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词条 Microcephalin
释义

  1. Structure

  2. Expression in the brain

  3. Evolution

  4. Controversy

  5. Model organisms

  6. Family members

  7. See also

  8. References

  9. Further reading

  10. External links

{{Infobox_gene}}{{Infobox protein family
| Symbol = Microcephalin
| Name = Microcephalin protein
| image =
| width =
| caption =
| 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 mutations in MCPH1, when homozygous, cause primary microcephaly—a severely diminished brain.[1][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.[2]

Structure

Microcephalin proteins contain the following three domains:

  • N-terminal BRCT domain
  • Central microcephalin protein domain ({{InterPro|IPR022047}})
  • C-terminal BRCT domain

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.[3] 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.[15][16]

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."[17] 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.[18][19]

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".[20] However, a later study by Rimol et al.[2] 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[10][11] 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.[12][13][14]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on mutant mice and six significant abnormalities were observed.[8] 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.[8]

Family members

In addition to MCPH1 the other five family members are: MCPH2, CDK5RAP2, MCPH4, ASPM and CENPJ.

See also

  • Genetic determinism
  • Race and genetics
  • Race and intelligence
  • Bruce Lahn
{{clear}}

References

1. ^{{OMIM|251200}}
2. ^1 {{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 }}
3. ^{{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 }}
4. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/neurological-assessment/ |title=Neurological assessment data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}
5. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/eye-morphology/ |title=Eye morphology data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}
6. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/salmonella-challenge/ |title=Salmonella infection data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}
7. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGX/citrobacter-challenge/ |title=Citrobacter infection data for Mcph1 |publisher=Wellcome Trust Sanger Institute}}
8. ^1 2 3 {{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}}
9. ^Mouse Resources Portal, Wellcome Trust Sanger Institute.
10. ^{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Mcph1 |title=International Knockout Mouse Consortium}}
11. ^{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431685 |title=Mouse Genome Informatics}}
12. ^{{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 }}
13. ^{{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 }}
14. ^{{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 }}
15. ^{{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 }}
16. ^{{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 }}
17. ^1 {{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 }}
18. ^1 {{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 }}
19. ^1 {{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 }}
20. ^1 {{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 }}
21. ^1 {{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 }}
22. ^1 {{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 }}
23. ^1 {{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 }}
24. ^1 2 {{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 }}
25. ^1 {{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 }}
26. ^1 {{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}}
27. ^1 {{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 }}
28. ^1 {{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 }}
29. ^1 {{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 }}
30. ^1 {{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 }}
31. ^1 {{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 }}
[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]
}}

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 }}
  • {{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

  • Neanderthal Brains - a lecture by Bruce Lahn - from the NYAS podcasts.

3 : Animal genes|Human evolution|Genes mutated in mice
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