Biology:ASPM (gene)

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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.[1] ASPM is located on chromosome 1, band q31 (1q31).[2] The ASPM gene contains 28 exons and codes for a 3477 amino‐acid‐long protein.[2] The ASPM protein is conserved across species including human, mouse, Drosophila, and C. elegans.[2] Defective forms of the ASPM gene are associated with autosomal recessive primary microcephaly.[1][3]

"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.[2][4]

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.[5] Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation.[6] 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.[7]

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.[8] 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.[9] 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.[10] In addition to mutated Aspm's 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.[11]

While mouse studies have established the role of Aspm mutations in microcephaly, several have linked this mutation to other significant defects.[12] 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.[13]

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.[14][15] 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.[15] 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.[16] In this 2018 study, researchers targeted Aspm exon 15, where a mutation in humans is linked to severe cases of microcephaly.[17] 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.[18][19][20] 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.[21] MCPH is characterized by a smaller cerebral cortex associated with mild to moderate mental retardation and no other neurological deficits.[2][22] 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.[22] MCPH has an incidence rate of 1/30,000 to 1/250,000 in western populations.[23] To date, mutations in six loci and four genes associated with microcephaly have been discovered in humans.[24] ASPM, one of these genes, is found at the MCPH5 locus.[25] The most common cause of MCPH in humans is homozygous genetic mutation of the ASPM gene, orthologous to the Drosophila abnormal spindle gene (asp).[2] In humans, the ASPM gene may play a strong role in the growth of the cerebral cortex.[24] A total of 22 mutations have been discovered in the ASPM gene in individuals from Pakistan, Turkey, Yemen, Saudi Arabia, Jordan, and the Netherlands.[2][17]

A study completed in Karnataka, South India by Kumar et al. analyzed the genetics of MCPH due to mutations in the ASPM gene.[22] The study included nine families with blood relatives across many familial generations.[22] Kumar et al. performed High‐resolution G‐banding chromosome analysis and haplotype analysis of individuals and families of those affected by MCPH.[22] 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.[22]

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.[24] The study was approved by the Institutional Review Board of Quaid-I-Azam University in Islamabad, Pakistan, and involved extraction of DNA and PCR techniques in order to genetically map the ASPM gene.[24]  Genotyping using microsatellite regions in the gene revealed that MCPH5 locus mutations were the most common cause of MCPH.[24] Genotyping further linked mutations in the MCPH2 locus, MCPH4 locus, and the MCPH6 locus to microcephaly.[24] Sequence analysis of ASPM in humans revealed four novel mutations; these four types of mutations are an insertion of four nucleotides (9118insCATT), a nonsense mutation (L3080X), a deletion of seven nucleotides (1260delTCAAGTC), and a missense mutation (Q3180P).[24] Gul et al. found that parents who were heterozygous carriers for ASPM had normal cerebral circumferences and normal intelligence levels.[24] The scientists were unable to identify mutations at the MCPH5 locus in nine families who had members affected by MCPH.[24] They concluded that the mutations could be located in the regulatory sequences of ASPM, or that a gene other than ASPM located in the same region could be mutated.[24]

The types of mutations causing MCPH in humans was expanded by a study done by Pichon et al. on an individual with primary microcephaly, as the study revealed a translocation breakpoint in the ASPM gene.[26] 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.[26]  In order to precisely locate the translocation breakpoint, the BamHI digestion fragments of "RP11-32D17" were analyzed.[26] The translocation breakpoint was located to be within intron 17 of the ASPM gene.[26] 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.[26]

Evolution

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.[27] It is also found with an unusually high percentage among the people of Papua New Guinea, with a 59.4% occurrence.[28]

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.[29][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.[30][31] 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.[28][32]

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.[32][33][34] 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.[35][36]

