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][2][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.[8]
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.[12] 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.[14][15]
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."[16]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.[17][18]
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".[19] However, a later study by Rimol et al.[8] 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.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[24][31] Twenty four tests were carried out on mutant mice and six significant abnormalities were observed.[24]Homozygousmutant 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.[24]
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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. PMID15056608.
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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. PMID15056607.
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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. PMID16687438.
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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. PMID16151009. Lay summary – The New York Times (September 8, 2005).
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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. PMID17220170.
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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. PMID17185582.
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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. PMID17717170.
Xu X, Lee J, Stern DF (August 2004). "Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1". The Journal of Biological Chemistry. 279 (33): 34091–4. doi:10.1074/jbc.C400139200. PMID15220350.
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. PMID15056608.
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". Intelligence. 36 (6): 689–93. doi:10.1016/j.intell.2008.04.001.