Jump to content

ASPM (gene)

From Wikipedia, the free encyclopedia
ASPM
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesASPM,ASP, Calmbp1, MCPH5, abnormal spindle microtubule assembly, assembly factor for spindle microtubules
External IDsOMIM:605481;MGI:1334448;HomoloGene:7650;GeneCards:ASPM;OMA:ASPM - orthologs
Orthologs
SpeciesHumanMouse
Entrez

259266

12316

Ensembl

ENSG00000066279

ENSMUSG00000033952

UniProt

Q8IZT6

Q8CJ27

RefSeq (mRNA)

NM_018136
NM_001206846

NM_009791

RefSeq (protein)

NP_001193775
NP_060606

NP_033921

Location (UCSC)Chr 1: 197.08 – 197.15 MbChr 1: 139.38 – 139.42 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Abnormal spindle-like microcephaly-associated protein,also known asabnormal spindle protein homologorAsp homolog,is aproteinthat in humans is encoded by theASPMgene.[5]ASPM is located onchromosome 1,band q31 (1q31).[6]TheASPMgene contains 28 exons and codes for a 3477 amino‐acid‐long protein.[6]The ASPM protein is conserved across species including human, mouse,Drosophila,andC. elegans.[6]Defective forms of the ASPM gene are associated withautosomalrecessive primarymicrocephaly.[5][7]

"ASPM" is an acronym for "AbnormalSpindle-like,Microcephaly-associated ", which reflects its being anorthologto theDrosophila melanogaster"abnormal spindle" (asp) gene. Theexpressedprotein product of the asp gene is essential for normalmitotic spindlefunction in embryonicneuroblastsand regulation of neurogenesis.[6][8]

A new allele of ASPM arose sometime in the past 14,000 years (mean estimate 5,800 years), during theHolocene,it seems to have swept through much of the European and Middle-Eastern population. Although the new allele is evidently beneficial, researchers do not know what it does.[citation needed]

Animal studies[edit]

The mouse gene,Aspm,is expressed in the primary sites of prenatal cerebral corticalneurogenesis.The difference betweenAspmand ASPM is a single, large insertion coding for so-calledIQ domains.[9]Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation.[10]The function is conserved, theC. elegansprotein ASPM-1 was shown to be localized to spindle asters, where it regulates spindle organization and rotation by interacting with calmodulin, dynein and NuMA-related LIN-5.[11]

One mouse study looking atmedulloblastomagrowth in mice to study theAspmgene, anorthologto human ASPM, suggests thatAspmexpression may drive postnatalcerebellarneurogenesis.[12]This process occurs late inembryogenesisand immediately after birth over a time span of about 2 weeks in mice and 12 months in humans, and is regulated by the expression of theShhgene.[13]In proliferating cerebellar granule neuron progenitors (CGNPs), Shh expression in mouse models showed four times the amount ofAspmexpression than those deprived of Shh expressionin-vivo.This induction ofAspmand up-regulation during cerebellarneurogenesiswas also seen in real-timePCR,where its expression was relatively high at the peak of neurogenesis and much lower at the end of neurogenesis. Additionally, the study indicates thatAspmis necessary for cerebellar neurogenesis. In the presence ofAspmKOmutations and deletions, experimental mice models show decreased cerebellar volume underMRI,compared to the controls.[14]In addition to mutatedAspm'seffects on neurogenesis, these mutations may also play a role in neuraldifferentiation.When looking at adult brains inAspmKO mice, there was a trend in overall size reduction, and variations in cortical thickness between mutant andwild typemodels. In the somatosensory cortex, KO mice had a significantly thicker layer I cortex, thinner layer VI cortex, and an overall decrease in cortical thickness in thecortical plate.Certain transcription factors expressions were also abnormal in the KO mice. For example,Tbr1andSatb2had an increased presence in the cortical sub-plate, the first of which is important for differentiation and neuronal migration, and the second of which is a regulator oftranscriptionand chromosomal remodeling.[15]

While mouse studies have established the role ofAspmmutations in microcephaly, several have linked this mutation to other significant defects.[16]One study showednerve fiberimpairments in which the shape and form of cortex andwhite mattertissue was altered. This was shown postnatally comparing KO mice and controls, where both cell number and cortical thickness was decreased in KO mice. Using acell stainingmethodology for histological analysis, the study also showed shorter distances between adjacent neurons in KO mice, indicating abnormalities in cell alignment in the absence of normalAspm.[17]

