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Abnormal spindle-like microcephaly-associated protein, also known as abnormal spindle protein homolog or Asp homolog, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''ASPM''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. ASPM is located on
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ar ...
, band q31 (1q31). The ''ASPM'' gene contains 28 exons and codes for a 3477 amino‐acid‐long protein. The ASPM protein is conserved across species including human, mouse, ''Drosophila'', and ''C. elegans''. Defective forms of the ASPM gene are associated with
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
recessive primary
microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
. "ASPM" is an acronym for "Abnormal Spindle-like, Microcephaly-associated", which reflects its being an
ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
to the ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' "abnormal spindle" (''asp'') gene. The expressed protein product of the asp gene is essential for normal
mitotic spindle In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...
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 The Holocene ( ) is the current geological epoch. It began approximately 11,650 cal years Before Present (), after the Last Glacial Period, which concluded with the Holocene glacial retreat. The Holocene and the preceding Pleistocene togethe ...
, 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 Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
. 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 Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...
growth in mice to study the ''Aspm'' gene, an
ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
to human ASPM, suggests that ''Aspm'' expression may drive postnatal
cerebellar The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
. This process occurs late in
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and pl ...
. This induction of ''Aspm'' and up-regulation during cerebellar
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
, 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 The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
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 The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
. Certain transcription factors expressions were also abnormal in the KO mice. For example,
Tbr1 T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the ''TBR1'' gene. This gene is also known by several other names: ''T-Brain 1'', ''TBR-1'', ''TES-56'', and ''MGC141978''. TBR1 is ...
and
Satb2 SATB is an initialism that describes the scoring of compositions for choirs, and also choirs (or consorts) of instruments. The initials are for the voice types: S for soprano, A for alto, T for tenor and B for bass. Choral music Four-part harm ...
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 Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
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 An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
impairments in which the shape and form of cortex and
white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribution ...
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 Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...
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 In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...
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. 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. Ferrets also show more similarities to humans in terms of brain structure; ferrets' brains have
gyrification Gyrification is the process of forming the characteristic folds of the cerebral cortex. The peak of such a fold is called a ''gyrus'' (pl. ''gyri''), and its trough is called a '' sulcus'' (pl. ''sulci''). The neurons of the cerebral cortex re ...
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. 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 Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
(MCPH) is a distinct subtype that is genetically inherited as an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
trait. MCPH is characterized by a smaller cerebral cortex associated with mild to moderate mental retardation 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. MCPH has an incidence rate of 1/30,000 to 1/250,000 in western populations. To date,
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
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 Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
genetic mutation of the ''ASPM'' gene'','' orthologous to the ''Drosophila'' abnormal spindle gene (''asp''). In humans, the ''ASPM'' gene may play a strong role in the growth of the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
. A total of 22 mutations have been discovered in the ''ASPM'' gene in individuals from Pakistan, Turkey, Yemen, Saudi Arabia, Jordan, and the Netherlands. A study completed in Karnataka, South India by Kumar et al. analyzed the genetics of MCPH due to mutations in the ''ASPM'' gene. The study included nine families with blood relatives across many familial generations. Kumar et al. performed High‐resolution G‐banding chromosome analysis and
haplotype A haplotype ( haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA or ...
analysis of individuals and families of those affected by MCPH. 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. 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. 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.  
Genotyping Genotyping is the process of determining differences in the genetic make-up ( genotype) of an individual by examining the individual's DNA sequence using biological assays and comparing it to another individual's sequence or a reference sequence. ...
using
microsatellite A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. ...
regions in the gene revealed that MCPH5 locus mutations were the most common cause of MCPH. Genotyping further linked mutations in the MCPH2 locus, MCPH4 locus, and the MCPH6 locus to microcephaly. 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 In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
(L3080X), a deletion of seven nucleotides (1260delTCAAGTC), and a
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...
(Q3180P). Gul et al. found that parents who were
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
carriers for ''ASPM'' had normal cerebral circumferences and normal intelligence levels. The scientists were unable to identify mutations at the MCPH5 locus in nine families who had members affected by MCPH. They concluded that the mutations could be located in the
regulatory sequences A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...
of ''ASPM'', or that a gene other than ''ASPM'' located in the same region could be mutated. 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. Pichon et al. obtained BAC clones with ''Bam''HI digestion fragments of the "RP11-32D17" insert and used
Fluorescence in situ Hybridization Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed b ...
(FISH) in order to label the clones with fluorescein-12-dUTP.  In order to precisely locate the translocation breakpoint, the ''Bam''HI digestion fragments of "RP11-32D17" were analyzed. The translocation breakpoint was located to be within intron 17 of the ''ASPM'' gene. 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.


Evolution

A new
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
(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. * It is also found with an unusually high percentage among the people of
Papua New Guinea Papua New Guinea (abbreviated PNG; , ; tpi, Papua Niugini; ho, Papua Niu Gini), officially the Independent State of Papua New Guinea ( tpi, Independen Stet bilong Papua Niugini; ho, Independen Stet bilong Papua Niu Gini), is a country i ...
, with a 59.4% occurrence. 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. 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 In genetics, a selective sweep is the process through which a new beneficial mutation that increases its frequency and becomes fixed (i.e., reaches a frequency of 1) in the population leads to the reduction or elimination of genetic variation among ...
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 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that c ...
gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in the
Chinese Chinese can refer to: * Something related to China * Chinese people, people of Chinese nationality, citizenship, and/or ethnicity **''Zhonghua minzu'', the supra-ethnic concept of the Chinese nation ** List of ethnic groups in China, people of ...
. The SV2B gene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep in
African-Americans African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ensl ...
.


See also

*
Microcephalin Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in ''MCPH1'', when homozygous, cause primary microcephaly—a severely diminished brain. Hence, it has been assumed that variants have a role in ...


References


External links


GeneReviews/NCBI/NIH/UW entry on Primary Autosomal Recessive Microcephaly
* {{DEFAULTSORT:Aspm (Gene) Developmental neuroscience