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{{protein
{{protein
| Name = microcephaly,<br />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 web | author = Singh N, Heroux A, Thompson JR, Mer G |title=Structure of the N-terminal BRCT domain of human microcephalin (MCPH1) | publisher = [[Protein Data Bank]] | url = http://www.rcsb.org/pdb/explore/pubmed.do?structureId=3PA6 | year = 2010 | doi = 10.2210/pdb3ktf/pdb}}</ref>
| image =Microcephalin.png
| image =Microcephalin.png
| width =
| width =
Line 38: Line 38:
}}
}}
'''''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"/>
'''''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 or [[behavior]] has yet been demonstrated in either this or another similarly studied microcephaly gene, ''[[ASPM (gene)|ASPM]]''.<ref name = "AutoR3-5"/><ref name = "AutoR3-6"/> 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.<ref name="Rimol_2010">{{cite journal | author = Rimol LM, Agartz I, Djurovic S, Brown AA, Roddey JC, Kähler AK, Mattingsdal M, Athanasiu L, Joyner AH, Schork NJ, Halgren E, Sundet K, Melle I, Dale AM, Andreassen OA | 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 | month = January | pmid = 20080800 | pmc = 2806758 | doi = 10.1073/pnas.0908454107 | url = |bibcode = 2010PNAS..107..384R }}</ref>
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 or [[behavior]] has yet been demonstrated in either this or another similarly studied microcephaly gene, ''[[ASPM (gene)|ASPM]]''.<ref name = "AutoR3-5"/><ref name = "AutoR3-6"/> 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.<ref name="Rimol_2010">{{cite journal |bibcode =2010PNAS..107..384R |jstor=40536283}}</ref>


==Structure==
==Structure==
Line 116: Line 116:
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/citrobacter-challenge/ |title=''Citrobacter'' infection data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}</ref>
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/citrobacter-challenge/ |title=''Citrobacter'' infection data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | author = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages = 925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal |doi=10.1111/j.1755-3768.2010.4142.x}}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
|}
[[Model organism]]s have been used in the study of MCPH1 function. A conditional [[knockout mouse]] line, called ''Mcph1<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Mcph1 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431685 |title=Mouse Genome Informatics}}</ref> 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.<ref name="pmid21677750">{{Cite pmid|21677750}}</ref><ref name="mouse_library">{{cite journal | doi = 10.1038/474262a | title = Mouse library set to be knockout | year = 2011 | author = Dolgin E | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | pmid = 21677718 }}</ref><ref name="mouse_for_all_reasons">{{cite journal | doi = 10.1016/j.cell.2006.12.018 | title = A Mouse for All Reasons | year = 2007 | journal = Cell | volume = 128 | pages = 9–13 | pmid = 17218247 |author=Collins FS, Rossant J, Wurst W| issue = 1 }}</ref>
[[Model organism]]s have been used in the study of MCPH1 function. A conditional [[knockout mouse]] line, called ''Mcph1<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Mcph1 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431685 |title=Mouse Genome Informatics}}</ref> 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.<ref name="pmid21677750">{{cite journal |pmid=21677750}}</ref><ref name="mouse_library">{{cite journal |doi=10.1038/474262a}}</ref><ref name="mouse_for_all_reasons">{{cite journal |doi=10.1016/j.cell.2006.12.018}}</ref>


Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal| author=van der Weyden L, White JK, Adams DJ, Logan DW| title=The mouse genetics toolkit: revealing function and mechanism. | journal=Genome Biol | year= 2011 | volume= 12 | issue= 6 | pages= 224 | pmid=21722353 | doi=10.1186/gb-2011-12-6-224 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21722353 | pmc=3218837}} </ref> Twenty four tests were carried out on [[mutant]] mice and six significant abnormalities were observed.<ref name="mgp_reference" /> [[Homozygous]] [[mutant]] animals were infertile, did not have a [[Pinna (anatomy)|pinna]] reflex, had a moderate degree of [[hearing impairment]], abnormal cornea morphology, lens morphology and [[cataracts]], and displayed chromosomal instability in a [[micronucleus test]].<ref name="mgp_reference" />
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal |doi=10.1186/gb-2011-12-6-224}} </ref> Twenty four tests were carried out on [[mutant]] mice and six significant abnormalities were observed.<ref name="mgp_reference" /> [[Homozygous]] [[mutant]] animals were infertile, did not have a [[Pinna (anatomy)|pinna]] reflex, had a moderate degree of [[hearing impairment]], abnormal cornea morphology, lens morphology and [[cataracts]], and displayed chromosomal instability in a [[micronucleus test]].<ref name="mgp_reference" />