Another significant impact of mutatedAspmis seen ingermlineabnormalities within mouse models. Mutations inAspmwere shown to reduce fertility in both female and male mice, indicated by a decrease in the rate of pregnancy and consequently the number of offspring, as well as a decrease in female ovarian size, as well as male sperm count and testicular size. The focus on severe germline mutations (as opposed to only mild microcephaly) in these mouse models raises the question as to whether or not human ASPM selection may be more significantly linked to reproduction than brain size.[18][19] In addition to mouse models, a study using ferrets reveals more about ASPM and its role in determining cortical size and thickness. The researchers from this study chose ferrets over mouse models due to incongruencies betweenAspmeffects in mice versus ASPM effects in humans - humans with microcephaly due to this gene mutation tend to have significantly reduced brain sizes (about 50% reduction), whereas the analogous mutation in mice only results in mild brain size reduction.[19]Ferrets also show more similarities to humans in terms of brain structure; ferrets' brains havegyrificationin high amounts similar to humans, different from the relatively smooth brains of mice. As a result, there is less cortical surface area in mice compared to that of ferrets and humans.[20]In this 2018 study, researchers targetedAspmexon 15, where a mutation in humans is linked to severe cases of microcephaly.[21]With a loss of function inAspm,ferrets withAspmmutations saw a 40% decrease in overall brain size coupled with no reduction in body size, similar to the effects of loss of ASPM in humans. The study also looked at the neurodevelopmental pathways and mechanisms leading to neurogenesis in the KO ferrets compared to the WT controls, specifically studying three different neuron progenitor cell (NPC) types, all of which express the mitotic markerKi-67and undergoradial glialmigration to the cortical plate.[22][23][24]They found that outer subventricular zone (OSVZ) NPCs were largely displaced, especially frontally and dorsally which mirrors the effects seen in cortical volume reductions due to ASPM KO.

Human studies[edit]

Human primarymicrocephaly(MCPH) is a distinct subtype that is genetically inherited as anautosomal recessivetrait.[25]MCPH is characterized by a smaller cerebral cortex associated with mild to moderate mental retardation and no other neurological deficits.[6][26]Additionally, MCPH is associated with the absence of environmental causes such as intrauterine infections, exposure to prenatal radiation or drugs, maternal phenylketonuria, and birth asphyxia.[26]MCPH has an incidence rate of 1/30,000 to 1/250,000 in western populations.[27]To date,mutationsin sixlociand four genes associated with microcephaly have been discovered in humans.[28]ASPM,one of these genes, is found at the MCPH5 locus.[29]The most common cause of MCPH in humans ishomozygousgenetic mutation of theASPMgene,orthologous to theDrosophilaabnormal spindle gene (asp).[6]In humans, theASPMgene may play a strong role in the growth of thecerebral cortex.[28]A total of 22 mutations have been discovered in theASPMgene in individuals from Pakistan, Turkey, Yemen, Saudi Arabia, Jordan, and the Netherlands.[6][21]

A study completed in Karnataka, South India by Kumar et al. analyzed the genetics of MCPH due to mutations in theASPMgene.[26]The study included nine families with blood relatives across many familial generations.[26]Kumar et al. performed High‐resolutionG‐bandingchromosome analysis andhaplotypeanalysis of individuals and families of those affected by MCPH.[26]Kumar et al. found that the South Indian families affected by mutations in the MCPH5 locus did not share a common disease haplotype; thus the authors proposed that different mutations in theASPMgene are responsible for MCPH.[26]

A similar genetic study of MCPH in Pakistani families was done by Gul et al. in order to evaluate the relationship betweenASPMgene mutations and microcephaly.[28]The study was approved by the Institutional Review Board of Quaid-I-Azam University in Islamabad, Pakistan, and involved extraction of DNA andPCRtechniques in order to genetically map theASPMgene.[28]Genotypingusingmicrosatelliteregions in the gene revealed that MCPH5 locus mutations were the most common cause of MCPH.[28]Genotyping further linked mutations in the MCPH2 locus, MCPH4 locus, and the MCPH6 locus to microcephaly.[28]Sequence analysis ofASPMin humans revealed four novel mutations; these four types of mutations are aninsertionof four nucleotides (9118insCATT), anonsense mutation(L3080X), adeletionof seven nucleotides (1260delTCAAGTC), and amissense mutation(Q3180P).[28]Gul et al. found that parents who wereheterozygouscarriers forASPMhad normal cerebral circumferences and normal intelligence levels.[28]The scientists were unable to identify mutations at the MCPH5 locus in nine families who had members affected by MCPH.[28]They concluded that the mutations could be located in theregulatory sequencesofASPM,or that a gene other thanASPMlocated in the same region could be mutated.[28]

