Abnormal spindle-like microcephaly-associated protein, also known as abnormal spindle protein homolog or Asp homolog, is a protein that in humans is encoded by the ASPM gene. ASPM is located on chromosome 1, band q31 (1q31). The ASPM gene contains 28 exons and codes for a 3477 amino-acid-long protein.

"ASPM" is an acronym for "Abnormal Spindle-like, Microcephaly-associated", which reflects its being an ortholog to the Drosophila melanogaster "abnormal spindle" (asp) gene. The expressed protein product of the asp gene is essential for normal mitotic spindle function in embryonic neuroblasts and regulation of neurogenesis.

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.

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. Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation. 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.

One mouse study looking at medulloblastoma growth in mice to study the Aspm gene, an ortholog to human ASPM, suggests that Aspm expression may drive postnatal cerebellar neurogenesis. This process occurs late in embryogenesis and immediately after birth over a time span of about 2 weeks in mice and 12 months in humans, and is regulated by the expression of the Shh gene. In proliferating cerebellar granule neuron progenitors (CGNPs), Shh expression in mouse models showed four times the amount of Aspm expression than those deprived of Shh expression in-vivo. This induction of Aspm and up-regulation during cerebellar neurogenesis was also seen in real-time PCR, where its expression was relatively high at the peak of neurogenesis and much lower at the end of neurogenesis. Additionally, the study indicates that Aspm is necessary for cerebellar neurogenesis. In the presence of Aspm KO mutations and deletions, experimental mice models show decreased cerebellar volume under MRI, compared to the controls. In addition to mutated Aspm effects on neurogenesis, these mutations may also play a role in neural differentiation. When looking at adult brains in Aspm KO mice, there was a trend in overall size reduction, and variations in cortical thickness between mutant and wild type models. In the somatosensory cortex, KO mice had a significantly thicker layer I cortex, thinner layer VI cortex, and an overall decrease in cortical thickness in the cortical plate. Certain transcription factors expressions were also abnormal in the KO mice. For example, Tbr1 and Satb2 had an increased presence in the cortical sub-plate, the first of which is important for differentiation and neuronal migration, and the second of which is a regulator of transcription and chromosomal remodeling.

While mouse studies have established the role of Aspm mutations in microcephaly, several have linked this mutation to other significant defects. One study showed nerve fiber impairments in which the shape and form of cortex and white matter tissue was altered. This was shown postnatally comparing KO mice and controls, where both cell number and cortical thickness was decreased in KO mice. Using a cell staining methodology for histological analysis, the study also showed shorter distances between adjacent neurons in KO mice, indicating abnormalities in cell alignment in the absence of normal Aspm.

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.

<!-- Deleted image removed: thumb|On the left is a normal ferret brain (WT, intact Aspm gene), while the right is a 3-D rendering of a genetically modified ferret brain (Aspm KO). -->

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. In this 2018 study, researchers targeted Aspm exon 15, where a mutation in humans is linked to severe cases of microcephaly. 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. 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 microcephaly (MCPH) is a distinct subtype that is genetically inherited as an autosomal recessive trait. MCPH is characterized by a smaller cerebral cortex associated with mild to moderate intellectual disability and no other neurological deficits. Additionally, MCPH is associated with the absence of environmental causes such as intrauterine infections, exposure to prenatal radiation or drugs, maternal phenylketonuria, and birth asphyxia. To date, mutations in six loci and four genes associated with microcephaly have been discovered in humans. ASPM, one of these genes, is found at the MCPH5 locus. The most common cause of MCPH in humans is homozygous genetic mutation of the ASPM gene, orthologous to the Drosophila abnormal spindle gene (asp). Pichon et al. obtained BAC clones with BamHI digestion fragments of the "RP11-32D17" insert and used fluorescence in situ hybridization (FISH) in order to label the clones with fluorescein-12-dUTP. It is also found with an unusually high percentage among the people of Papua New Guinea, with a 59.4% occurrence. Currently, two alleles of this gene exist: the older (pre-5,800 years ago) and the newer (post-5,800 years ago). About 10% of humans have two copies of the new ASPM allele, while about 50% have two copies of the old allele. The other 40% of humans have one copy of each. Of those with an instance of the new allele, 50% of them are an identical copy. The allele affects genotype over a large (62 kbp) region, a so called selective sweep which signals a rapid spread of a mutation (such as the new ASPM) through the population; this indicates that the mutation is somehow advantageous to the individual.

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.

Other genes related to brain development appear to have come under selective pressure in different populations. The DAB1 gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in the Chinese. The SV2B gene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep in African Americans.

See also

  • Microcephalin

References

  • GeneReviews/NCBI/NIH/UW entry on Primary Autosomal Recessive Microcephaly