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Microcephalin
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<h2 id="structure">Structure</h2> <p>Microcephalin proteins contain the following three domains: </p> <ul><li><a href="/facts/N-terminus/yKYpuaBJ">N-terminal</a> <a href="/facts/BRCT_domain/6eCVhWlY">BRCT domain</a></li> <li>Central microcephalin protein domain (<a href="/facts/InterPro/pKwNm8t7">InterPro</a>: <i><a href="https://www.ebi.ac.uk/interpro/entry/IPR022047">IPR022047</a></i>)</li> <li><a href="/facts/C-terminus/ws4scHgT">C-terminal</a> BRCT domain</li></ul> <h2 id="expression-in-the-brain">Expression in the brain</h2> <p>MCPH1 is expressed in the <a href="/facts/Fetus/evocHd0Y">fetal</a> brain, in the developing <a href="/facts/Forebrain/X3H1IqLq">forebrain</a>, and on the walls of the <a href="/facts/Lateral_ventricles/gwTt9Voz">lateral ventricles</a>. <a href="/facts/Cell_(biology)/bLM9UQvy">Cells</a> of this area divide, producing <a href="/facts/Neuron/G7CyTVdH">neurons</a> that migrate to eventually form the <a href="/facts/Cerebral_cortex/GpXosGHP">cerebral cortex</a>. </p> <h2 id="evolution">Evolution</h2> <p>A derived form of <i>MCPH1</i> 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 <a href="/facts/Sub-Saharan_Africa/p4u389aa">Sub-Saharan Africa</a>; this rapid spread suggests a <a href="/facts/Selective_sweep/tgWztazB">selective sweep</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> However, scientists have not identified the <a href="/facts/Evolutionary_pressure/8zrwXR50">evolutionary pressures</a> that may have caused the spread of these mutations.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> This variant of the gene is thought to contribute to increased brain volume<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> and may correlate with the incidence of <a href="/facts/Tonal_language/eprhXrWJ">tonal languages</a>,<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> though modern distributions of <a href="/facts/Chromosome/FRGf11FC">chromosomes</a> bearing the ancestral forms of <i>MCPH1</i> and <i><a href="/facts/ASPM_(gene)/mT73pEFU">ASPM</a></i> showed neither microcephalin or ASPM had any significant effect on <a href="/facts/IQ/rozfcXsk">IQ</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>The derived form of <i>MCPH1</i> 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 <a href="/facts/Archaic_human_admixture_with_modern_humans/AtMLD75q">admixture between modern humans and extinct <i>Homo</i> spp</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> While <a href="/facts/Neanderthal/19rBo6ze">Neanderthals</a> 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.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h2 id="controversy">Controversy</h2> <p>The research results began to attract considerable controversy[<i>when?</i>] in the science world. <a href="/facts/John_Derbyshire/efG5wLFS">John Derbyshire</a> wrote that as a result of the findings, "our cherished national dream of a well-mixed and harmonious meritocracy [...] may be unattainable."<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> <a href="/facts/Richard_Lewontin/oQS5My85">Richard Lewontin</a> considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." <a href="/facts/Bruce_Lahn/60V0zoAQ">Bruce Lahn</a> 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.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Later studies have not found those gene variants to be associated with mental ability or cognition.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>Later <a href="/facts/Genome-wide_association_study/qemSYa3a">genetic association studies</a> by Mekel-Bobrov et al. and Evans et al. also reported that the genotype for MCPH1 was under positive selection. An analysis by Timpson <i>et al.</i>, found "no meaningful associations with brain size and various cognitive measures".<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> A later 2010 study by Rimol et al.