The types of mutations causing MCPH in humans was expanded by a study done by Pichon et al. on an individual with primary microcephaly, as the study revealed atranslocationbreakpoint in theASPMgene.[30]Pichon et al. obtained BAC clones withBamHI digestion fragments of the "RP11-32D17" insert and usedFluorescence in situ Hybridization(FISH) in order to label the clones with fluorescein-12-dUTP.[30]In order to precisely locate the translocation breakpoint, theBamHIdigestion fragments of "RP11-32D17" were analyzed.[30]The translocation breakpoint was located to be within intron 17 of theASPMgene.[30]The translocation resulted in a truncated ASPM protein, which is most likely a non-functioning protein also seen in truncating point mutations reported in MCPH patients.[30]

Evolution[edit]

A newallele(version) of ASPM appeared sometime within the last 14,100 years, with a mean estimate of 5,800 years ago. The new allele has a frequency of about 50% in populations of the Middle East and Europe, it is less frequent in East Asia, and has low frequencies among Sub-Saharan African populations.[31]It is also found with an unusually high percentage among the people ofPapua New Guinea,with a 59.4% occurrence.[32]

The mean estimated age of the ASPM allele of 5,800 years ago roughly correlates with the development of written language, spread of agriculture and development of cities.[33][better source needed]Currently, two alleles of this gene exist: the older (pre-5,800 years ago) and the newer (post-5,800 years ago). About 10% of humans have two copies of the new ASPM allele, while about 50% have two copies of the old allele. The other 40% of humans have one copy of each. Of those with an instance of the new allele, 50% of them are an identical copy.[34][35]The allele affects genotype over a large (62 kbp) region, a so calledselective sweepwhich signals a rapid spread of a mutation (such as the new ASPM) through the population; this indicates that the mutation is somehow advantageous to the individual.[32][36]

Testing the IQ of those with and without new ASPM allele has shown no difference in average IQ, providing no evidence to support the notion that the gene increases intelligence.[36][37][38] Other genes related to brain development appear to have come under selective pressure in different populations. TheDAB1gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in theChinese.TheSV2Bgene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep inAfrican-Americans.[39][40]

See also[edit]

