ASPM (gene)

Abnormal spindle-like microcephaly-associated protein, also known as abnormal spindle protein homolog or Asp homolog, is a

A new allele of ASPM arose sometime in the past 14,000 years (mean estimate 5,800 years), during the Holocene, it seems to have swept through much of the European and Middle-Eastern population. Although the new allele is evidently beneficial, researchers do not know what it does.^{[citation needed]}

Animal studies

The mouse gene, Aspm, is expressed in the primary sites of prenatal cerebral cortical neurogenesis. The difference between Aspm and ASPM is a single, large insertion coding for so-called IQ domains.^[9] Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation.^[10] The function is conserved, the C. elegans protein ASPM-1 was shown to be localized to spindle asters, where it regulates spindle organization and rotation by interacting with calmodulin, dynein and NuMA-related LIN-5.^[11]

One mouse study looking at

Another significant impact of mutated Aspm is seen in germline abnormalities within mouse models. Mutations in Aspm were shown to reduce fertility in both female and male mice, indicated by a decrease in the rate of pregnancy and consequently the number of offspring, as well as a decrease in female ovarian size, as well as male sperm count and testicular size. The focus on severe germline mutations (as opposed to only mild microcephaly) in these mouse models raises the question as to whether or not human ASPM selection may be more significantly linked to reproduction than brain size.^[18][19] In addition to mouse models, a study using ferrets reveals more about ASPM and its role in determining cortical size and thickness. The researchers from this study chose ferrets over mouse models due to incongruencies between Aspm effects in mice versus ASPM effects in humans - humans with microcephaly due to this gene mutation tend to have significantly reduced brain sizes (about 50% reduction), whereas the analogous mutation in mice only results in mild brain size reduction.^[19] Ferrets also show more similarities to humans in terms of brain structure; ferrets' brains have gyrification in high amounts similar to humans, different from the relatively smooth brains of mice. As a result, there is less cortical surface area in mice compared to that of ferrets and humans.^[20] In this 2018 study, researchers targeted Aspm exon 15, where a mutation in humans is linked to severe cases of microcephaly.^[21] With a loss of function in Aspm, ferrets with Aspm mutations saw a 40% decrease in overall brain size coupled with no reduction in body size, similar to the effects of loss of ASPM in humans. The study also looked at the neurodevelopmental pathways and mechanisms leading to neurogenesis in the KO ferrets compared to the WT controls, specifically studying three different neuron progenitor cell (NPC) types, all of which express the mitotic marker Ki-67 and undergo radial glial migration to the cortical plate.^[22][23][24] They found that outer subventricular zone (OSVZ) NPCs were largely displaced, especially frontally and dorsally which mirrors the effects seen in cortical volume reductions due to ASPM KO.

Human studies

Human primary

A study completed in Karnataka, South India by Kumar et al. analyzed the genetics of MCPH due to mutations in the ASPM gene.[26] The study included nine families with blood relatives across many familial generations.^[26] Kumar et al. performed High‐resolution G‐banding chromosome analysis and haplotype analysis of individuals and families of those affected by MCPH.^[26] Kumar et al. found that the South Indian families affected by mutations in the MCPH5 locus did not share a common disease haplotype; thus the authors proposed that different mutations in the ASPM gene are responsible for MCPH.^[26]

A similar genetic study of MCPH in Pakistani families was done by Gul et al. in order to evaluate the relationship between ASPM gene mutations and microcephaly.

A new allele (version) of ASPM appeared sometime within the last 14,100 years, with a mean estimate of 5,800 years ago. The new allele has a frequency of about 50% in populations of the Middle East and Europe, it is less frequent in East Asia, and has low frequencies among Sub-Saharan African populations.^[31] It is also found with an unusually high percentage among the people of Papua New Guinea, with a 59.4% occurrence.^[32]

The mean estimated age of the ASPM allele of 5,800 years ago roughly correlates with the development of written language, spread of agriculture and development of cities.

Testing the IQ of those with and without new ASPM allele has shown no difference in average IQ, providing no evidence to support the notion that the gene increases intelligence.[36]^[37][38] Other genes related to brain development appear to have come under selective pressure in different populations. The

• Microcephalin

References