== Family members ==
== Family members ==
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<ref name="microcephalin">
<ref name="microcephalin">
{{cite journal
{{cite journal |doi=10.1086/341283}}
| author = Jackson, A.P., ''et al.''
| year = 2002
| title = Identification of Microcephalin, a Protein Implicated in Determining the Size of the Human Brain
| journal = [[Am. J. Hum. Genet.]]
| volume = 71
| pages = 136–142
| pmid = 12046007
| doi = 10.1086/341283
| issue = 1
| pmc = 419993}}
</ref>
</ref>


<ref name="AutoR3-1">
<ref name="AutoR3-1">
{{cite journal
{{cite journal |doi=10.1016/S0092-8674(03)00430-6}}
| author = Lin, S.Y. & Elledge, S.J.
| year = 2003
| title = Multiple tumor suppressor pathways negatively regulate telomerase
| journal = [[Cell (journal)|Cell]]
| volume = 113
| pages = 881–889
| pmid = 12837246
| doi = 10.1016/S0092-8674(03)00430-6
| issue = 7}}
</ref>
</ref>


<ref name="AutoR3-2">
<ref name="AutoR3-2">
{{cite journal
{{cite journal |doi=10.1086/301966}}
| author = Jackson, A.P., ''et al.''
| year = 1998
| title = Primary Autosomal Recessive Microcephaly (MCPH1) Maps to Chromosome 8p22-pter
| journal = [[Am. J. Hum. Genet.]]
| volume = 63
| pages = 541–546
| accessdate = 10 February 2011
| pmid = 9683597
| doi = 10.1086/301966
| issue = 2
| pmc = 1377307}}
</ref>
</ref>


<ref name="AutoR3-3">{{cite journal
<ref name="AutoR3-3">
{{cite journal |doi=10.1093/hmg/ddh127}}
| author = Wang, Y.Q. & B. Su
| year = 2004
| title = Molecular evolution of microcephalin, a gene determining human brain size
| journal = [[Hum. Mol. Genet.]]
| volume = 13
| pages = 1131–1137
| doi = 10.1093/hmg/ddh127
| pmid = 15056608
| issue = 11}}
</ref>
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<ref name="AutoR3-4">
<ref name="AutoR3-4">
{{cite journal
{{cite journal |doi=10.1093/hmg/ddh126}}
| author = Evans, P.D., ''et al.''
| year = 2004
| title = Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size
| journal = [[Hum. Mol. Genet.]]
| volume = 13
| pages = 1139–1145
| doi = 10.1093/hmg/ddh126
| pmid = 15056607
| issue = 11}}
</ref>
</ref>


<ref name="AutoR3-5">{{cite journal
<ref name="AutoR3-5">
{{cite journal |doi=10.1093/hmg/ddl126}}
| author = R.P. Woods, ''et al.''
| year = 2006
| title = Normal variants of Microcephalin and ASPM do not account for brain size variability
| journal = [[Hum. Mol. Genet.]]
| volume = 15
| issue = 12
| pages = 2025–2029
| doi = 10.1093/hmg/ddl126
| pmid = 16687438}}
</ref>
</ref>


<ref name="AutoR3-6">{{cite journal
<ref name="AutoR3-6">
{{cite journal |doi=10.1098/rsbl.2006.0586}}
|author=J.P. Rushton, P.A. Vernon & T.A. Bons
</ref>
|month=22 Apr.,
|year=2007
|title=No evidence that polymorphisms of brain regulator genes ''Microcephalin'' and ''ASPM'' are associated with general mental ability, head circumference or altruism
|journal=[[Biol. Lett.]]
|volume=3
|issue=2
|pages=157–160
|doi=10.1098/rsbl.2006.0586
|pmid=17251122
|pmc=2104484
}}</ref>


