Microcephalin

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microcephaly, primary autosomal recessive 1
Crystallographic structure of the N-terminal BRCT domain of human microcephalin (MCPH1)[1]
Identifiers
SymbolMCPH1
Alt. symbolsMicrocephalin,[2] BRIT1[3]
NCBI gene79648
HGNC6954
OMIM607117
UniProtQ8NEM0
Other data
LocusChr. 8 p23
Search for
StructuresSwiss-model
DomainsInterPro

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microcephaly, primary autosomal recessive 2
Identifiers
SymbolMCPH2
NCBI gene4181
HGNC6955
OMIM604317
Other data
LocusChr. 19 q13.1-13.2

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microcephaly, primary autosomal recessive 3
Identifiers
SymbolCDK5RAP2
Alt. symbolsMCPH3
NCBI gene23702
HGNC6956
OMIM604804
Other data
LocusChr. 9 q33.3

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microcephaly, primary autosomal recessive 4
Identifiers
SymbolMCPH4
NCBI gene23701
HGNC6957
OMIM604321
Other data
LocusChr. 15 q15-21

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microcephaly, primary autosomal recessive 5
Identifiers
SymbolASPM
Alt. symbolsMCPH5
NCBI gene64590
HGNC6958
OMIM608716
Other data
LocusChr. 1 q31

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microcephaly, primary autosomal recessive 6
Identifiers
SymbolCENPJ
Alt. symbolsMCPH6
NCBI gene170629
HGNC17120
OMIM608393
Other data
LocusChr. 13 q12.2

Template:FixBunching Microcephalin (MCPH1) is one of six genes causing primary microcephaly (Online Mendelian Inheritance in Man (OMIM): 251200) when non-functional mutations exist in the homozygous state. Derived from the Greek words for "small" and "head", this condition is characterised by a severely diminished brain.[2][4] Hence it has been assumed that variants have a role in brain development,[5][6] but in normal individuals no effect on mental ability, brain size or behavior has been attributed to either this or another similarly studied microcephaly gene, ASPM.[7][8]

Structure

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.

Evolution

A derived form of MCPH1 called haplogroup D appeared about 37,000 years ago (anytime between 14,000 and 60,000 years ago) and has spread to become the most common form throughout the world except Sub-Saharan Africa.[9][10] Modern distributions of chromosomes bearing the ancestral forms of MCPH1 and ASPM are correlated with the incidence of tonal languages, although the nature of this relationship can only be guessed at.[11]

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.[10] While Neanderthals were suggested to be the possible source of this haplotype, it was not found in the individuals used to prepare the first draft of the Neanderthal genome.[12][13]

On the other hand the sample of 89 individuals with only nine Africans used in the study has been criticized as being inadequate for the conclusion the paper draws, and comparable studies demonstrate that undersampling specific areas of East/Central Africa may lead to unwarranted conclusions.[14] Additionally, scientists have not identified the evolutionary pressures that caused the supposed spread of these mutations.[15]

Controversy

Although Chinese himself, Bruce Lahn's public announcements that some brain-genes are more advanced on some continents than on others were conscripted by websites promoting white "racialism". An American White supremacist magazine embraced the research as "the moment the antiracists and egalitarians have dreaded."[16]

Lahn's study 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."[17] Richard Lewontin considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." Lahn maintains that the science of his studies are sound, and freely admits that a direct link between these particular genes and either cognition or intelligence has not yet been conclusively established. Bruce Lahn is now engaging himself with other areas of study.[18][19]

Later genetic association studies by Mekel-Bobrov et al and Evans et al reported that the genotype for MCPH1 was under positive selection. An analysis by Timpson et al, however, found "no meaningful associations with brain size and various cognitive measures".[20]

Other names

The microcephaly-related loci MCPH 3, 5 and 6 are usually classified by their alternate names CDK5RAP2, ASPM and CENPJ respectively, according to their other roles. (More information can be found from the articles dedicated to them and links in the information boxes.)

