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Abnormal spindle-like microcephaly-associated protein, also known asabnormal spindle protein homolog orAsp homolog, is aprotein that in humans is encoded by theASPMgene.[5] ASPM is located onchromosome 1, band q31 (1q31).[6] TheASPM gene contains 28 exons and codes for a 3477 amino-acid-long protein.[6] The ASPM protein is conserved across species including human, mouse,Drosophila, andC. elegans.[6] Defective forms of the ASPM gene are associated withautosomal recessive primarymicrocephaly.[5][7]
"ASPM" is an acronym for "AbnormalSpindle-like,Microcephaly-associated", which reflects its being anortholog to theDrosophila melanogaster "abnormal spindle" (asp) gene. Theexpressed protein product of the asp gene is essential for normalmitotic spindle function in embryonicneuroblasts and regulation of neurogenesis.[6][8]
A new allele of ASPM arose sometime in the past 14,000 years (mean estimate 5,800 years), during theHolocene, 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]
The mouse gene,Aspm, is expressed in the primary sites of prenatal cerebral corticalneurogenesis. The difference betweenAspm and ASPM is a single, large insertion coding for so-calledIQ domains.[9] Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation.[10] The function is conserved, theC. 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 atmedulloblastoma growth in mice to study theAspm gene, anortholog to human ASPM, suggests thatAspm expression may drive postnatalcerebellarneurogenesis.[12] This process occurs late inembryogenesis 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 theShh gene.[13] In proliferating cerebellar granule neuron progenitors (CGNPs), Shh expression in mouse models showed four times the amount ofAspm expression than those deprived of Shh expressionin-vivo. This induction ofAspm and up-regulation during cerebellarneurogenesis was also seen in real-timePCR, where its expression was relatively high at the peak of neurogenesis and much lower at the end of neurogenesis. Additionally, the study indicates thatAspm is necessary for cerebellar neurogenesis. In the presence ofAspmKO mutations and deletions, experimental mice models show decreased cerebellar volume underMRI, compared to the controls.[14] In addition to mutatedAspm's effects on neurogenesis, these mutations may also play a role in neuraldifferentiation. When looking at adult brains inAspm KO mice, there was a trend in overall size reduction, and variations in cortical thickness between mutant andwild 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 thecortical plate. Certain transcription factors expressions were also abnormal in the KO mice. For example,Tbr1 andSatb2 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 oftranscription and chromosomal remodeling.[15]
While mouse studies have established the role ofAspm mutations in microcephaly, several have linked this mutation to other significant defects.[16] One study showednerve fiber impairments in which the shape and form of cortex andwhite 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 acell 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 normalAspm.[17]
Another significant impact of mutatedAspm is seen ingermline abnormalities within mouse models. Mutations inAspm 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 betweenAspm 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 havegyrification 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 targetedAspm exon 15, where a mutation in humans is linked to severe cases of microcephaly.[21] With a loss of function inAspm, ferrets withAspm 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 markerKi-67 and undergoradial 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 primarymicrocephaly (MCPH) is a distinct subtype that is genetically inherited as anautosomal recessive trait.[25] MCPH is characterized by a smaller cerebral cortex associated with mild to moderate mental retardation and no other neurological deficits.[6][26] 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.[26] MCPH has an incidence rate of 1/30,000 to 1/250,000 in western populations.[27] To date,mutations in sixloci and four genes associated with microcephaly have been discovered in humans.[28]ASPM, one of these genes, is found at the MCPH5 locus.[29] The most common cause of MCPH in humans ishomozygous genetic mutation of theASPM gene, orthologous to theDrosophila abnormal spindle gene (asp).[6] In humans, theASPM gene may play a strong role in the growth of thecerebral cortex.[28] A total of 22 mutations have been discovered in theASPM gene in individuals from Pakistan, Turkey, Yemen, Saudi Arabia, Jordan, and the Netherlands.[6][21]
A study completed in Karnataka, South India by Kumar et al. analyzed the genetics of MCPH due to mutations in theASPM gene.[26] The study included nine families with blood relatives across many familial generations.[26] Kumar et al. performed High-resolutionG-banding chromosome analysis andhaplotype 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 theASPM 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 betweenASPM gene mutations and microcephaly.[28] The study was approved by the Institutional Review Board of Quaid-I-Azam University in Islamabad, Pakistan, and involved extraction of DNA andPCR techniques in order to genetically map theASPM gene.[28]Genotyping usingmicrosatellite regions in the gene revealed that MCPH5 locus mutations were the most common cause of MCPH.[28] Genotyping further linked mutations in the MCPH2 locus, MCPH4 locus, and the MCPH6 locus to microcephaly.[28] Sequence analysis ofASPM in humans revealed four novel mutations; these four types of mutations are aninsertion of four nucleotides (9118insCATT), anonsense mutation (L3080X), adeletion of seven nucleotides (1260delTCAAGTC), and amissense mutation (Q3180P).[28] Gul et al. found that parents who wereheterozygous carriers forASPM had normal cerebral circumferences and normal intelligence levels.[28] The scientists were unable to identify mutations at the MCPH5 locus in nine families who had members affected by MCPH.[28] They concluded that the mutations could be located in theregulatory sequences ofASPM, or that a gene other thanASPM located in the same region could be mutated.[28]
The types of mutations causing MCPH in humans were expanded by a study done by Pichon et al. on an individual with primary microcephaly, as the study revealed atranslocation breakpoint in theASPM gene.[30] Pichon et al. obtained BAC clones withBamHI digestion fragments of the "RP11-32D17" insert and usedFluorescence in situ Hybridization (FISH) in order to label the clones with fluorescein-12-dUTP.[30] In order to precisely locate the translocation breakpoint, theBamHI digestion fragments of "RP11-32D17" were analyzed.[30] The translocation breakpoint was located to be within intron 17 of theASPM gene.[30] The translocation resulted in a truncated ASPM protein, which is most likely a non-functioning protein also seen in truncating point mutations reported in MCPH patients.[30]
A newallele (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 ofPapua 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.[33][better source needed] 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.[34][35] The allele affects genotype over a large (62 kbp) region, a so calledselective 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.[32][36]
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. TheDAB1 gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in theChinese. TheSV2B gene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep inAfrican Americans.[39][40]