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000066279–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000033952–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abPattison L, Crow YJ, Deeble VJ, Jackson AP, Jafri H, Rashid Y, Roberts E, Woods CG (December 2000)."A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31".American Journal of Human Genetics.67(6): 1578–80.doi:10.1086/316910.PMC1287934.PMID11078481.
  6. ^abcdefgBond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG (October 2002). "ASPM is a major determinant of cerebral cortical size".Nature Genetics.32(2): 316–20.doi:10.1038/ng995.PMID12355089.S2CID14855140.
  7. ^Kaindl AM, Passemard S, Kumar P, Kraemer N, Issa L, Zwirner A, Gerard B, Verloes A, Mani S, Gressens P (March 2010). "Many roads lead to primary autosomal recessive microcephaly".Progress in Neurobiology.90(3): 363–83.doi:10.1016/j.pneurobio.2009.11.002.PMID19931588.S2CID35631370.
  8. ^Kouprina N, Pavlicek A, Collins NK, Nakano M, Noskov VN, Ohzeki J, Mochida GH, Risinger JI, Goldsmith P, Gunsior M, Solomon G, Gersch W, Kim JH, Barrett JC, Walsh CA, Jurka J, Masumoto H, Larionov V (August 2005). "The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein".Human Molecular Genetics.14(15): 2155–65.doi:10.1093/hmg/ddi220.PMID15972725.
  9. ^Bähler M, Rhoads A (February 2002)."Calmodulin signaling via the IQ motif".FEBS Letters.513(1): 107–13.doi:10.1016/S0014-5793(01)03239-2.PMID11911888.S2CID12717952.
  10. ^Fish JL, Kosodo Y, Enard W, Pääbo S, Huttner WB (July 2006)."Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells".Proceedings of the National Academy of Sciences of the United States of America.103(27): 10438–10443.Bibcode:2006PNAS..10310438F.doi:10.1073/pnas.0604066103.PMC1502476.PMID16798874.
  11. ^van der Voet M, Berends CW, Perreault A, Nguyen-Ngoc T, Gönczy P, Vidal M, Boxem M, van den Heuvel S (March 2009). "NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/G Alpha".Nature Cell Biology.11(3): 269–77.doi:10.1038/ncb1834.PMID19219036.S2CID1264690.
  12. ^Williams SE, Garcia I, Crowther AJ, Li S, Stewart A, Liu H, Lough KJ, O'Neill S, Veleta K, Oyarzabal EA, Merrill JR, Shih YY, Gershon TR (November 2015)."Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice".Development.142(22): 3921–32.doi:10.1242/dev.124271.PMC4712878.PMID26450969.
  13. ^Roussel MF, Hatten ME (2011)."Cerebellum development and medulloblastoma".Current Topics in Developmental Biology.94:235–82.doi:10.1016/B978-0-12-380916-2.00008-5.PMC3213765.PMID21295689.
  14. ^Williams SE, Garcia I, Crowther AJ, Li S, Stewart A, Liu H, Lough KJ, O'Neill S, Veleta K, Oyarzabal EA, Merrill JR, Shih YY, Gershon TR (November 2015)."Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice".Development.142(22): 3921–32.doi:10.1242/dev.124271.PMC4712878.PMID26450969.
  15. ^Fujimori A, Itoh K, Goto S, Hirakawa H, Wang B, Kokubo T, Kito S, Tsukamoto S, Fushiki S (September 2014). "Disruption of Aspm causes microcephaly with abnormal neuronal differentiation".Brain & Development.36(8): 661–9.doi:10.1016/j.braindev.2013.10.006.PMID24220505.S2CID8410732.
  16. ^Létard P, Drunat S, Vial Y, Duerinckx S, Ernault A, Amram D, et al. (March 2018)."Autosomal recessive primary microcephaly due to ASPM mutations: An update"(PDF).Human Mutation.39(3): 319–332.doi:10.1002/humu.23381.hdl:10067/1492390151162165141.PMID29243349.S2CID46817009.
  17. ^Ogi H, Nitta N, Tando S, Fujimori A, Aoki I, Fushiki S, Itoh K (February 2018). "Longitudinal Diffusion Tensor Imaging Revealed Nerve Fiber Alterations in Aspm Mutated Microcephaly Model Mice".Neuroscience.371:325–336.doi:10.1016/j.neuroscience.2017.12.012.PMID29253521.S2CID46821998.
  18. ^Ponting CP (May 2006)."A novel domain suggests a ciliary function for ASPM, a brain size determining gene".Bioinformatics.22(9): 1031–5.doi:10.1093/bioinformatics/btl022.PMID16443634.
  19. ^abPulvers JN, Bryk J, Fish JL, Wilsch-Bräuninger M, Arai Y, Schreier D, Naumann R, Helppi J, Habermann B, Vogt J, Nitsch R, Tóth A, Enard W, Pääbo S, Huttner WB (September 2010)."Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline".Proceedings of the National Academy of Sciences of the United States of America.107(38): 16595–600.doi:10.1073/pnas.1010494107.PMC2944708.PMID20823249.
  20. ^Johnson MB, Sun X, Kodani A, Borges-Monroy R, Girskis KM, Ryu SC, Wang PP, Patel K, Gonzalez DM, Woo YM, Yan Z, Liang B, Smith RS, Chatterjee M, Coman D, Papademetris X, Staib LH, Hyder F, Mandeville JB, Grant PE, Im K, Kwak H, Engelhardt JF, Walsh CA, Bae BI (April 2018)."Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size".Nature.556(7701): 370–375.Bibcode:2018Natur.556..370J.doi:10.1038/s41586-018-0035-0.PMC6095461.PMID29643508.
  21. ^abBond 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 (November 2003)."Protein-truncating mutations in ASPM cause variable reduction in brain size".American Journal of Human Genetics.73(5): 1170–7.doi:10.1086/379085.PMC1180496.PMID14574646.
