Microcephalin: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
some integrating of the leading paragraph
Removal request "Removing spammy content from c. 270 gene articles" from WP:AWBTASKS
 
(230 intermediate revisions by 96 users not shown)
Line 1: Line 1:
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{protein
{{Infobox_gene}}
| Name = microcephaly, primary autosomal recessive 1
{{Infobox protein family
| caption =
| image =
| Symbol = Microcephalin
| Name = Microcephalin protein
| image = Microcephalin.png
| alt = Microcephalin (MCPH1) is a gene that is expressed during fetal brain development
| width =
| width =
| caption = Microcephalin.png
| HGNCid = 6954
| Symbol = MCPH1
| Pfam = PF12258
| AltSymbols =
| Pfam_clan =
| EntrezGene = 79648
| InterPro = IPR022047
| OMIM = 607117
| SMART =
| RefSeq =
| PROSITE =
| UniProt = Q8NEM0
| MEROPS =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| 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"/> However, 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 ''[[Cerebral cortex|cortical]] surface area'' and total brain volume) but only in females, 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 | doi-access = free }}</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
== Expression in the brain ==
| OMIM = 604317
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]].
| RefSeq =

| UniProt =
==Evolution==
| PDB =
A derived form of ''MCPH1'' 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 | doi-access = free }}</ref> and may correlate with the incidence of [[tonal language]]s,<ref name = "AutoR3-9"/> though modern distributions of [[chromosome]]s bearing the ancestral forms of ''MCPH1'' and ''[[ASPM (gene)|ASPM]]'' showed neither microcephalin or ASPM had any significant effect on [[IQ]].<ref name="AutoR3-11"/>
| ECnumber =

| Chromosome = 19
The derived form of ''MCPH1'' 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"/>
| Arm = q

| Band = 13.1-13.2
==Controversy==
| LocusSupplementaryData =
The research results{{clarify |date=April 2019 |reason=which research results?}} began to attract considerable controversy{{when|date=January 2020}} 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"/> Later studies have not found those gene variants to be associated with mental ability or cognition.<ref name="AutoR3-16"/><ref name="AutoR3-11"/><ref name="AutoR3-6"/>
}}

{{protein
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"/> A later 2010 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 (DNA)|upstream and downstream]] [[regulatory elements]], and allowed for separate effects for males and females.
| Name = microcephaly, primary autosomal recessive 3

| caption =
== Other MCPH genes ==
| image =
In addition to MCPH1, other genes have been designated MCPH genes based on their role in brain size. These include ''[[WDR62]]'' (''MCPH2''), ''[[CDK5RAP2]]'' (''MCPH3''), ''[[KNL1]]'' (''MCPH4''), [[ASPM (gene)|''ASPM'']] (''MCPH5''), ''[[CENPJ]]'' (''MCPH6''), ''[[STIL]]'' (''MCPH7''), ''[[CEP135]]'' (''MCPH8''), ''[[CEP152]]'' (''MCPH9''), ''[[ZNF335]]'' (''MCPH10''), ''[[PHC1]]'' (''MCPH11'') and ''[[CDK6]]'' (''MCPH12'').<ref>{{cite journal | vauthors = Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA, Ilyas AM, Pushparaj P, Ahmed F, Algahtani HA, Al-Qahtani MH, Saleh Jamal H | display-authors = 6 | title = Molecular genetics of human primary microcephaly: an overview | journal = BMC Medical Genomics | volume = 8 | issue = Suppl 1 | pages = S4 | date = 2015-01-15 | pmid = 25951892 | pmc = 4315316 | doi = 10.1186/1755-8794-8-S1-S4 | doi-access = free }}</ref>
| width =

| HGNCid = 6956
== Research studies ==
| Symbol = MCPH3
In March 2019, Chinese scientists reported inserting the human brain-related MCPH1 gene into laboratory [[rhesus monkey]]s, resulting in the transgenic monkeys performing better and answering faster on "short-term memory tests involving matching colors and shapes", compared to control non-transgenic monkeys, according to the researchers.<ref name="DSVR-20191229">{{cite news | vauthors = Burrell T |title=Scientists Put a Human Intelligence Gene Into a Monkey. Other Scientists are Concerned. |url=https://www.discovermagazine.com/mind/scientists-put-a-human-intelligence-gene-into-a-monkey-other-scientists-are |date=29 December 2019 |work=[[Discover (magazine)|Discover]] |access-date=30 December 2019 }}</ref><ref name="NSR-20190327">{{cite journal |author=Shi, Lei |display-authors=et al. |title=Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development |date=27 March 2019 |journal=[[Chinese Academy of Sciences|Chinese National Science Review]] |volume=6 |issue=3 |pages=480–493 |doi=10.1093/nsr/nwz043|pmid=34691896 | pmc=8291473 |doi-access=free }}</ref>
| AltSymbols = CDK5RAP2

