Microcephalin: Difference between revisions

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{{protein
{{Infobox_gene}}
| Name = microcephaly, primary autosomal recessive 1
{{Infobox protein family
| caption =  
| Symbol = Microcephalin
| Name = Microcephalin protein
| image =  
| image =  
| width =  
| width =  
| HGNCid = 6954
| caption =  
| Symbol = MCPH1
| Pfam = PF12258
| AltSymbols = Microcephalin<ref name="microcephalin">
| Pfam_clan =  
{{cite journal
| InterPro = IPR022047
| author = Jackson, A.P., ''et al.'' |
| SMART =  
| year = 2002
| PROSITE =  
| title = Identification of Microcephalin, a Protein Implicated in Determining the Size of the Human Brain
| MEROPS =
| journal = [[Am. J. Hum. Genet.]]
| SCOP =  
| volume = 71
| TCDB =  
| pages = 136-142
| OPM family =  
| pmid = 12046007}}
| OPM protein =  
</ref>, BRIT1<ref>
| CAZy =  
{{cite journal
| author = Lin, S.Y. & Elledge, S.J.
| year = 2003
| title = Multiple tumor suppressor pathways negatively regulate telomerase
| journal = [[Cell]]
| volume = 113
| pages = 881-889
| pmid = 12837246}}
</ref>
| EntrezGene = 79648
| OMIM = 607117
| RefSeq =  
| UniProt = Q8NEM0
| PDB =  
| PDB =  
| ECnumber =
| Chromosome = 8
| Arm = p
| Band = 23
| LocusSupplementaryData =
}}
}}
{{protein
'''Microcephalin''' ('''MCPH1''') is a [[gene]] that is expressed during fetal brain development. Certain [[mutation]]s in MCPH1, when [[homozygous]], cause primary [[microcephaly]]—a severely diminished [[Human brain|brain]].<ref name = "microcephalin"/><ref>{{OMIM|251200}}</ref><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 | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 1 | pages = 384–8 | date = January 2010 | pmid = 20080800 | pmc = 2806758 | doi = 10.1073/pnas.0908454107 | bibcode = 2010PNAS..107..384R | jstor = 40536283 }}</ref>
| Name = microcephaly, primary autosomal recessive 2
 
| caption =
==Structure==
| image =
Microcephalin proteins contain the following three domains:
| width =
* [[N-terminus|N-terminal]] [[BRCT domain]]
| HGNCid = 6955
* Central microcephalin protein domain ({{InterPro|IPR022047}})
| Symbol = MCPH2
* [[C-terminus|C-terminal]] BRCT domain
| AltSymbols =
| EntrezGene = 4181
| OMIM = 604317
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 19
| Arm = q
| Band = 13.1-13.2
| LocusSupplementaryData =
}}
{{protein
| Name = microcephaly, primary autosomal recessive 3
| caption =
| image =
| width =
| HGNCid = 6956
| Symbol = CDK5RAP2
| AltSymbols = MCPH3
| EntrezGene = 23702
| OMIM = 604804
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 9
| Arm = q
| Band = 33.3
| LocusSupplementaryData =
}}
{{protein
| Name = microcephaly, primary autosomal recessive 4
| caption =
| image =
| width =
| HGNCid = 6957
| Symbol = MCPH4
| AltSymbols =
| EntrezGene = 23701
| OMIM = 604321
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 15
| Arm = q
| Band = 15-21
| LocusSupplementaryData =
}}
{{protein
| Name = microcephaly, primary autosomal recessive 5
| caption =
| image =
| width =
| HGNCid = 6958
| Symbol = ASPM
| AltSymbols = MCPH5
| EntrezGene = 64590
| OMIM = 608716
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 1
| Arm = q
| Band = 31
| LocusSupplementaryData =
}}
{{protein
| Name = microcephaly, primary autosomal recessive 6
| caption =
| image =
| width =
| HGNCid = 17120
| Symbol = CENPJ
| AltSymbols = MCPH6
| EntrezGene = 170629
| OMIM = 608393
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 13
| Arm = q
| Band = 12.2
| LocusSupplementaryData =
}}
'''''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>
{{cite journal
| 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
| url = http://www.journals.uchicago.edu/AJHG/journal/issues/v63n2/980122/980122.html
| pmid = 9683597}}
</ref><ref name="microcephalin"/>
Hence it has been assumed that normal variants have a role in brain development.<ref>{{cite journal
| 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}}
</ref><ref>
{{cite journal
| 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}}
</ref> But no effect on [[mind|mental]] ability, brain size or [[behavior]] is attributable to either this or another similarly studied microcephaly gene, ''[[ASPM]]''.<ref>{{cite journal
| 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}}
</ref>
<ref>{{cite journal
|author=J.P. Rushton, P.A. Vernon & T.A. Bons
|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
}}</ref>


