primary autosomal recessive 1

Crystallographic structure of the N-terminal BRCT domain of human microcephalin (MCPH1)[1]
Symbol MCPH1
Alt. symbols Microcephalin,[2] BRIT1[3]
Entrez 79648
HUGO 6954
OMIM 607117
UniProt Q8NEM0
Other data
Locus Chr. 8 p23
Microcephalin protein
Symbol Microcephalin
Pfam PF12258
InterPro IPR022047

Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in MCPH1, when homozygous, cause primary microcephaly — a severely diminished brain.[2][4][5] Hence it has been assumed that variants have a role in brain development,[6][7] but in normal individuals no effect on mental ability or behavior has yet been demonstrated in either this or another similarly studied microcephaly gene, ASPM.[8][9] However, an association has been established between normal variation in brain structure as measured with MRI (i.e., primarily cortical surface area and total brain volume) and common genetic variants within both the MCPH1 gene and another similarly studied microcephaly gene, CDK5RAP2.[10]


Microcephalin proteins contain the following three domains:

Expression in the brain

MCPH1 is expressed in the fetal brain, in the developing forebrain, and on the walls of the lateral ventricles. Cells of this area divide, producing neurons that migrate to eventually form the cerebral cortex.


A derived form of MCPH1 called haplogroup D appeared about 37,000 years ago (any time between 14,000 and 60,000 years ago) and has spread to become the most common form of microcephalin throughout the world except Sub-Saharan Africa; this rapid spread suggests a selective sweep.[11][12] However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations.[13] This variant of the gene is thought to contribute to increased brain volume.[14] Modern distributions of chromosomes bearing the ancestral forms of MCPH1 and ASPM are correlated with the incidence of tonal languages, but the nature of this relationship is far from clear.[15]

Haplogroup D may have originated from a lineage separated from modern humans approximately 1.1 million years ago and later introgressed into humans. This finding supports the possibility of admixture between modern humans and extinct Homo spp.[12] While Neanderthals have been suggested as the possible source of this haplotype, the haplotype was not found in the individuals used to prepare the first draft of the Neanderthal genome.[16][17]


The research results began to attract considerable controversy in the science world. John Derbyshire, writing in The National Review Online, wrote that as a result of the findings, "our cherished national dream of a well-mixed and harmonious meritocracy [...] may be unattainable."[18] Richard Lewontin considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." Bruce Lahn maintains that the science of the studies is sound, and freely admits that a direct link between these particular genes and either cognition or intelligence has not been clearly established. Lahn is now engaging himself with other areas of study.[19][20]

Later genetic association studies by Mekel-Bobrov et al. and Evans et al. also reported that the genotype for MCPH1 was under positive selection. An analysis by Timpson et al., found "no meaningful associations with brain size and various cognitive measures".[21] However, a later study by Rimol et al.[10] demonstrated a link between brain size and structure and two microcephaly genes, MCPH1 (only in females) and CDK5RAP2 (only in males). In contrast to previous studies, which only considered small numbers of exonic single nucleotide polymorphisms (SNPs) and did not investigate sex-specific effects, this study used microarray technology to genotype a range of SNPs associated with all four MCPH genes, including upstream and downstream regions, and allowed for separate effects for males and females.

Model organisms

Model organisms have been used in the study of MCPH1 function. A conditional knockout mouse line, called Mcph1tm1a(EUCOMM)Wtsi[28][29] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[30][31][32]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[26][33] Twenty four tests were carried out on mutant mice and six significant abnormalities were observed.[26] Homozygous mutant animals were infertile, did not have a pinna reflex, had a moderate degree of hearing impairment, abnormal cornea morphology, lens morphology and cataracts, and displayed chromosomal instability in a micronucleus test.[26]

Family members

In addition to MCPH1 the other five family members are: MCPH2, CDK5RAP2, MCPH4, ASPM and CENPJ.

