Microcephalin

microcephaly, primary autosomal recessive 1
Crystallographic structure of the N-terminal BRCT domain of human microcephalin (MCPH1)[1]
Identifiers
Symbol	MCPH1
Alt. symbols	Microcephalin,[2] BRIT1[3]
Entrez	79648
HUGO	6954
OMIM	607117
UniProt	Q8NEM0
Other data
Locus	Chr. 8 p23

Microcephalin protein
Identifiers
Symbol	Microcephalin
Pfam	PF12258
InterPro	IPR022047
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Microcephalin (MCPH1) is one of six genes causing primary microcephaly (Online 'Mendelian Inheritance in Man' (OMIM) 251200) when non-functional mutations exist in the homozygous state. Derived from the Greek words for "small" and "head", this condition is characterised by a severely diminished brain.^[2][4] Hence it has been assumed that variants have a role in brain development,^[5][6] but in normal individuals no effect on mental ability, brain size or behavior has been attributed to either this or another similarly studied microcephaly gene, ASPM.^[7][8]

Structure

Microcephalin proteins contain the following three domains:

• N-terminal BRCT domain
• Central microcephalin protein domain (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 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] 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.^[12]

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.^[13][14]

Controversy

The research results began to attract considerable controversy in the science world. John Derbyshire, writing in 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."^[15] Richard Lewontin considers the two published papers as "egregious examples of going well beyond the data to try to make a splash." Lahn maintains that the science of the studies are sound, and freely admits that a direct link between these particular genes and either cognition or intelligence has not been clearly established. Bruce Lahn is now engaging himself with other areas of study.^[16][17]

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., however, found "no meaningful associations with brain size and various cognitive measures".^[18]

Family members

In addition to MCPH1. the other five family members are:

microcephaly, primary autosomal recessive 2 Identifiers Symbol MCPH2 Entrez 4181 HUGO 6955 OMIM 604317 Other data Locus Chr. 19 q13.1-13.2

microcephaly, primary autosomal recessive 3 Identifiers Symbol CDK5RAP2 Alt. symbols MCPH3 Entrez 55755 HUGO 18672 OMIM 604804 Other data Locus Chr. 9 q33.3

microcephaly, primary autosomal recessive 4 Identifiers Symbol MCPH4 Entrez 23701 HUGO 6957 OMIM 604321 Other data Locus Chr. 15 q15-21

microcephaly, primary autosomal recessive 5 Identifiers Symbol ASPM Alt. symbols MCPH5 Entrez 259266 HUGO 19048 OMIM 608716 Other data Locus Chr. 1 q31

microcephaly, primary autosomal recessive 6 Identifiers Symbol CENPJ Alt. symbols MCPH6 Entrez 55835 HUGO 17272 OMIM 608393 Other data Locus Chr. 13 q12.2

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.)

See also

• Genetic determinism
• Race and genetics
• Race and intelligence
• Bruce Lahn

References

1. ^ PDB 3KTF; Singh N, Heroux A, Thompson JR, Mer G (2010). "Structure of the N-terminal BRCT domain of human microcephalin (MCPH1)". To be published. doi:10.2210/pdb3ktf/pdb. 
2. ^ ^{a b} Jackson, A.P., et al. (2002). "Identification of Microcephalin, a Protein Implicated in Determining the Size of the Human Brain". Am. J. Hum. Genet. 71 (1): 136–142. doi:10.1086/341283. PMC 419993. PMID 12046007. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=419993. 
3. ^ Lin, S.Y. & Elledge, S.J. (2003). "Multiple tumor suppressor pathways negatively regulate telomerase". Cell 113 (7): 881–889. doi:10.1016/S0092-8674(03)00430-6. PMID 12837246. 
4. ^ Jackson, A.P., et al. (1998). "Primary Autosomal Recessive Microcephaly (MCPH1) Maps to Chromosome 8p22-pter". Am. J. Hum. Genet. 63 (2): 541–546. doi:10.1086/301966. PMC 1377307. PMID 9683597. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1377307. Retrieved 10 February 2011. 
5. ^ Wang, Y.Q. & B. Su (2004). "Molecular evolution of microcephalin, a gene determining human brain size". Hum. Mol. Genet. 13 (11): 1131–1137. doi:10.1093/hmg/ddh127. PMID 15056608. 
6. ^ Evans, P.D., et al. (2004). "Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size". Hum. Mol. Genet. 13 (11): 1139–1145. doi:10.1093/hmg/ddh126. PMID 15056607. 
7. ^ R.P. Woods, et al. (2006). "Normal variants of Microcephalin and ASPM do not account for brain size variability". Hum. Mol. Genet. 15 (12): 2025–2029. doi:10.1093/hmg/ddl126. PMID 16687438. 
8. ^ J.P. Rushton, P.A. Vernon & T.A. Bons (22 Apr., 2007). "No evidence that polymorphisms of brain regulator genes Microcephalin and ASPM are associated with general mental ability, head circumference or altruism". Biol. Lett. 3 (2): 157–160. doi:10.1098/rsbl.2006.0586. PMC 2104484. PMID 17251122. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2104484. 
9. ^ Evans, P.D., et al. (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 – New York Times: Researchers Say Human Brain Is Still Evolving. 
10. ^ ^{a b} 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
11. ^ Mekel-Bobrov, N., et al. (2007). "The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence". Hum. Mol. Genet. 16 (6): adv. access. doi:10.1093/hmg/ddl487. PMID 17220170. 
12. ^ Dediu, D. & D.R. Ladd (2007). "Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and Microcephalin". Proc. Nat. Acad. Sci. 104 (26): 10944–9. Bibcode 2007PNAS..10410944D. doi:10.1073/pnas.0610848104. PMC 1904158. PMID 17537923. http://www.ling.ed.ac.uk/~s0340638/tonegenes/tonegenessummary.html. 
13. ^ Elizabeth Pennisi (2009). "NEANDERTAL GENOMICS: Tales of a Prehistoric Human Genome". Science 323 (5916): 866–871. doi:10.1126/science.323.5916.866. PMID 19213888. 
14. ^ Richard E. Green et al (2010). "A Draft Sequence of the Neandertal Genome". Science 328 (5979): 710–722. Bibcode 2010Sci...328..710G. doi:10.1126/science.1188021. PMID 20448178. 
15. ^ John Derbyshire (November 2005). "The specter of difference". National Review. http://findarticles.com/p/articles/mi_m1282/is_20_57/ai_n15895156/pg_3?tag=artBody;col1. Retrieved 2008-09-21. ^{[dead link]}
16. ^ scientists study of brain gene sparks a backlash
17. ^ Balter, M. (December 2006). "Bruce Lahn profile: Brain man makes waves with claims of recent human evolution". Science 314 (5807): 1871–1873. doi:10.1126/science.314.5807.1871. PMID 17185582. 
18. ^ Timpson, N., et al. (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. Bibcode 2007Sci...317.1036T. doi:10.1126/science.1141705. PMID 17717170. 

External links

• Neanderthal Brains - a lecture by Bruce Lahn - from the NYAS podcasts.
• GeneReviews/NCBI/NIH/UW entry on Primary Autosomal Recessive Microcephaly
• Medterms
• JBC
• OUP Journals
• EMBL
• Bates, T; Luciano, M; Lind, P; Wright, M; Montgomery, G; Martin, N (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. doi:10.1016/j.intell.2008.04.001. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W4M-4SHN0GS-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a8668cfde935719079d7ad9a80629557.