<ref name="AutoR3-7">
<ref name="AutoR3-7">
{{cite journal |bibcode=2005Sci...309.1717E |laysummary=http://www.nytimes.com/2005/09/08/science/08cnd-brain.html |laysource=The New York Times |laydate=September 8, 2005}}
{{cite journal
| author = Evans, P.D., ''et al.''
| year = 2005
| title = ''Microcephalin'', a gene regulating brain size, continues to evolve adaptively in humans
| journal = [[Science (journal)|Science]]
| volume = 309
| pages = 1717–20
| doi = 10.1126/science.1113722
| laysummary = http://www.nytimes.com/2005/09/08/science/08cnd-brain.html?ex=1283832000&en=631902c8dabfb269&ei=5090&partner=rssuserland&emc=rss
| laysource = New York Times: Researchers Say Human Brain Is Still Evolving
| pmid = 16151009
| issue = 5741
| bibcode=2005Sci...309.1717E}}
</ref>
</ref>


<ref name="AutoR3-9">
<ref name="AutoR3-9">
{{cite journal
{{cite journal |bibcode=2007PNAS..10410944D}}
| author = Dediu, D. & D.R. Ladd
| year = 2007
| title = Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin | journal = [[Proc. Nat. Acad. Sci.]]
| doi = 10.1073/pnas.0610848104
| url = http://www.ling.ed.ac.uk/~s0340638/tonegenes/tonegenessummary.html
| volume = 104
| pages = 10944–9
| pmid = 17537923
| issue = 26
| pmc = 1904158|bibcode = 2007PNAS..10410944D }}
</ref>
</ref>


<ref name="AutoR3-10">
<ref name="AutoR3-10">[http://www.pnas.org/cgi/content/abstract/0606966103v1 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</ref>
{{cite journal |bibcode=2006PNAS..10318178E |jstor=30051829}}
</ref>


<ref name = "Human genome tales">
<ref name = "Human genome tales">{{cite journal|journal = Science |year = 2009 |wolume = 32|issue = 5916|pages = 866–871 |doi = 10.1126/science.323.5916.866 |title = NEANDERTAL GENOMICS: Tales of a Prehistoric Human Genome |author = Elizabeth Pennisi|volume = 323|pmid = 19213888}}</ref>
{{cite journal |doi=10.1126/science.323.5916.866}}
</ref>


<ref name = "green">{{Cite journal | author = Richard E. Green et al
<ref name = "green">
{{cite journal |bibcode = 2010Sci...328..710G}}
| title = A Draft Sequence of the Neandertal Genome | journal = Science
</ref>
| volume = 328 | issue = 5979 | pages = 710–722 | doi = 10.1126/science.1188021 | pmid = 20448178 | year = 2010|bibcode = 2010Sci...328..710G }}</ref>


<ref name="AutoR3-11">{{cite journal
<ref name="AutoR3-11">
{{cite journal |doi=10.1093/hmg/ddl487}}
| author = Mekel-Bobrov, N., ''et al.''
| title = The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence
| year = 2007
| journal = [[Hum. Mol. Genet.]]
| pages = adv. access
| doi = 10.1093/hmg/ddl487
| volume = 16
| pmid = 17220170
| issue = 6}}
</ref>
</ref>


<ref name="AutoR3-13">{{cite news
<ref name="AutoR3-13">{{cite news
|url=http://www.johnderbyshire.com/Opinions/HumanSciences/specterofdifference.html
|url=http://findarticles.com/p/articles/mi_m1282/is_20_57/ai_n15895156/pg_3?tag=artBody;col1
|title=The specter of difference
|title=The specter of difference
|author=John Derbyshire
|author=John Derbyshire
Line 285: Line 194:
|year=2005
|year=2005
|month=November
|month=November
}}</ref>
}} {{Dead link|date=August 2010|bot=RjwilmsiBot}}</ref>