== Expression in the brain ==
== Expression in the brain ==
Line 186: Line 32:
==Evolution==
==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 more common form throughout the world except [[Sub-Saharan Africa]]. The timing of its emergence may have closely preceded the [[Upper Paleolithic]], when people started colonising Europe, although the margin of error is substantial<ref>
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]].<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"/>  This variant of the gene is thought to contribute to increased brain volume.<ref>{{cite journal | vauthors = Lari M, Rizzi E, Milani L, Corti G, Balsamo C, Vai S, Catalano G, Pilli E, Longo L, Condemi S, Giunti P, Hänni C, De Bellis G, Orlando L, Barbujani G, Caramelli D | title = The microcephalin ancestral allele in a Neanderthal individual | journal = PLOS One | volume = 5 | issue = 5 | pages = e10648 | date = May 2010 | pmid = 20498832 | pmc = 2871044 | doi = 10.1371/journal.pone.0010648 | bibcode = 2010PLoSO...510648L }}</ref> 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"/>
{{cite journal
 
| author = Evans, P.D., ''et al.''
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 [[Archaic human admixture with modern humans|admixture between modern humans and extinct ''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"/>
| year = 2005
 
| title = ''Microcephalin'', a gene regulating brain size, continues to evolve adaptively in humans
==Controversy==
| journal = [[Science (journal)|Science]]
 
| volume = 309
The research results began to attract considerable controversy in the science world. [[John Derbyshire]] 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." [[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.<ref name = "AutoR3-14"/><ref name = "AutoR3-15"/>
| pages = 1717-20
 
| doi = 10.1126/science.1113722
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_2010"/> 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.
| 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}}
== Model organisms ==
</ref> and there is evidence that the transition to the Upper Paleolithic occurred in Africa before spreading to Europe.<ref>{{cite journal
 
|author=Ambrose, S.H.
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
|year=1998
|+ ''Mcph1'' knockout mouse phenotype
|title=Chronology of the Later Stone Age and food production in East Africa
|-
|journal=J. Archaeol. Sci.
! Characteristic!! Phenotype
|volume=25
 
|issue=4
|-
|pages=377-392
| [[Homozygote]] viability || bgcolor="#488ED3"|Normal
|doi=10.1006/jasc.1997.0277
|-
|laysummary=http://www.sciencedaily.com/releases/1998/07/980707073901.htm
| Fertility || bgcolor="#C40000"|Abnormal
|laysource="Modern" Behavior Began 40,000 Years Ago In Africa, Evidence Suggests (Science Daily.com)}}
|-
</ref> Doubts concerning origins aside, modern distributions of [[chromosome]]s bearing the ancestral forms of ''MCPH1'' and ''[[ASPM|MCPH5]]'' coincide with the incidence of [[tonal language]]s, although the nature of this relationship can only be guessed at.<ref>
| Body weight || bgcolor="#488ED3"|Normal
{{cite journal
|-
| author = Dediu, D. & D.R. Ladd
| [[Open Field (animal test)|Anxiety]] || bgcolor="#488ED3"|Normal
| 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.]]
| Neurological assessment || bgcolor="#C40000"|Abnormal<ref name="Neurological assessment">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/neurological-assessment/ |title=Neurological assessment data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}</ref>
| doi = 10.1073/pnas.0610848104
|-
| url = http://www.ling.ed.ac.uk/~s0340638/tonegenes/tonegenessummary.html}}
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#C40000"|Abnormal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#C40000"|Abnormal<ref name="Eye morphology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/eye-morphology/ |title=Eye morphology data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
|-
| [[Haematology]] || bgcolor="#488ED3"|Normal
|-
| [[Micronucleus test]] || bgcolor="#C40000"|Abnormal
|-
| Heart weight || bgcolor="#488ED3"|Normal
|-
| Skin Histopathology || bgcolor="#488ED3"|Normal
|-
| Brain histopathology || bgcolor="#488ED3"|Normal
|-
| Eye Histopathology || bgcolor="#C40000"|Abnormal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/salmonella-challenge/ |title=''Salmonella'' 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 |last1=Gerdin |first1=AK |journal=Acta Ophthalmologica |volume=88 |pages=0}}</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 journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | 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 | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | date = June 2011 | pmid = 21722353 | pmc = 3218837 | 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 ==
In addition to MCPH1 the other five family members are: [[MCPH2]], [[CDK5RAP2]], [[MCPH4]], [[ASPM (gene)|ASPM]] and [[CENPJ]].
 
