MCPH1: a window into brain development and evolution

Abstract

The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these 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.

Phenotypes in siblings with homozygous mutations of TRAPPC9 and/or MCPH1 support a bifunctional model of MCPH1

“…Experiments on chicken cells using various truncated forms of chicken Mcph1 showed that BRCT1 is necessary for centrosomal localization, whereas BRCT2 and BRCT3 are required for IRIF formation and response to DNA damage (Pulvers et al., ). The study of the two major transcripts of MCPH1 (full‐length MCPH1, and a transcript lacking exons 9 to 14) also showed that the C‐terminus of the protein was necessary for DNA damage response.…”

The DNA damage response molecule MCPH1 in brain development and beyond

“…The mouse ortholog of MCPH1, containing 822 aa, has 57% homology to the human protein [6]. Several Mcph1-knockout mouse models have been generated [44]. The first…”

“…The brain size is primarily dependent on the capacity of neuroprogenitor proliferation and self-renewal [43,44].…”

Revisiting the false positive rate in detecting recent positive selection

“…Some evidence suggests that the human brain is still adaptively evolving [1], and that positive selection may also play an essential role in the development of speech [2], and in the enabling of adults to digest the lactose contained in milk [3][4][5][6]. Moreover, understanding how and why selection acts can help us to reveal the mechanisms that underlie diseases and microbial resistance [7].…”

“…This increasing interest can be seen in the increasing number of citations of three key methodological papers [8][9][10] (Figure 1). 1 demography could be one of the major reasons for 86% of the unique candidates. This has consequences.…”