Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans

  title={Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans},
  author={Patrick Evans and Sandra L. Gilbert and Nitzan Mekel-Bobrov and Eric J. Vallender and Jeffrey R. Anderson and Leila M. Vaez-Azizi and Sarah A. Tishkoff and Richard R. Hudson and Bruce T. Lahn},
  pages={1717 - 1720}
The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose ∼37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve… 

Comment on "Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens" and "Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans"

It is shown that models of human history that include both population growth and spatial structure can generate the observed patterns without selection.

The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.

The overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ, and highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Cytoskeletal genes regulating brain size.

Normal variants of Microcephalin and ASPM do not account for brain size variability.

No evidence that the selected alleles were associated with increases or decreases in brain volume is found, which suggests that the selective pressure on these genes may be related to subtle neurobiological effects or to their expression outside the brain.

MCPH , a disorder of neurogenic mitosis affecting foetal brain growth

One of the most notable trends in human evolution is the dramatic increase in brain size that has occurred in the great ape clade, culminating in humans, which is believed to have resulted in the authors' ability to perform higher cognitive functions.

Response to Comment on "Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens" and "Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans"

Computer simulations are presented to argue that the haplotype structure found at the microcephalin and ASPM genes can be better explained by demographic history rather than by selection.

Primary microcephaly: do all roads lead to Rome?

Molecular evolutionary analysis of human primary microcephaly genes

It can be inferred that protein-coding sequence of MCPH genes might not be the sole determinant of increase in relative brain size during primate evolutionary history.

MCPH1: a window into brain development and evolution

An overview of MCPH1 is presented from multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.



Molecular evolution of microcephalin, a gene determining human brain size.

The synonymous/non-synonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes.

Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size.

It is proposed that genes regulating brain size during development may have the general propensity to contribute to brain evolution in primates and particularly humans.

Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids,

Evolution of the human ASPM gene, a major determinant of brain size.

Evidence is provided suggesting that human ASPM went through an episode of accelerated sequence evolution by positive Darwinian selection after the split of humans and chimpanzees but before the separation of modern non-Africans from Africans.

Identification of microcephalin, a protein implicated in determining the size of the human brain.

It is reported that a gene within this interval, encoding a BRCA1 C-terminal domain-containing protein, is mutated in MCPH1 families sharing an ancestral 8p23 haplotype, and this gene, microcephalin, is expressed in the developing cerebral cortex of the fetal brain.

Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.

It is shown that the evolution of ASPM is significantly accelerated in great apes, especially along the ape lineages leading to humans, which is consistent with its putative role in the evolutionary enlargement of the human brain.

ASPM is a major determinant of cerebral cortical size

It is shown that the most common cause of MCPH is homozygous mutation of ASPM, the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts.

Molecular genetics of human microcephaly

There has recently been a rapid advance in the use of genetic mapping techniques to identify genetic loci responsible for microcephaly, and although several loci have been mapped, the condition is clearly genetically and clinically heterogeneous.

Mutations in microcephalin cause aberrant regulation of chromosome condensation.

It is demonstrated that an siRNA-mediated depletion of MCPH1 is sufficient to reproduce this phenotype and also show that MCPh1-deficient cells exhibit delayed decondensation postmitosis, implicate microcephalin as a novel regulator of chromosome condensation and link the apparently disparate fields of neurogenesis and chromosome biology.