See also

References

  1. ↑ 1.0 1.1 "A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31". American Journal of Human Genetics 67 (6): 1578–80. December 2000. doi:10.1086/316910. PMID 11078481. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "ASPM is a major determinant of cerebral cortical size". Nature Genetics 32 (2): 316–20. October 2002. doi:10.1038/ng995. PMID 12355089. 
  3. ↑ "Many roads lead to primary autosomal recessive microcephaly". Progress in Neurobiology 90 (3): 363–83. March 2010. doi:10.1016/j.pneurobio.2009.11.002. PMID 19931588. 
  4. ↑ "The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein". Human Molecular Genetics 14 (15): 2155–65. August 2005. doi:10.1093/hmg/ddi220. PMID 15972725. 
  5. ↑ "Calmodulin signaling via the IQ motif". FEBS Letters 513 (1): 107–13. February 2002. doi:10.1016/S0014-5793(01)03239-2. PMID 11911888. 
  6. ↑ "Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells". Proceedings of the National Academy of Sciences of the United States of America 103 (27): 10438–10443. July 2006. doi:10.1073/pnas.0604066103. PMID 16798874. Bibcode: 2006PNAS..10310438F. 
  7. ↑ "NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Galpha". Nature Cell Biology 11 (3): 269–77. March 2009. doi:10.1038/ncb1834. PMID 19219036. 
  8. ↑ "Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice". Development 142 (22): 3921–32. November 2015. doi:10.1242/dev.124271. PMID 26450969. 
  9. ↑ "Cerebellum development and medulloblastoma". Current Topics in Developmental Biology 94: 235–82. 2011. doi:10.1016/B978-0-12-380916-2.00008-5. PMID 21295689. 
  10. ↑ "Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice". Development 142 (22): 3921–32. November 2015. doi:10.1242/dev.124271. PMID 26450969. 
  11. ↑ "Disruption of Aspm causes microcephaly with abnormal neuronal differentiation". Brain & Development 36 (8): 661–9. September 2014. doi:10.1016/j.braindev.2013.10.006. PMID 24220505. 
  12. ↑ "Autosomal recessive primary microcephaly due to ASPM mutations: An update". Human Mutation 39 (3): 319–332. March 2018. doi:10.1002/humu.23381. PMID 29243349. https://www.repository.cam.ac.uk/bitstream/1810/291936/3/ASPM%20Hum%20Mut_2017%2005%2018.pdf. 
  13. ↑ "Longitudinal Diffusion Tensor Imaging Revealed Nerve Fiber Alterations in Aspm Mutated Microcephaly Model Mice". Neuroscience 371: 325–336. February 2018. doi:10.1016/j.neuroscience.2017.12.012. PMID 29253521. 
  14. ↑ "A novel domain suggests a ciliary function for ASPM, a brain size determining gene". Bioinformatics 22 (9): 1031–5. May 2006. doi:10.1093/bioinformatics/btl022. PMID 16443634. 
  15. ↑ 15.0 15.1 "Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline". Proceedings of the National Academy of Sciences of the United States of America 107 (38): 16595–600. September 2010. doi:10.1073/pnas.1010494107. PMID 20823249. 
  16. ↑ "Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size". Nature 556 (7701): 370–375. April 2018. doi:10.1038/s41586-018-0035-0. PMID 29643508. Bibcode: 2018Natur.556..370J. 
  17. ↑ 17.0 17.1 "Protein-truncating mutations in ASPM cause variable reduction in brain size". American Journal of Human Genetics 73 (5): 1170–7. November 2003. doi:10.1086/379085. PMID 14574646. 
  18. ↑ "OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling". Nature Neuroscience 13 (6): 690–9. June 2010. doi:10.1038/nn.2553. PMID 20436478. https://hal.science/hal-00531149/file/PEER_stage2_10.1038%252Fnn.2553.pdf. 
  19. ↑ "Comparative analysis of the subventricular zone in rat, ferret and macaque: evidence for an outer subventricular zone in rodents". PLOS ONE 7 (1): e30178. 2012-01-17. doi:10.1371/journal.pone.0030178. PMID 22272298. Bibcode: 2012PLoSO...730178M. 
  20. ↑ "Neurogenic radial glia in the outer subventricular zone of human neocortex". Nature 464 (7288): 554–561. March 2010. doi:10.1038/nature08845. PMID 20154730. Bibcode: 2010Natur.464..554H. 
  21. ↑ "Handbook of clinical neurology, volume 30, congenital malformations of the brain and skull, part I, edited by P. J. Vinken and G. W. Bruyn, 706 pp, illustrated, $114.50, North-Holland Publishing Company, Amsterdam, 1977" (in en). Annals of Neurology 4 (6): 588. 1978. doi:10.1002/ana.410040673. ISSN 0364-5134. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 "Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations". Clinical Genetics 66 (4): 341–8. October 2004. doi:10.1111/j.1399-0004.2004.00304.x. PMID 15355437. http://eprints.iisc.ac.in/2343/1/Kumar-Clin_Genet-04.pdf. 
  23. ↑ "Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter". American Journal of Human Genetics 63 (2): 541–6. August 1998. doi:10.1086/301966. PMID 9683597. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 24.6 24.7 24.8 24.9 "Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene". Neurogenetics 7 (2): 105–10. May 2006. doi:10.1007/s10048-006-0042-4. PMID 16673149. 
  25. ↑ "Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings". American Journal of Human Genetics 76 (5): 717–28. May 2005. doi:10.1086/429930. PMID 15806441. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 "A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly". European Journal of Human Genetics 12 (5): 419–21. May 2004. doi:10.1038/sj.ejhg.5201169. PMID 14997185. 
  27. ↑ "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans". Science 309 (5741): 1717–1720. September 2005. doi:10.1126/science.1113722. PMID 16151009. Bibcode: 2005Sci...309.1717E. 
  28. ↑ 28.0 28.1 "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens". Science 309 (5741): 1720–1722. September 2005. doi:10.1126/science.1116815. PMID 16151010. Bibcode: 2005Sci...309.1720M. 
  29. ↑ Per the 2006 Discovery Channel/Channel 4 documentary series What Makes Us Human?
  30. ↑ "Human brains enjoy ongoing evolution". New Scientist. 2005. 
  31. ↑ "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans". Science 309 (5741): 1717–20. September 2005. doi:10.1126/science.1113722. PMID 16151009. Bibcode: 2005Sci...309.1717E. 
  32. ↑ 32.0 32.1 "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'". Science 313 (5784): 172; author reply 172. July 2006. doi:10.1126/science.1122712. PMID 16840683. 
  33. ↑ "Normal variants of Microcephalin and ASPM do not account for brain size variability". Human Molecular Genetics 15 (12): 2025–2029. June 2006. doi:10.1093/hmg/ddl126. PMID 16687438. 
  34. ↑ "The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence". Human Molecular Genetics 16 (6): 600–608. March 2007. doi:10.1093/hmg/ddl487. PMID 17220170. 
  35. ↑ "Localizing recent adaptive evolution in the human genome". PLOS Genetics 3 (6): e90. June 2007. doi:10.1371/journal.pgen.0030090. PMID 17542651. 
  36. ↑ "Humans Have Spread Globally, and Evolved Locally". New York Times. 2007-06-26. https://www.nytimes.com/2007/06/26/science/26human.html?pagewanted=1&_r=3&ex=1340596800. 

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