<ref name="AutoR3-14">[http://online.wsj.com/public/article/SB115040765329081636-T5DQ4jvnwqOdVvsP_XSVG_lvgik_20060628.html?mod=blogs scientists study of brain gene sparks a backlash]</ref>
<ref name="AutoR3-14">[http://online.wsj.com/public/article/SB115040765329081636-T5DQ4jvnwqOdVvsP_XSVG_lvgik_20060628.html?mod=blogs scientists study of brain gene sparks a backlash]</ref>


<ref name="AutoR3-15">{{cite journal
<ref name="AutoR3-15">
{{cite journal |doi=10.1126/science.314.5807.1871}}
|author=Balter, M.
|month=December
|year=2006
|title=Bruce Lahn profile: Brain man makes waves with claims of recent human evolution
|journal=[[Science (journal)|Science]]
|volume=314
|issue=5807
|pages=1871–1873
|doi=10.1126/science.314.5807.1871
|pmid=17185582}}
</ref>
</ref>


<ref name="AutoR3-16">{{cite journal
<ref name="AutoR3-16">
{{cite journal |bibcode = 2007Sci...317.1036T }}
|author=Timpson, N., ''et al.''
|month=August
|year=2007
|title=Comment on Papers by Evans et al. and Mekel-Bobrov et al. on Evidence for Positive Selection of MCPH1 and ASPM
|journal=[[Science (journal)|Science]]
|volume=317
|issue=5841
|pages=1036
|doi=10.1126/science.1141705
|pmid=17717170|bibcode = 2007Sci...317.1036T }}
</ref>
</ref>


Line 319: Line 210:
== External links ==
== External links ==
*[http://www.nyas.org/podcasts/snc/neanderthal.mp3 Neanderthal Brains - a lecture by Bruce Lahn] - from the [[New York Academy of Sciences|NYAS]] podcasts.
*[http://www.nyas.org/podcasts/snc/neanderthal.mp3 Neanderthal Brains - a lecture by Bruce Lahn] - from the [[New York Academy of Sciences|NYAS]] podcasts.
*{{cite journal |pmid=20301772 |url=http://www.ncbi.nlm.nih.gov/books/NBK9587/}}
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=microcephaly GeneReviews/NCBI/NIH/UW entry on Primary Autosomal Recessive Microcephaly]
*[http://www.medterms.com/script/main/art.asp?articlekey=34399 Medterms]
*[http://www.medterms.com/script/main/art.asp?articlekey=34399 Medterms]
*{{cite journal |doi=10.1074/jbc.C400139200}}
*[http://www.jbc.org/cgi/content/abstract/279/33/34091 JBC]
*{{cite journal |doi=10.1093/hmg/ddh127}}
*[http://hmg.oupjournals.org/cgi/content/short/ddh127v1 OUP Journals]
*[http://harvester.embl.de/harvester/Q6RA/Q6RA50.htm EMBL]
*[http://harvester.embl.de/harvester/Q6RA/Q6RA50.htm EMBL]{{dead link}}
*{{cite journal |doi=10.1016/j.intell.2008.04.001}}
*{{cite journal|title=Recently-derived variants of brain-size genes ASPM, MCPH1, CDK5RAP and BRCA1 not associated with general cognition, reading or language| year=2008 | doi=10.1016/j.intell.2008.04.001 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W4M-4SHN0GS-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a8668cfde935719079d7ad9a80629557|author=Bates, T|journal=Intelligence|volume=36|pages=689|last2=Luciano|first2=M|last3=Lind|first3=P|last4=Wright|first4=M|last5=Montgomery|first5=G|last6=Martin|first6=N|issue=6}}


[[Category:Genes]]
[[Category:Genes]]

Revision as of 14:41, 6 May 2013

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." 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.[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 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[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)". Protein Data Bank. doi:10.2210/pdb3ktf/pdb.{{cite web}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b . doi:10.1086/341283. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  3. ^ . doi:10.1016/S0092-8674(03)00430-6. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  4. ^ . doi:10.1086/301966. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  5. ^ . doi:10.1093/hmg/ddh127. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  6. ^ . doi:10.1093/hmg/ddh126. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  7. ^ . doi:10.1093/hmg/ddl126. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
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External links

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