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> demonstrated a link between brain size and structure and two microcephaly genes, <i>MCPH1</i> (only in females) and <i><a href="/facts/CDK5RAP2/0oKx61ou">CDK5RAP2</a></i> (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 <a href="/facts/Upstream_and_downstream_(DNA)/DXRN7G9P">upstream and downstream</a> <a href="/facts/Regulatory_elements/8jstgLKD">regulatory elements</a>, and allowed for separate effects for males and females. </p> <h2 id="other-mcph-genes">Other MCPH genes</h2> <p>In addition to MCPH1, other genes have been designated MCPH genes based on their role in brain size. These include <i><a href="/facts/WDR62/fVqT4bBb">WDR62</a></i> (<i>MCPH2</i>), <i><a href="/facts/CDK5RAP2/0oKx61ou">CDK5RAP2</a></i> (<i>MCPH3</i>), <i><a href="/facts/KNL1/158RVReQ">KNL1</a></i> (<i>MCPH4</i>), <a href="/facts/ASPM_(gene)/mT73pEFU"><i>ASPM</i></a> (<i>MCPH5</i>), <i><a href="/facts/CENPJ/FqL7v2FW">CENPJ</a></i> (<i>MCPH6</i>), <i><a href="/facts/STIL/slLhmANp">STIL</a></i> (<i>MCPH7</i>), <i><a href="/facts/CEP135/QVIIobYG">CEP135</a></i> (<i>MCPH8</i>), <i><a href="/facts/CEP152/wE7xLF0b">CEP152</a></i> (<i>MCPH9</i>), <i>ZNF335</i> (<i>MCPH10</i>), <i><a href="/facts/PHC1/Rvr32Xtt">PHC1</a></i> (<i>MCPH11</i>) and <i><a href="/facts/CDK6/Ksc3VAvY">CDK6</a></i> (<i>MCPH12</i>).<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="research-studies">Research studies</h2> <p>In March 2019, Chinese scientists reported inserting the human brain-related MCPH1 gene into laboratory <a href="/facts/Rhesus_monkey/TkffMX9v">rhesus monkeys</a>, 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.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Bruce_Lahn/60V0zoAQ">Bruce Lahn</a></li> <li><a href="/facts/Genetic_determinism/3m6amPFG">Genetic determinism</a></li> <li><a href="/facts/Race_and_genetics/nVMHIrGU">Race and genetics</a></li> <li><a href="/facts/Race_and_intelligence/MhE2V3sm">Race and intelligence</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Xu X, Lee J, Stern DF (August 2004). <a href="https://doi.org/10.1074%2Fjbc.C400139200">"Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1"</a>. <i>The Journal of Biological Chemistry</i>. 279 (33): 34091–4. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.C400139200">10.1074/jbc.C400139200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15220350">15220350</a>.</li> <li>Wang YQ, Su B (June 2004). <a href="https://doi.org/10.1093%2Fhmg%2Fddh127">"Molecular evolution of microcephalin, a gene determining human brain size"</a>. <i>Human Molecular Genetics</i>. 13 (11): 1131–7. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fhmg%2Fddh127">10.1093/hmg/ddh127</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15056608">15056608</a>.</li> <li>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". <i>Intelligence</i>. 36 (6): 689–93. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.intell.2008.04.001">10.1016/j.intell.2008.04.001</a>.</li> <li>Passemard S, Kaindl AM, Titomanlio L, Gerard B, Gressens P, Verloes A (1993). <a href="https://www.ncbi.nlm.nih.gov/books/NBK9587/">"Primary Autosomal Recessive Microcephaly"</a>. In Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds.). <i>GeneReviews</i>. University of Washington, Seattle. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/20301772">20301772</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://web.archive.org/web/20160304031907/http://www.nyas.org/podcasts/snc/neanderthal.mp3">"Neanderthal Brains"</a>—a lecture by Bruce Lahn from the <a href="/facts/New_York_Academy_of_Sciences/S1UMvded">NYAS</a> podcasts</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419993" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419993</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Online Mendelian Inheritance in Man (OMIM): 251200 <a href="/wiki/Online_Mendelian_Inheritance_in_Man" target="_blank">/wiki/Online_Mendelian_Inheritance_in_Man</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377307" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377307</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="https://doi.org/10.1093%2Fhmg%2Fddh127" target="_blank">https://doi.org/10.1093%2Fhmg%2Fddh127</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. <a href="https://doi.org/10.1093%2Fhmg%2Fddh126" target="_blank">https://doi.org/10.1093%2Fhmg%2Fddh126</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://doi.org/10.1093%2Fhmg%2Fddl126" target="_blank">https://doi.org/10.1093%2Fhmg%2Fddl126</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2104484" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2104484</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806758" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806758</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>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. Nicholas Wade (September 8, 2005). "Researchers Say Human Brain Is Still Evolving". 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