| EntrezGene = 23702
== See also ==
| OMIM = 604804
* [[Bruce Lahn]]
| RefSeq =
* [[Genetic determinism]]
| UniProt =
* [[Race and genetics]]
| PDB =
* [[Race and intelligence]]
| ECnumber =

| Chromosome = 9
== References ==
| Arm = q
{{reflist | 32em | refs =
| Band = 33.3

| LocusSupplementaryData =
<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 }}
{{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 = MCPH5
| AltSymbols = ASPM
| 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 = MCPH6
| AltSymbols = CENPJ
| EntrezGene = 170629
| OMIM = 608393
| RefSeq =
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 13
| Arm = q
| Band = 12.2
| LocusSupplementaryData =
}}
The '''''microcephalins''''' (Greek for "small head) are a group of six genes (called ''MCPH1'' to ''MCPH6''), in which two copies of a loss-of-function mutations causes primary [[microcephaly]] ({{OMIM|251200}}), a condition characterised by a severely diminished 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>
{{cite journal
| 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}}
</ref>
</ref>

Hence it has been assumed that normal variants of the these genes have a role in brain development,<ref>{{cite journal
<!-- <ref name="AutoR3-1">
| author = Wang, Y.Q. & B. Su
{{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 }}
| year = 2004
</ref> -->
| title = Molecular evolution of microcephalin, a gene determining human brain size

| journal = [[Hum. Mol. Genet.]]
<ref name="AutoR3-2">
| volume = 13
{{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 }}
| 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 evidence to support this is lacking so far<ref>{{cite journal
| author = Woods, R.P., ''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> and the selective pressures for the continual evolution of at least two of them are unknown.<ref>{{cite journal
| 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}}
</ref>
</ref>


<ref name="AutoR3-3">
==Evolution==
{{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 | doi-access = free }}
</ref>


<ref name="AutoR3-4">
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]]. It is therefore very possible that the timing of its emergence narrowly preceded the [[Upper Paleolithic]], when people started colonising Europe.<ref>
{{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 | doi-access = free }}
{{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}}
</ref> The distribution of [[chromosome]]s bearing the ancestral forms of ''MCPH1'' and ''[[ASPM|MCPH5]]'' coincide with the incidence of [[tonal language]]s, although the exact nature of the relationship is unknown.<ref>
{{cite journal
| 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}}
</ref>
</ref>


<ref name="AutoR3-5">
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 9 Africans used in the study has been criticized as being inadequate for the conclusion the paper draws, and comparable studies demostrate 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>
{{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 | doi-access = free }}
</ref>


<ref name="AutoR3-6">
== Expression in the brain ==
{{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 }}
MCPH1 is expressed in the 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]].
</ref>


<ref name="AutoR3-7">
==Other names==
{{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 | s2cid = 85864492}}
The microcephaly-related genes ''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 news |author=Nicholas Wade |date=September 8, 2005 |title=Researchers Say Human Brain Is Still Evolving |newspaper=The New York Times |url=https://www.nytimes.com/2005/09/08/science/08cnd-brain.html |url-access=subscription}}</ref>


<ref name="AutoR3-9">
==Sources and notes==
{{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 | doi-access = free }}
<references />
</ref>


<ref name="AutoR3-10">
== External links ==
{{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 | doi-access = free }}
* [http://www.nyas.org/podcasts/snc/neanderthal.mp3 Neanderthal Brains - a lecture by Bruce Lahn] - from the [[New York Academy of Sciences|NYAS]] podcasts.
</ref>


<ref name = "Human genome tales">
==Further reading==
{{cite journal | vauthors = Pennisi E | author-link = Elizabeth Pennisi | 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 | s2cid = 206584252 }}
*[http://www.medterms.com/script/main/art.asp?articlekey=34399 Medterms]
</ref>
*[http://www.jbc.org/cgi/content/abstract/279/33/34091 JBC]

*[http://hmg.oupjournals.org/cgi/content/short/ddh127v1 OUP Journals]
<ref name = "green">
*[http://harvester.embl.de/harvester/Q6RA/Q6RA50.htm EMBL]
{{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 | doi-access = free }}
</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-style = vanc |access-date=2008-09-21 |work=[[National Review]] |date=November 2005 }}
</ref>

<ref name="AutoR3-14">{{cite web | first = Antonio | last = Regalado | name-list-style = 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>

<ref name="AutoR3-15">
{{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 | s2cid = 9478090 }}
</ref>

<ref name="AutoR3-16">
{{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 | doi-access = free }}
</ref>

}}

== Further reading ==
{{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 | doi-access = free }}
* {{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 | doi-access = free }}
* {{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 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK9587/ |year=1993 | vauthors = Passemard S, Kaindl AM, Titomanlio L, Gerard B, Gressens P, Verloes A |chapter=Primary Autosomal Recessive Microcephaly |title=GeneReviews |publisher=University of Washington, Seattle | veditors = Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP }}
{{refend}}