== See also ==
* [[Genetic determinism]]
* [[Race and genetics]]
* [[Race and intelligence]]
* [[Bruce Lahn]]
 
{{clear}}
 
== References ==
{{reflist | 32em | refs =
 
<ref name="microcephalin">
{{cite journal | vauthors = Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG | display-authors = 6 | title = Identification of microcephalin, a protein implicated in determining the size of the human brain | journal = American Journal of Human Genetics | volume = 71 | issue = 1 | pages = 136–42 | date = July 2002 | pmid = 12046007 | pmc = 419993 | doi = 10.1086/341283 }}
</ref>
 
<!-- <ref name="AutoR3-1">
{{cite journal | vauthors = Lin SY, Elledge SJ | title = Multiple tumor suppressor pathways negatively regulate telomerase | journal = Cell | volume = 113 | issue = 7 | pages = 881–9 | date = June 2003 | pmid = 12837246 | doi = 10.1016/S0092-8674(03)00430-6 }}
</ref> -->
 
<ref name="AutoR3-2">
{{cite journal | vauthors = Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, Mannan J, Karbani G, Corry P, Levene MI, Mueller RF, Markham AF, Lench NJ, Woods CG | display-authors = 6 | title = Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter | journal = American Journal of Human Genetics | volume = 63 | issue = 2 | pages = 541–6 | date = August 1998 | pmid = 9683597 | pmc = 1377307 | doi = 10.1086/301966 }}
</ref>
 
<ref name="AutoR3-3">
{{cite journal | vauthors = Wang YQ, Su B | title = Molecular evolution of microcephalin, a gene determining human brain size | journal = Human Molecular Genetics | volume = 13 | issue = 11 | pages = 1131–7 | date = June 2004 | pmid = 15056608 | doi = 10.1093/hmg/ddh127 }}
</ref>
 
<ref name="AutoR3-4">
{{cite journal | vauthors = Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT | title = Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size | journal = Human Molecular Genetics | volume = 13 | issue = 11 | pages = 1139–45 | date = June 2004 | pmid = 15056607 | doi = 10.1093/hmg/ddh126 }}
</ref>
 
<ref name="AutoR3-5">
{{cite journal | vauthors = Woods RP, Freimer NB, De Young JA, Fears SC, Sicotte NL, Service SK, Valentino DJ, Toga AW, Mazziotta JC | title = Normal variants of Microcephalin and ASPM do not account for brain size variability | journal = Human Molecular Genetics | volume = 15 | issue = 12 | pages = 2025–9 | date = June 2006 | pmid = 16687438 | doi = 10.1093/hmg/ddl126 }}
</ref>
 
<ref name="AutoR3-6">
{{cite journal | vauthors = Rushton JP, Vernon PA, Bons TA | title = No evidence that polymorphisms of brain regulator genes Microcephalin and ASPM are associated with general mental ability, head circumference or altruism | journal = Biology Letters | volume = 3 | issue = 2 | pages = 157–60 | date = April 2007 | pmid = 17251122 | pmc = 2104484 | doi = 10.1098/rsbl.2006.0586 }}
</ref>
 
<ref name="AutoR3-7">
{{cite journal | vauthors = Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT | title = Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans | journal = Science | volume = 309 | issue = 5741 | pages = 1717–20 | date = September 2005 | pmid = 16151009 | doi = 10.1126/science.1113722 | bibcode = 2005Sci...309.1717E | laydate = September 8, 2005 | laysummary = https://www.nytimes.com/2005/09/08/science/08cnd-brain.html | laysource = The New York Times }}
</ref>
</ref>


