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{{protein
{{protein
| Name = microcephaly, primary autosomal recessive 1
| Name = microcephaly,<br />primary autosomal recessive 1
| caption = [[X-ray_crystallography#Biological_macromolecular_crystallography|Crystallographic structure]] of the [[N-terminus|N-terminal]] [[BRCT domain]] of human microcephalin (MCPH1)<ref name="Singh_2010">{{PDB|3KTF}}; {{cite journal | author = Singh N, Heroux A, Thompson JR, Mer G|title=Structure of the N-terminal BRCT domain of human microcephalin (MCPH1) | journal = To be published | year = 2010 | doi = 10.2210/pdb3ktf/pdb}}</ref>
| caption = [[X-ray_crystallography#Biological_macromolecular_crystallography|Crystallographic structure]] of the [[N-terminus|N-terminal]] [[BRCT domain]] of human microcephalin (MCPH1)<ref name="Singh_2010">{{PDB|3KTF}}; {{cite journal | author = Singh N, Heroux A, Thompson JR, Mer G|title=Structure of the N-terminal BRCT domain of human microcephalin (MCPH1) | journal = To be published | year = 2010 | doi = 10.2210/pdb3ktf/pdb}}</ref>
| image =Microcephalin.png
| image =Microcephalin.png
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}}
}}
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{{protein
{{Infobox protein family
| Symbol = Microcephalin
| Name = microcephaly, primary autosomal recessive 2
| Name = Microcephalin protein
| image =
| width =
| caption =
| Pfam = PF12258
| Pfam_clan =
| InterPro = IPR022047
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| PDB =
}}
{{FixBunching|end}}

'''''Microcephalin''''' ('''''MCPH1''''') is one of six [[gene]]s causing primary [[microcephaly]] ({{OMIM|251200}}) when non-functional [[mutation]]s exist in the [[homozygous]] state. Derived from the [[Greek language|Greek]] words for "small" and "head", this condition is characterised by a severely diminished [[human brain|brain]].<ref name = "microcephalin"/><ref name = "AutoR3-2"/>
Hence it has been assumed that variants have a role in brain development,<ref name = "AutoR3-3"/><ref name = "AutoR3-4"/> but in normal individuals no effect on [[mind|mental]] ability, brain size or [[behavior]] has been attributed to either this or another similarly studied microcephaly gene, ''[[ASPM (gene)|ASPM]]''.<ref name = "AutoR3-5"/><ref name = "AutoR3-6"/>

==Structure==
Microcephalin proteins contain the following three domains:
* [[N-terminus|N-terminal]] [[BRCT domain]]
* Central microcephalin protein domain ({{InterPro|IPR022047}})
* [[C-terminus|C-terminal]] BRCT domain

== Expression in the brain ==
MCPH1 is expressed in the [[fetus|fetal]] brain, in the developing [[forebrain]], and on the walls of the [[lateral ventricles]]. [[cell (biology)|Cells]] of this area divide, producing [[neuron]]s 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|selective sweep]].<ref name = "AutoR3-7"/><ref name = "AutoR3-10"/> However, scientists have not identified the [[evolutionary pressure]]s that may have caused the spread of these mutations.<ref name = "AutoR3-11"/> Modern distributions of [[chromosome]]s bearing the ancestral forms of ''MCPH1'' and ''[[ASPM (gene)|ASPM]]'' are correlated with the incidence of [[tonal language]]s, but the nature of this relationship is far from clear.<ref name = "AutoR3-9"/>

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 ''[[archaic Homo sapiens|Homo]]'' spp.<ref name = "AutoR3-10"/> While [[Neanderthal]]s 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.<ref name = "Human genome tales"/><ref name = "green"/>

==Controversy==
Although [[Chinese people|Chinese]] himself, researcher [[Bruce Lahn]]'s public presentations on the haplogroup D results were conscripted by websites promoting white "racialism". An American White supremacist magazine embraced the research as "the moment the antiracists and egalitarians have dreaded."<ref name = "AutoR3-12"/>

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 are 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, however, found "no meaningful associations with brain size and various cognitive measures".<ref name = "AutoR3-16"/>

== Family members ==

In addition to MCPH1. the other five family members are:

{|
|- valign="top"
|{{protein
| Name = microcephaly,<br />primary autosomal recessive 2
| caption =
| caption =
| image =
| image =
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| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
|{{protein
{{FixBunching|mid}}
| Name = microcephaly,<br />primary autosomal recessive 3
{{protein
| Name = microcephaly, primary autosomal recessive 3
| caption =
| caption =
| image =
| image =
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| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
|{{protein
{{FixBunching|mid}}
| Name = microcephaly,<br />primary autosomal recessive 4
{{protein
| Name = microcephaly, primary autosomal recessive 4
| caption =
| caption =
| image =
| image =
Line 79: Line 129:
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
|{{protein
{{FixBunching|mid}}
| Name = microcephaly,<br />primary autosomal recessive 5
{{protein
| Name = microcephaly, primary autosomal recessive 5
| caption =
| caption =
| image =
| image =
Line 99: Line 148:
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
|{{protein
{{FixBunching|mid}}
| Name = microcephaly,<br />primary autosomal recessive 6
{{protein
| Name = microcephaly, primary autosomal recessive 6
| caption =
| caption =
| image =
| image =
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| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
|}
{{FixBunching|end}}
'''''Microcephalin''''' ('''''MCPH1''''') is one of six [[gene]]s causing primary [[microcephaly]] ({{OMIM|251200}}) when non-functional [[mutation]]s exist in the [[homozygous]] state. Derived from the [[Greek language|Greek]] words for "small" and "head", this condition is characterised by a severely diminished [[human brain|brain]].<ref name = "microcephalin"/><ref name = "AutoR3-2"/>
Hence it has been assumed that variants have a role in brain development,<ref name = "AutoR3-3"/><ref name = "AutoR3-4"/> but in normal individuals no effect on [[mind|mental]] ability, brain size or [[behavior]] has been attributed to either this or another similarly studied microcephaly gene, ''[[ASPM (gene)|ASPM]]''.<ref name = "AutoR3-5"/><ref name = "AutoR3-6"/>

==Structure==
Microcephalin proteins contain the following three domains:
* [[N-terminus|N-terminal]] [[BRCT domain]]
* Central microcephalin protein domain ({{InterPro|IPR022047}})
* [[C-terminus|C-terminal]] BRCT domain

== Expression in the brain ==
MCPH1 is expressed in the [[fetus|fetal]] brain, in the developing [[forebrain]], and on the walls of the [[lateral ventricles]]. [[cell (biology)|Cells]] of this area divide, producing [[neuron]]s 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|selective sweep]].<ref name = "AutoR3-7"/><ref name = "AutoR3-10"/> However, scientists have not identified the [[evolutionary pressure]]s that may have caused the spread of these mutations.<ref name = "AutoR3-11"/> Modern distributions of [[chromosome]]s bearing the ancestral forms of ''MCPH1'' and ''[[ASPM (gene)|ASPM]]'' are correlated with the incidence of [[tonal language]]s, but the nature of this relationship is far from clear.<ref name = "AutoR3-9"/>

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 ''[[archaic Homo sapiens|Homo]]'' spp.<ref name = "AutoR3-10"/> While [[Neanderthal]]s 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.<ref name = "Human genome tales"/><ref name = "green"/>

==Controversy==
Although [[Chinese people|Chinese]] himself, researcher [[Bruce Lahn]]'s public presentations on the haplogroup D results were conscripted by websites promoting white "racialism". An American White supremacist magazine embraced the research as "the moment the antiracists and egalitarians have dreaded."<ref name = "AutoR3-12"/>

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 are 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, however, found "no meaningful associations with brain size and various cognitive measures".<ref name = "AutoR3-16"/>


==Other names==
The microcephaly-related loci ''MCPH 3'', ''5'' and ''6'' are usually classified by their alternate names [[CDK5RAP2]], [[ASPM (gene)|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.)
The microcephaly-related loci ''MCPH 3'', ''5'' and ''6'' are usually classified by their alternate names [[CDK5RAP2]], [[ASPM (gene)|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.)


Revision as of 20:03, 27 December 2010

Template:FixBunching

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

Template:FixBunching

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

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 (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.[9][10] However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations.[11] 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.[12]

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 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.[13][14]

Controversy

Although Chinese himself, researcher Bruce Lahn's public presentations on the haplogroup D results were conscripted by websites promoting white "racialism". An American White supremacist magazine embraced the research as "the moment the antiracists and egalitarians have dreaded."[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."[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 are 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, however, found "no meaningful associations with brain size and various cognitive measures".[19]

Family members

In addition to MCPH1. the other five family members are:

microcephaly,
primary autosomal recessive 2
Identifiers
SymbolMCPH2
NCBI gene4181
HGNC6955
OMIM604317
Other data
LocusChr. 19 q13.1-13.2
microcephaly,
primary autosomal recessive 3
Identifiers
SymbolCDK5RAP2
Alt. symbolsMCPH3
NCBI gene23702
HGNC6956
OMIM604804
Other data
LocusChr. 9 q33.3
microcephaly,
primary autosomal recessive 4
Identifiers
SymbolMCPH4
NCBI gene23701
HGNC6957
OMIM604321
Other data
LocusChr. 15 q15-21
microcephaly,
primary autosomal recessive 5
Identifiers
SymbolASPM
Alt. symbolsMCPH5
NCBI gene64590
HGNC6958
OMIM608716
Other data
LocusChr. 1 q31
microcephaly,
primary autosomal recessive 6
Identifiers
SymbolCENPJ
Alt. symbolsMCPH6
NCBI gene170629
HGNC17120
OMIM608393
Other data
LocusChr. 13 q12.2

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. ^ 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)
  12. ^ 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.
  13. ^ 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)
  14. ^ 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)
  15. ^ Chris Brand (2005). "Race realism takes a step forward". American Renaissance. Retrieved 2008-09-21. {{cite web}}: Unknown parameter |month= ignored (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. doi:10.1126/science.1141705. PMID 17185582. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Microcephalin&oldid=404510570"