  72. Thompson P, Cannon TD, Toga AW (2002) Mapping genetic influences on human brain structure. Ann Med 34:523–536CrossRefPubMedGoogle Scholar
  73. Wang YQ, Su B (2004) Molecular evolution of microcephalin, a gene determining human brain size. Hum Mol Genet 13:1131–1137CrossRefPubMedGoogle Scholar
  74. Wang JK, Li Y, Su B (2008) A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Hum Mol Genet 17:1329–1335CrossRefPubMedGoogle Scholar
  75. 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 347:1260–1265CrossRefPubMedPubMedCentralGoogle Scholar
  76. 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 188:635–649CrossRefPubMedPubMedCentralGoogle Scholar
  77. 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 108:2390–2395CrossRefPubMedPubMedCentralGoogle Scholar
  78. Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76:717–728CrossRefPubMedPubMedCentralGoogle Scholar
  79. 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–W605CrossRefPubMedPubMedCentralGoogle Scholar
  80. Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556PubMedGoogle Scholar
  81. Yang Z (1998) Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol Biol Evol 15:568–573CrossRefPubMedGoogle Scholar
  82. Yang Z, Swanson WJ (2002) Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes. Mol Biol Evol 19:49–57CrossRefPubMedGoogle Scholar
  83. 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 47:3–10CrossRefPubMedGoogle Scholar
  84. Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449PubMedPubMedCentralGoogle Scholar
  85. Yang Z, Wong WS, Nielsen R (2005) Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118CrossRefPubMedGoogle Scholar
  86. Zambrano A, Otth C, Mujica L, Concha II, Maccioni RB (2007) Interleukin-3 prevents neuronal death induced by amyloid peptide. BMC Neurosci 8:82CrossRefPubMedPubMedCentralGoogle Scholar
  87. Zhang J (2003) Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165:2063–2070PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ming Li
    • 1
  • Liang Huang
    • 2
  • Kaiqin Li
    • 1
  • Yongxia Huo
    • 1
  • Chunhui Chen
    • 3
  • Jinkai Wang
    • 4
  • Jiewei Liu
    • 4
  • Zhenwu Luo
    • 5
  • Chuansheng Chen
    • 6
  • Qi Dong
    • 3
  • Yong-gang Yao
    • 1
  • Bing Su
    • 4
  • Xiong-jian Luo
    • 1
  1. 1.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of ZoologyChinese Academy of SciencesKunmingChina
  2. 2.First Affiliated Hospital of Gannan Medical UniversityGanzhouChina
  3. 3.State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijingChina
  4. 4.State Key Laboratory of Genetic Resources and EvolutionKunming Institute of Zoology, Chinese Academy of SciencesKunmingChina
  5. 5.Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA
  6. 6.Department of Psychology and Social BehaviorUniversity of CaliforniaIrvineUSA

Personalised recommendations