See also

References

  1. ^ PDB: 3KTF​; Singh N, Heroux A, Thompson JR, Mer G (2010). "Structure of the N-terminal BRCT domain of human microcephalin (MCPH1)". To be published. doi:10.2210/pdb3ktf/pdb.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b Jackson, A.P.; et al. (2002). "Identification of Microcephalin, a Protein Implicated in Determining the Size of the Human Brain". Am. J. Hum. Genet. 71 (1): 136–142. doi:10.1086/341283. PMC 419993. PMID 12046007. {{cite journal}}: Explicit use of et al. in: |author= (help)
  3. ^ Lin, S.Y. & Elledge, S.J. (2003). "Multiple tumor suppressor pathways negatively regulate telomerase". Cell. 113 (7): 881–889. doi:10.1016/S0092-8674(03)00430-6. PMID 12837246.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Jackson, A.P.; et al. (1998). "Primary Autosomal Recessive Microcephaly (MCPH1) Maps to Chromosome 8p22-pter". Am. J. Hum. Genet. 63 (2): 541–546. doi:10.1086/301966. PMC 1377307. PMID 9683597. {{cite journal}}: Explicit use of et al. in: |author= (help) [dead link]
  5. ^ Wang, Y.Q. & B. Su (2004). "Molecular evolution of microcephalin, a gene determining human brain size". Hum. Mol. Genet. 13 (11): 1131–1137. doi:10.1093/hmg/ddh127. PMID 15056608.
  6. ^ Evans, P.D.; et al. (2004). "Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size". Hum. Mol. Genet. 13 (11): 1139–1145. doi:10.1093/hmg/ddh126. PMID 15056607. {{cite journal}}: Explicit use of et al. in: |author= (help)
  7. ^ R.P. Woods; et al. (2006). "Normal variants of Microcephalin and ASPM do not account for brain size variability". Hum. Mol. Genet. 15 (12): 2025–2029. doi:10.1093/hmg/ddl126. PMID 16687438. {{cite journal}}: Explicit use of et al. in: |author= (help)
  8. ^ J.P. Rushton, P.A. Vernon & T.A. Bons (2007). "No evidence that polymorphisms of brain regulator genes Microcephalin and ASPM are associated with general mental ability, head circumference or altruism". Biol. Lett. 3 (2): 157–160. doi:10.1098/rsbl.2006.0586. PMC 2104484. PMID 17251122. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Evans, P.D.; et al. (2005). "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans". Science. 309 (5741): 1717–20. doi:10.1126/science.1113722. PMID 16151009. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)
  10. ^ a b PNAS article Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage Published online before print November 7, 2006 by Proceedings of the National Academy of Sciences of the USA
  11. ^ Dediu, D. & D.R. Ladd (2007). "Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin". Proc. Nat. Acad. Sci. 104 (26): 10944–9. doi:10.1073/pnas.0610848104. PMC 1904158. PMID 17537923.
  12. ^ Elizabeth Pennisi (2009). "NEANDERTAL GENOMICS: Tales of a Prehistoric Human Genome". Science. 323 (5916): 866–871. doi:10.1126/science.323.5916.866. PMID 19213888. {{cite journal}}: Unknown parameter |wolume= ignored (help)
  13. ^ Richard E. Green; et al. (2010). "A Draft Sequence of the Neandertal Genome". Science. 328 (5979): 710–722. doi:10.1126/science.1188021. PMID 20448178. {{cite journal}}: Explicit use of et al. in: |author= (help)
  14. ^ Shimada MK, Panchapakesan K, Tishkoff SA, Nato AQ, Hey J (2007). "Divergent haplotypes and human history as revealed in a worldwide survey of X-linked DNA sequence variation". Mol. Biol. Evol. 24 (3): 687–98. doi:10.1093/molbev/msl196. PMID 17175528.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Mekel-Bobrov, N.; et al. (2007). "The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence". Hum. Mol. Genet. 16 (6): adv. access. doi:10.1093/hmg/ddl487. PMID 17220170. {{cite journal}}: Explicit use of et al. in: |author= (help)
  16. ^ Chris Brand (2005). "Race realism takes a step forward". American Renaissance. Retrieved 2008-09-21. {{cite web}}: Unknown parameter |month= ignored (help)
  17. ^ John Derbyshire (2005). "The specter of difference". National Review. Retrieved 2008-09-21. {{cite news}}: Unknown parameter |month= ignored (help) [dead link]
  18. ^ scientists study of brain gene sparks a backlash
  19. ^ Balter, M. (2006). "Bruce Lahn profile: Brain man makes waves with claims of recent human evolution". Science. 314 (5807): 1871–1873. doi:10.1126/science.314.5807.1871. PMID 17185582. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Timpson, N.; et al. (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. doi:10.1126/science.1141705. PMID 17185582. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)

External links

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