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. ([[Neanderthal]]s being one possibility).<ref>[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> 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.<ref name="pmid17175528">{{cite journal |author=Shimada MK, Panchapakesan K, Tishkoff SA, Nato AQ, Hey J |title=Divergent haplotypes and human history as revealed in a worldwide survey of X-linked DNA sequence variation |journal=Mol. Biol. Evol. |volume=24 |issue=3 |pages=687-98 |year=2007 |pmid=17175528 |doi=10.1093/molbev/msl196 |issn=}}</ref> Additionally, scientists have not identified the [[evolutionary pressure]]s that caused the supposed spread of these mutations.<ref>{{cite journal
<ref name="AutoR3-9">
| author = Mekel-Bobrov, N., ''et al.''
{{cite journal | vauthors = Dediu D, Ladd DR | title = Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 26 | pages = 10944–9 | date = June 2007 | pmid = 17537923 | pmc = 1904158 | doi = 10.1073/pnas.0610848104 | bibcode = 2007PNAS..10410944D | jstor = 25436044 }}
| 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}}
</ref>
</ref>


==Controversy==
<ref name="AutoR3-10">
Although [[Chinese people|Chinese]] himself, [[Bruce Lahn]]'s public announcements some brain-genes are more advanced on some continents than on others were conscripted by websites promoting white "racialism". An American xenophobic magazine embraced the research as "the moment the antiracists and egalitarians have dreaded." 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."
{{cite journal | vauthors = Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR, Lahn BT | title = Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 48 | pages = 18178–83 | date = November 2006 | pmid = 17090677 | pmc = 1635020 | doi = 10.1073/pnas.0606966103 | bibcode = 2006PNAS..10318178E | jstor = 30051829 }}
</ref>
 
<ref name = "Human genome tales">
{{cite journal | vauthors = Pennisi E | title = Neandertal genomics. Tales of a prehistoric human genome | journal = Science | volume = 323 | issue = 5916 | pages = 866–71 | date = February 2009 | pmid = 19213888 | doi = 10.1126/science.323.5916.866 }}
</ref>
 
<ref name = "green">
{{cite journal | vauthors = Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Ž, Gušic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PL, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo S | display-authors = 6 | title = A draft sequence of the Neandertal genome | journal = Science | volume = 328 | issue = 5979 | pages = 710–722 | date = May 2010 | pmid = 20448178 | doi = 10.1126/science.1188021 | bibcode = 2010Sci...328..710G | pmc=5100745}}
</ref>
 
<ref name="AutoR3-11">
{{cite journal | vauthors = Mekel-Bobrov N, Posthuma D, Gilbert SL, Lind P, Gosso MF, Luciano M, Harris SE, Bates TC, Polderman TJ, Whalley LJ, Fox H, Starr JM, Evans PD, Montgomery GW, Fernandes C, Heutink P, Martin NG, Boomsma DI, Deary IJ, Wright MJ, de Geus EJ, Lahn BT | display-authors = 6 | title = The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence | journal = Human Molecular Genetics | volume = 16 | issue = 6 | pages = 600–8 | date = March 2007 | pmid = 17220170 | doi = 10.1093/hmg/ddl487 }}
</ref>
 
<ref name="AutoR3-13">
{{cite news |url=http://www.johnderbyshire.com/Opinions/HumanSciences/specterofdifference.html | title = The specter of difference | first = John | last = Derbyshire | name-list-format = vanc |accessdate=2008-09-21 |work=[[National Review]] |date=November 2005 }}
</ref>
 
<ref name="AutoR3-14">{{cite web | first = Antonio | last = Regalado | name-list-format = vanc | date = June 2006 | url = https://www.wsj.com/articles/SB115040765329081636 | title = Scientist's Study Of Brain Genes Sparks a Backlash | work = The Wall Street Journal }}</ref>


Lahn's study began to attract considerable controversy in the science world, where he was criticized for overinterpreting and sensationalizing his findings. One of the co-authors, Sarah Tishkoff, distanced herself from the study saying that she was bothered how the paper drew a link between the genetic changes and the rise of civilization. She felt that any conclusions about why the mutations spread were premature and that it is "very simplistic" to confer so many behavioural traits on a single gene. [[Richard Lewontin]] considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." All the while maintaining that the science of his studies were sound, Lahn has nevertheless conceded that there is no real evidence [[natural selection]] had acted on cognition or intelligence through the genes. Tainted by the experience, he is engaging himself with other areas of study.<ref>[http://online.wsj.com/public/article/SB115040765329081636-T5DQ4jvnwqOdVvsP_XSVG_lvgik_20060628.html?mod=blogs scientists study of brain gene sparks a backlash]</ref><ref>{{cite journal
<ref name="AutoR3-15">
|author=Balter, M.
{{cite journal | vauthors = Balter M | title = Bruce Lahn profile. Brain man makes waves with claims of recent human evolution | journal = Science | volume = 314 | issue = 5807 | pages = 1871–3 | date = December 2006 | pmid = 17185582 | doi = 10.1126/science.314.5807.1871 }}
|month=Dec
|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}}
</ref>
</ref>