  22. ^Fietz SA, Kelava I, Vogt J, Wilsch-Bräuninger M, Stenzel D, Fish JL, Corbeil D, Riehn A, Distler W, Nitsch R, Huttner WB (June 2010)."OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling"(PDF).Nature Neuroscience.13(6): 690–9.doi:10.1038/nn.2553.PMID20436478.S2CID11633062.
  23. ^Martínez-Cerdeño V, Cunningham CL, Camacho J, Antczak JL, Prakash AN, Cziep ME, Walker AI, Noctor SC (2012-01-17)."Comparative analysis of the subventricular zone in rat, ferret and macaque: evidence for an outer subventricular zone in rodents".PLOS ONE.7(1): e30178.Bibcode:2012PLoSO...730178M.doi:10.1371/journal.pone.0030178.PMC3260244.PMID22272298.
  24. ^Hansen DV, Lui JH, Parker PR, Kriegstein AR (March 2010). "Neurogenic radial glia in the outer subventricular zone of human neocortex".Nature.464(7288): 554–561.Bibcode:2010Natur.464..554H.doi:10.1038/nature08845.PMID20154730.S2CID4412132.
  25. ^"Handbook of clinical neurology, volume 30, congenital malformations of the brain and skull, part I, edited by P. J. Vinken and G. W. Bruyn, 706 pp, illustrated, $114.50, North-Holland Publishing Company, Amsterdam, 1977".Annals of Neurology.4(6): 588. 1978.doi:10.1002/ana.410040673.ISSN0364-5134.
  26. ^abcdefKumar A, Blanton SH, Babu M, Markandaya M, Girimaji SC (October 2004)."Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations"(PDF).Clinical Genetics.66(4): 341–8.doi:10.1111/j.1399-0004.2004.00304.x.PMID15355437.S2CID25779591.
  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 (August 1998)."Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter".American Journal of Human Genetics.63(2): 541–6.doi:10.1086/301966.PMC1377307.PMID9683597.
  28. ^abcdefghijGul A, Hassan MJ, Mahmood S, Chen W, Rahmani S, Naseer MI, Dellefave L, Muhammad N, Rafiq MA, Ansar M, Chishti MS, Ali G, Siddique T, Ahmad W (May 2006). "Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene".Neurogenetics.7(2): 105–10.doi:10.1007/s10048-006-0042-4.PMID16673149.S2CID22685315.
  29. ^Woods CG, Bond J, Enard W (May 2005)."Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings".American Journal of Human Genetics.76(5): 717–28.doi:10.1086/429930.PMC1199363.PMID15806441.
  30. ^abcdePichon B, Vankerckhove S, Bourrouillou G, Duprez L, Abramowicz MJ (May 2004)."A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly".European Journal of Human Genetics.12(5): 419–21.doi:10.1038/sj.ejhg.5201169.PMID14997185.
  31. ^Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT (September 2005). "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans".Science.309(5741): 1717–1720.Bibcode:2005Sci...309.1717E.doi:10.1126/science.1113722.PMID16151009.S2CID85864492.
  32. ^abMekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA, Lahn BT (September 2005). "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens".Science.309(5741): 1720–1722.Bibcode:2005Sci...309.1720M.doi:10.1126/science.1116815.PMID16151010.S2CID30403575.
  33. ^Per the 2006Discovery Channel/Channel 4documentary seriesWhat Makes Us Human?
  34. ^Inman M (2005). "Human brains enjoy ongoing evolution".New Scientist.
  35. ^Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT (September 2005). "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans".Science.309(5741): 1717–20.Bibcode:2005Sci...309.1717E.doi:10.1126/science.1113722.PMID16151009.S2CID85864492.
  36. ^abCurrat M, Excoffier L, Maddison W, Otto SP, Ray N, Whitlock MC, Yeaman S (July 2006). "Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans'".Science.313(5784): 172, author reply 172.doi:10.1126/science.1122712.PMID16840683.S2CID288132.
  37. ^Woods RP, Freimer NB, De Young JA, Fears SC, Sicotte NL, Service SK, Valentino DJ, Toga AW, Mazziotta JC (June 2006)."Normal variants of Microcephalin and ASPM do not account for brain size variability".Human Molecular Genetics.15(12): 2025–2029.doi:10.1093/hmg/ddl126.PMID16687438.
  38. ^Mekel-Bobrov N, Posthuma D, Gilbert SL, Lind P, Gosso MF, Luciano M, Harris SE, Bates TC, Polderman TJ, Whalley LJ, Fox H, Starr JM, Evans PD, Montgomery GW, Fernandes C, Heutink P, Martin NG, Boomsma DI, Deary IJ, Wright MJ, de Geus EJ, Lahn BT (March 2007)."The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence".Human Molecular Genetics.16(6): 600–608.doi:10.1093/hmg/ddl487.PMID17220170.
  39. ^Williamson SH, Hubisz MJ, Clark AG, Payseur BA, Bustamante CD, Nielsen R (June 2007)."Localizing recent adaptive evolution in the human genome".PLOS Genetics.3(6): e90.doi:10.1371/journal.pgen.0030090.PMC1885279.PMID17542651.
  40. ^Wade N (2007-06-26)."Humans Have Spread Globally, and Evolved Locally".New York Times.Retrieved2009-08-01.

External links[edit]

Retrieved from "https://en.wikipedia.org/w/index.php?title=ASPM_(gene)&oldid=1188017056"