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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."<ref name = "AutoR3-13"/> [[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 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. Bruce Lahn is now engaging himself with other areas of study.<ref name = "AutoR3-14"/><ref name = "AutoR3-15"/>
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."<ref name = "AutoR3-13"/> [[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 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. Bruce Lahn is now engaging himself with other areas of study.<ref name = "AutoR3-14"/><ref name = "AutoR3-15"/>


Later [[Genome-wide association study|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".<ref name = "AutoR3-16"/> However, a later study by Rimol et al. <ref name="Rimol et al., 2010">{{vcite journal |author=Lars M. Rimol, Ingrid Agartz, Srdjan Djurovic, Andrew A. Brown, J. Cooper Roddey, Anna K. Kähler, Lavinia Athanasiu, Alexander H. Joyner, Nicholas J. Schork, Eric Halgren, Kjetil Sundet, Ingrid Melle, Anders M. Dale, Ole A. Andreassen, for the Alzheimer's Disease Neuroimaging Initiative |title='''Sex-Dependent Association of Common Variants of Microcephaly Genes with Brain Structure.''' |journal=Proc Natl Acad Sci U S A. |volume=107 |issue=1 |pages=384-8 |year=2010 |pmid=20080800}}</ref> demonstrated a link between brain structure (i.e., ''cortical surface area'' and ''total brain volume'') 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 SNPs associated with all four MCPH genes, including upstream and downstream regions, and allowed for separate effects for males and females.
Later [[Genome-wide association study|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".<ref name = "AutoR3-16"/> However, a later study by Rimol et al. <ref name="Rimol et al., 2010">{{vcite journal |author=Lars M. Rimol, Ingrid Agartz, Srdjan Djurovic, Andrew A. Brown, J. Cooper Roddey, Anna K. Kähler, Lavinia Athanasiu, Alexander H. Joyner, Nicholas J. Schork, Eric Halgren, Kjetil Sundet, Ingrid Melle, Anders M. Dale, Ole A. Andreassen, for the Alzheimer's Disease Neuroimaging Initiative |title='''Sex-Dependent Association of Common Variants of Microcephaly Genes with Brain Structure.''' |journal=Proc Natl Acad Sci U S A. |volume=107 |issue=1 |pages=384-8 |year=2010 |pmid=20080800}}</ref> demonstrated a link between brain 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 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==

Revision as of 13:19, 12 May 2012

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
Microcephalin protein
Identifiers
SymbolMicrocephalin
PfamPF12258
InterProIPR022047
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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 or behavior has yet been demonstrated in either this or another similarly studied microcephaly gene, ASPM.[7][8] 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.[9]


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 (any time between 14,000 and 60,000 years ago) and has spread to become the most common form throughout the world except Sub-Saharan Africa; this rapid spread suggests a selective sweep.[10][11] However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations.[12] 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.[13]

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.[11] 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.[14][15]

Controversy

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."[16] 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 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. Bruce Lahn is now engaging himself with other areas of study.[17][18]

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".[19] However, a later study by Rimol et al. [9] demonstrated a link between brain 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 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[26][27] 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.[28][29][30]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[24][31] Twenty four tests were carried out on mutant mice and six significant abnormalities were observed.[24] 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.[24]

Family members

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

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}}: |access-date= requires |url= (help); Explicit use of et al. in: |author= (help)
  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. ^ a b Lars M. Rimol, Ingrid Agartz, Srdjan Djurovic, Andrew A. Brown, J. Cooper Roddey, Anna K. Kähler, Lavinia Athanasiu, Alexander H. Joyner, Nicholas J. Schork, Eric Halgren, Kjetil Sundet, Ingrid Melle, Anders M. Dale, Ole A. Andreassen, for the Alzheimer's Disease Neuroimaging Initiative. Sex-Dependent Association of Common Variants of Microcephaly Genes with Brain Structure.. Proc Natl Acad Sci U S A.. 2010;107(1):384-8. PMID 20080800.
  10. ^ Evans, P.D.; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)
  11. ^ 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
  12. ^ 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)
  13. ^ 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. Bibcode:2007PNAS..10410944D. doi:10.1073/pnas.0610848104. PMC 1904158. PMID 17537923.
  14. ^ 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)
  15. ^ Richard E. Green; et al. (2010). "A Draft Sequence of the Neandertal Genome". Science. 328 (5979): 710–722. Bibcode:2010Sci...328..710G. doi:10.1126/science.1188021. PMID 20448178. {{cite journal}}: Explicit use of et al. in: |author= (help)
  16. ^ John Derbyshire (2005). "The specter of difference". National Review. Retrieved 2008-09-21. {{cite news}}: Unknown parameter |month= ignored (help) [dead link]
  17. ^ scientists study of brain gene sparks a backlash
  18. ^ 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)
  19. ^ 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. Bibcode:2007Sci...317.1036T. doi:10.1126/science.1141705. PMID 17717170. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
  20. ^ "Neurological assessment data for Mcph1". Wellcome Trust Sanger Institute.
  21. ^ "Eye morphology data for Mcph1". Wellcome Trust Sanger Institute.
  22. ^ "Salmonella infection data for Mcph1". Wellcome Trust Sanger Institute.
  23. ^ "Citrobacter infection data for Mcph1". Wellcome Trust Sanger Institute.
  24. ^ a b c d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  25. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  26. ^ "International Knockout Mouse Consortium".
  27. ^ "Mouse Genome Informatics".
  28. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21677750, please use {{cite journal}} with |pmid=21677750 instead.
  29. ^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  30. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMID 21722353.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Microcephalin&oldid=492197958"