Editing Microcephalin

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = Microcephalin
| Name = Microcephalin protein
| image = Microcephalin.png
| alt = Microcephalin (MCPH1) is a gene that is expressed during fetal brain development
| width = 
| caption = Microcephalin.png
| Pfam = PF12258
| Pfam_clan = 
| InterPro = IPR022047
| SMART = 
| PROSITE = 
| MEROPS =
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| PDB = 
}}

'''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>

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

== Expression in the brain ==
MCPH1 is expressed in the [[fetus|fetal]] brain, in the developing [[forebrain]], and on the walls of the [[lateral ventricles]]. [[cell (biology)|Cells]] of this area divide, producing [[neuron]]s that migrate to eventually form the [[cerebral cortex]].

==Evolution==
A derived form of ''MCPH1'' 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"/>

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"/>

==Controversy==
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"/>

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.

== Other MCPH genes ==
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>

== Research studies ==
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>

== See also ==
* [[Bruce Lahn]]
* [[Genetic determinism]]
* [[Race and genetics]]
* [[Race and intelligence]]

== 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>

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{{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 }}
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<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 | doi-access = free }}
</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 | doi-access = free }}
</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 | doi-access = free }}
</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 | s2cid = 85864492}}
*{{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">
{{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 }}
</ref>

<ref name="AutoR3-10">
{{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 }}
</ref>

<ref name = "Human genome tales">
{{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 }}
</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 | 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:Animal genes]]
[[Category:Genes mutated in mice]]
[[Category:Human evolution]]