==Other names==
<ref name="AutoR3-16">
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.)
{{cite journal | vauthors = Timpson N, Heron J, Smith GD, Enard W | title = Comment on papers by Evans et al. and Mekel-Bobrov et al. on Evidence for Positive Selection of MCPH1 and ASPM | journal = Science | volume = 317 | issue = 5841 | pages = 1036; author reply 1036 | date = August 2007 | pmid = 17717170 | doi = 10.1126/science.1141705 | bibcode = 2007Sci...317.1036T }}
</ref>


==See also==
}}
* [[Genetic determinism]]
* [[Race and genetics#Modern civilization and genetics|Race and genetics]]
* [[Race and Intelligence#The human genome and intelligence|Race and intelligence]]
* [[Bruce Lahn]]


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|32em}}
* {{cite journal | vauthors = Xu X, Lee J, Stern DF | title = Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 33 | pages = 34091–4 | date = August 2004 | pmid = 15220350 | doi = 10.1074/jbc.C400139200 }}
* {{cite journal | vauthors = Wang YQ, Su B | title = Molecular evolution of microcephalin, a gene determining human brain size | journal = Human Molecular Genetics | volume = 13 | issue = 11 | pages = 1131–7 | date = June 2004 | pmid = 15056608 | doi = 10.1093/hmg/ddh127 }}
* {{cite journal |doi=10.1016/j.intell.2008.04.001 |title=Recently-derived variants of brain-size genes ASPM, MCPH1, CDK5RAP and BRCA1 not associated with general cognition, reading or language |year=2008 | vauthors = Bates TC, Luciano M, Lind PA, Wright MJ, Montgomery GW, Martin NG |journal=Intelligence |volume=36 |issue=6 |pages=689–93 }}
* {{cite book | pmid = 20301772 |chapterurl=https://www.ncbi.nlm.nih.gov/books/NBK9587/ |year=1993 |last1=Passemard |first1=Sandrine |last2=Kaindl |first2=Angela M |last3=Titomanlio |first3=Luigi |last4=Gerard |first4=Benedicte |last5=Gressens |first5=Pierre |last6=Verloes |first6=Alain |chapter=Primary Autosomal Recessive Microcephaly |title=GeneReviews |editor1-first=Roberta A |editor1-last=Pagon |editor2-first=Thomas D |editor2-last=Bird |editor3-first=Cynthia R |editor3-last=Dolan |editor4-first=Karen |editor4-last=Stephens |editor5-first=Margaret P |editor5-last=Adam | name-list-format = vanc }}
{{refend}}


== 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.
*[http://www.medterms.com/script/main/art.asp?articlekey=34399 Medterms]
*[http://www.jbc.org/cgi/content/abstract/279/33/34091 JBC]
*[http://hmg.oupjournals.org/cgi/content/short/ddh127v1 OUP Journals]
*[http://harvester.embl.de/harvester/Q6RA/Q6RA50.htm EMBL]


[[Category:Genes]]
[[Category:Animal genes]]
[[Category:Early hominids]]
[[Category:Human evolution]]
{{WikiDoc Sources}}
[[Category:Genes mutated in mice]]

Latest revision as of 08:33, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human
Microcephalin protein
Identifiers
SymbolMicrocephalin
PfamPF12258
InterProIPR022047

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.[1][2][3] Hence it has been assumed that variants have a role in brain development,[4][5] 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.[6][7] 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.[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 of microcephalin 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] This variant of the gene is thought to contribute to increased brain volume.[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.[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.[14][15]