== External links ==
* [https://web.archive.org/web/20160304031907/http://www.nyas.org/podcasts/snc/neanderthal.mp3 "Neanderthal Brains"]—a lecture by Bruce Lahn from the [[New York Academy of Sciences|NYAS]] podcasts


[[Category:Genes]]
[[Category:Animal genes]]
[[Category:Early hominids]]
[[Category:Genes mutated in mice]]
[[Category:Human evolution]]

Latest revision as of 02:59, 19 December 2023

MCPH1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMCPH1, BRIT1, MCT, microcephalin 1
External IDsOMIM: 607117; MGI: 2443308; HomoloGene: 32586; GeneCards: MCPH1; OMA:MCPH1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

79648

244329

Ensembl

ENSG00000147316
ENSG00000285262

ENSMUSG00000039842

UniProt

Q8NEM0

Q7TT79

RefSeq (mRNA)

NM_173189

RefSeq (protein)

NP_775281

Location (UCSC)Chr 8: 6.41 – 6.65 MbChr 8: 18.65 – 18.85 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Microcephalin protein
Microcephalin (MCPH1) is a gene that is expressed during fetal brain development
Microcephalin.png
Identifiers
SymbolMicrocephalin
PfamPF12258
InterProIPR022047
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.[5][6][7] Hence, it has been assumed that variants have a role in brain development.[8][9] However, in normal individuals no effect on mental ability or behavior has yet been demonstrated in either this or another similarly studied microcephaly gene, ASPM.[10][11] 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) but only in females, and common genetic variants within both the MCPH1 gene and another similarly studied microcephaly gene, CDK5RAP2.[12]

Structure[edit]

Microcephalin proteins contain the following three domains:

Expression in the brain[edit]

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[edit]

A derived form of MCPH1 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.[13][14] However, scientists have not identified the evolutionary pressures that may have caused the spread of these mutations.[15] This variant of the gene is thought to contribute to increased brain volume[16] and may correlate with the incidence of tonal languages,[17] though modern distributions of chromosomes bearing the ancestral forms of MCPH1 and ASPM showed neither microcephalin or ASPM had any significant effect on IQ.[15]

The derived form of MCPH1 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.[14] 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.[18][19]

Controversy[edit]

The research results[clarification needed] began to attract considerable controversy[when?] 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."[20] 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.[21][22] Later studies have not found those gene variants to be associated with mental ability or cognition.[23][15][11]

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".[23] A later 2010 study by Rimol et al.[12] 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 regulatory elements, and allowed for separate effects for males and females.

Other MCPH genes[edit]

In addition to MCPH1, other genes have been designated MCPH genes based on their role in brain size. These include WDR62 (MCPH2), CDK5RAP2 (MCPH3), KNL1 (MCPH4), ASPM (MCPH5), CENPJ (MCPH6), STIL (MCPH7), CEP135 (MCPH8), CEP152 (MCPH9), ZNF335 (MCPH10), PHC1 (MCPH11) and CDK6 (MCPH12).[24]

Research studies[edit]

In March 2019, Chinese scientists reported inserting the human brain-related MCPH1 gene into laboratory rhesus monkeys, resulting in the transgenic monkeys performing better and answering faster on "short-term memory tests involving matching colors and shapes", compared to control non-transgenic monkeys, according to the researchers.[25][26]

See also[edit]

References[edit]

  1. ^ a b c ENSG00000285262 GRCh38: Ensembl release 89: ENSG00000147316, ENSG00000285262 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000039842 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ Online Mendelian Inheritance in Man (OMIM): 251200
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ a b 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.
  12. ^ a b 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.
  13. ^ 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. S2CID 85864492.
  14. ^ a b 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.
  15. ^ a b c 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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. S2CID 206584252.
  19. ^ 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.
  20. ^ Derbyshire J (November 2005). "The specter of difference". National Review. Retrieved 2008-09-21.
  21. ^ Regalado A (June 2006). "Scientist's Study Of Brain Genes Sparks a Backlash". The Wall Street Journal.
  22. ^ 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. S2CID 9478090.
  23. ^ a b 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.
  24. ^ Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA, Ilyas AM, et al. (2015-01-15). "Molecular genetics of human primary microcephaly: an overview". BMC Medical Genomics. 8 (Suppl 1): S4. doi:10.1186/1755-8794-8-S1-S4. PMC 4315316. PMID 25951892.
  25. ^ Burrell T (29 December 2019). "Scientists Put a Human Intelligence Gene Into a Monkey. Other Scientists are Concerned". Discover. Retrieved 30 December 2019.
  26. ^ Shi, Lei; et al. (27 March 2019). "Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development". Chinese National Science Review. 6 (3): 480–493. doi:10.1093/nsr/nwz043. PMC 8291473. PMID 34691896.

Further reading[edit]

External links[edit]

Retrieved from "https://en.wikipedia.org/w/index.php?title=Microcephalin&oldid=1190649702"