See also


  1. PDB: 3KTF; Singh N, Heroux A, Thompson JR, Mer G (2010). "Structure of the N-terminal BRCT domain of human microcephalin (MCPH1)". Protein Data Bank. doi:10.2210/pdb3ktf/pdb.
  2. 1 2 Jackson, Andrew P.; Eastwood, Helen; Bell, Sandra M.; Adu, Jimi; Toomes, Carmel; Carr, Ian M.; Roberts, Emma; Hampshire, Daniel J.; et al. (2002). "Identification of Microcephalin, a Protein Implicated in Determining the Size of the Human Brain". The American Journal of Human Genetics. 71 (1): 136–42. doi:10.1086/341283. PMC 419993Freely accessible. PMID 12046007.
  3. Lin, Shiaw-Yih; Elledge, Stephen J (2003). "Multiple Tumor Suppressor Pathways Negatively Regulate Telomerase". Cell. 113 (7): 881–9. doi:10.1016/S0092-8674(03)00430-6. PMID 12837246.
  4. Online Mendelian Inheritance in Man (OMIM) 251200
  5. Jackson, Andrew P.; McHale, Duncan P.; Campbell, David A.; Jafri, Hussain; Rashid, Yasmin; Mannan, Jovaria; Karbani, Gulshan; Corry, Peter; et al. (1998). "Primary Autosomal Recessive Microcephaly (MCPH1) Maps to Chromosome 8p22-pter". The American Journal of Human Genetics. 63 (2): 541–6. doi:10.1086/301966. PMC 1377307Freely accessible. PMID 9683597.
  6. Wang, Y.-q.; Su, B (2004). "Molecular evolution of microcephalin, a gene determining human brain size". Human Molecular Genetics. 13 (11): 1131–7. doi:10.1093/hmg/ddh127. PMID 15056608.
  7. Evans, P. D.; Anderson, JR; Vallender, EJ; Choi, SS; Lahn, BT (2004). "Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size". Human Molecular Genetics. 13 (11): 1139–45. doi:10.1093/hmg/ddh126. PMID 15056607.
  8. Woods, R. P.; Freimer, NB; De Young, JA; Fears, SC; Sicotte, NL; Service, SK; Valentino, DJ; Toga, AW; Mazziotta, JC (2006). "Normal variants of Microcephalin and ASPM do not account for brain size variability". Human Molecular Genetics. 15 (12): 2025–9. doi:10.1093/hmg/ddl126. PMID 16687438.
  9. Rushton, J. P.; Vernon, P. A; Bons, T. A. (2007). "No evidence that polymorphisms of brain regulator genes Microcephalin and ASPM are associated with general mental ability, head circumference or altruism". Biology Letters. 3 (2): 157–60. doi:10.1098/rsbl.2006.0586. PMC 2104484Freely accessible. PMID 17251122.
  10. 1 2 Rimol, Lars M.; Agartz, Ingrid; Djurovic, Srdjan; Brown, Andrew A.; Roddey, J. Cooper; Kahler, Anna K.; Mattingsdal, Morten; Athanasiu, Lavinia; et al. (2010). "Sex-dependent association of common variants of microcephaly genes with brain structure". Proceedings of the National Academy of Sciences. 107 (1): 384–8. Bibcode:2010PNAS..107..384R. doi:10.1073/pnas.0908454107. JSTOR 40536283. PMC 2806758Freely accessible. PMID 20080800.
  11. Evans, Patrick D.; Gilbert, Sandra L.; Mekel-Bobrov, Nitzan; Vallender, Eric J.; Anderson, Jeffrey R.; Vaez-Azizi, Leila M.; Tishkoff, Sarah A.; Hudson, Richard R.; Lahn, Bruce T. (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. PMID 16151009. Lay summary The New York Times (September 8, 2005).
  12. 1 2 Evans, Patrick D.; Mekel-Bobrov, Nitzan; Vallender, Eric J.; Hudson, Richard R.; Lahn, Bruce T. (2006). "Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage". Proceedings of the National Academy of Sciences. 103 (48): 18178–83. Bibcode:2006PNAS..10318178E. doi:10.1073/pnas.0606966103. JSTOR 30051829. PMC 1635020Freely accessible. PMID 17090677.
  13. Mekel-Bobrov, N.; Posthuma, D.; Gilbert, S. L.; Lind, P.; Gosso, M. F.; Luciano, M.; Harris, S. E.; Bates, T. C.; et al. (2006). "The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence". Human Molecular Genetics. 16 (6): 600–8. doi:10.1093/hmg/ddl487. PMID 17220170.
  14. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010648
  15. Dediu, Dan; Ladd, D. Robert (2007). "Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin". Proceedings of the National Academy of Sciences. 104 (26): 10944–9. Bibcode:2007PNAS..10410944D. doi:10.1073/pnas.0610848104. JSTOR 25436044. PMC 1904158Freely accessible. PMID 17537923.
  16. Pennisi, E. (2009). "NEANDERTAL GENOMICS: Tales of a Prehistoric Human Genome". Science. 323 (5916): 866–71. doi:10.1126/science.323.5916.866. PMID 19213888.
  17. Green, Richard E.; Krause, Johannes; Briggs, Adrian W.; Maricic, Tomislav; Stenzel, Udo; Kircher, Martin; Patterson, Nick; Li, Heng; et al. (2010). "A Draft Sequence of the Neandertal Genome". Science. 328 (5979): 710–22. Bibcode:2010Sci...328..710G. doi:10.1126/science.1188021. PMID 20448178.
  18. John Derbyshire (November 2005). "The specter of difference". National Review. Retrieved 2008-09-21.
  19. scientists study of brain gene sparks a backlash
  20. Balter, M. (2006). "BRUCE LAHN PROFILE: Brain Man Makes Waves with Claims of Recent Human Evolution". Science. 314 (5807): 1871–3. doi:10.1126/science.314.5807.1871. PMID 17185582.
  21. Timpson, Nicholas; Heron, Jon; Davey Smith, George; Enard, Wolfgang (2007). "Comment on Papers by Evans et al. And Mekel-Bobrov et al. On Evidence for Positive Selection of MCPH1 and ASPM". Science. 317 (5841): 1036. Bibcode:2007Sci...317.1036T. doi:10.1126/science.1141705. PMID 17717170.
  22. "Neurological assessment data for Mcph1". Wellcome Trust Sanger Institute.
  23. "Eye morphology data for Mcph1". Wellcome Trust Sanger Institute.
  24. "Salmonella infection data for Mcph1". Wellcome Trust Sanger Institute.
  25. "Citrobacter infection data for Mcph1". Wellcome Trust Sanger Institute.
  26. 1 2 3 4 Gerdin, AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 0. doi:10.1111/j.1755-3768.2010.4142.x.
  27. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  28. "International Knockout Mouse Consortium".
  29. "Mouse Genome Informatics".
  30. Skarnes, William C.; Rosen, Barry; West, Anthony P.; Koutsourakis, Manousos; Bushell, Wendy; Iyer, Vivek; Mujica, Alejandro O.; Thomas, Mark; et al. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410Freely accessible. PMID 21677750.
  31. Dolgin, Elie (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  32. International Mouse Knockout Consortium; Collins, FS; Rossant, J; Wurst, W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  33. Van Der Weyden, Louise; White, Jacqueline K; Adams, David J; Logan, Darren W (2011). "The mouse genetics toolkit: Revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837Freely accessible. PMID 21722353.
This article is issued from Wikipedia - version of the 6/3/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.