Controversy

The research results began to attract considerable controversy in the science world. John Derbyshire 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.[8] 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. ↑ Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, et al. (July 2002). "Identification of microcephalin, a protein implicated in determining the size of the human brain". American Journal of Human Genetics. 71 (1): 136–42. doi:10.1086/341283. PMC 419993. PMID 12046007.
  2. ↑ Online Mendelian Inheritance in Man (OMIM) 251200
  3. ↑ Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, Mannan J, et al. (August 1998). "Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter". American Journal of Human Genetics. 63 (2): 541–6. doi:10.1086/301966. PMC 1377307. PMID 9683597.
  4. ↑ Wang YQ, Su B (June 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.
  5. ↑ Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT (June 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.
  6. ↑ Woods RP, Freimer NB, De Young JA, Fears SC, Sicotte NL, Service SK, Valentino DJ, Toga AW, Mazziotta JC (June 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.
  7. ↑ Rushton JP, Vernon PA, Bons TA (April 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 2104484. PMID 17251122.
  8. ↑ 8.0 8.1 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 (January 2010). "Sex-dependent association of common variants of microcephaly genes with brain structure". Proceedings of the National Academy of Sciences of the United States of America. 107 (1): 384–8. Bibcode:2010PNAS..107..384R. doi:10.1073/pnas.0908454107. JSTOR 40536283. PMC 2806758. PMID 20080800.
  9. ↑ Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT (September 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).
  10. ↑ 10.0 10.1 Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR, Lahn BT (November 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 of the United States of America. 103 (48): 18178–83. Bibcode:2006PNAS..10318178E. doi:10.1073/pnas.0606966103. JSTOR 30051829. PMC 1635020. PMID 17090677.
  11. ↑ Mekel-Bobrov N, Posthuma D, Gilbert SL, Lind P, Gosso MF, Luciano M, et al. (March 2007). "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.
  12. ↑ Lari M, Rizzi E, Milani L, Corti G, Balsamo C, Vai S, Catalano G, Pilli E, Longo L, Condemi S, Giunti P, Hänni C, De Bellis G, Orlando L, Barbujani G, Caramelli D (May 2010). "The microcephalin ancestral allele in a Neanderthal individual". PLOS One. 5 (5): e10648. Bibcode:2010PLoSO...510648L. doi:10.1371/journal.pone.0010648. PMC 2871044. PMID 20498832.
  13. ↑ Dediu D, Ladd DR (June 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 of the United States of America. 104 (26): 10944–9. Bibcode:2007PNAS..10410944D. doi:10.1073/pnas.0610848104. JSTOR 25436044. PMC 1904158. PMID 17537923.
  14. ↑ Pennisi E (February 2009). "Neandertal genomics. Tales of a prehistoric human genome". Science. 323 (5916): 866–71. doi:10.1126/science.323.5916.866. PMID 19213888.
  15. ↑ Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, et al. (May 2010). "A draft sequence of the Neandertal genome". Science. 328 (5979): 710–722. Bibcode:2010Sci...328..710G. doi:10.1126/science.1188021. PMC 5100745. PMID 20448178.
  16. ↑ Derbyshire J (November 2005). "The specter of difference". National Review. Retrieved 2008-09-21.
  17. ↑ Regalado A (June 2006). "Scientist's Study Of Brain Genes Sparks a Backlash". The Wall Street Journal.
  18. ↑ Balter M (December 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.
  19. ↑ Timpson N, Heron J, Smith GD, Enard W (August 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, author reply 1036. Bibcode:2007Sci...317.1036T. doi:10.1126/science.1141705. PMID 17717170.
  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. ↑ 24.0 24.1 24.2 24.3 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.
  25. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  26. ↑ "International Knockout Mouse Consortium".
  27. ↑ "Mouse Genome Informatics".
  28. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  29. ↑ Dolgin E (June 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 (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  31. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

  • Xu X, Lee J, Stern DF (August 2004). "Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1". The Journal of Biological Chemistry. 279 (33): 34091–4. doi:10.1074/jbc.C400139200. PMID 15220350.
  • Wang YQ, Su B (June 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.
  • Bates TC, Luciano M, Lind PA, Wright MJ, Montgomery GW, Martin NG (2008). "Recently-derived variants of brain-size genes ASPM, MCPH1, CDK5RAP and BRCA1 not associated with general cognition, reading or language". Intelligence. 36 (6): 689–93. doi:10.1016/j.intell.2008.04.001.
  • Passemard S, Kaindl AM, Titomanlio L, Gerard B, Gressens P, Verloes A (1993). "Primary Autosomal Recessive Microcephaly". In Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP. GeneReviews. PMID 20301772.

External links

Retrieved from "https://www.wikidoc.org/index.php?title=Microcephalin&oldid=1523475"