The human brain, particularly the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution. ASPM and MCPH are the major protagonist helped to shape and size of our brain. The developmental biology and genetics is the key to unlocking the mystery of human brain evolution.
KEYWORDS: Cerebral cortex, ASPM, MCPH
Put a human and a chimpanzee side by side, and it seems obvious which lineage has changed the most since the two diverged from a common ancestor millions of years ago. Such apparent physical differences, along with human speech, language and brainpower, have led many people to believe that natural selection has acted in a positive manner on more genes in humans than in chimps. The human brain is one of the most intricate, complicated and impressive organs ever to have evolved. Understanding its evolution requires integrating knowledge from a variety of disciplines in the natural and social sciences. The human brain, particularly the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution (Bloch, 2009). The analysis of a well-preserved skull from 54 million years ago contradicts some common assumptions about brain structure and evolution in the first primates (Bloch, 2009). Abnormal spindle mutated in microcephaly (ASPM) gene displayed significantly higher rates of protein evolution in primates than in rodents (Dorus et al. 2004). The trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. The phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerating evolution of underlying genes, particularly those linked to nervous system development (Dorus et al. 2004). One genetic variant of ASPM in humans arose nearly about 5,800 years ago and has since swept to high frequency under strong positive selection (Mekel-Bobrov et al. 2005). Humans and macaques shared a common ancestor 20-25 million years ago, whereas rats and mice are separated by 16-23 million years of evolution. All four species shared a common ancestor about 80 million years ago (Mekel-Bobrov et al. 2005).
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Selective pressure, random gene mutations are the basic cause of the evolution of human brain. Microcephaly, an inherited form of human disorder in which human brain size is greatly reduced (Kouprina et al. 2005). Mutations in the genes ASPM and Microcephalin (MCPH) were identified as two causes of microcephaly. These genes have been under selective pressure during primate evolution (Bloch, 2009; Dorus et al. 2004). ASPM encodes a protein involved in spindle formation, so it is tempting to think that changes in its sequence might result in an increased rate of cell division and human brain size (Kouprina et al. 2005). Several hundred genes involved in nervous system biology and they have significantly higher rates of protein evolution particularly in the genes in primates. Protein evolution rate is particularly high in the lineage leading from ancestral primates to humans. In an attempt to reconstruct the evolutionary history of the ASPM genes, large genomic clones containing the entire ASPM gene is isolated in several non-human primates. Sequence analysis of these clones revealed a high conservation in both coding and non coding regions and showed that evolution of the ASPM gene might have been under positive selection in hominoids (Kouprina et al. 2005). These clones could also provide important reagents for the future study of the ASPM gene regulation. ASPM and MCPH may be only the tip of the iceberg when it comes to genes that have helped to shape our brain (Kouprina et al. 2005).
GENES INVOLVED IN EVLUTION OF BRAIN:
ASPM GENE: The ASPM gene is the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts (Bond, 2002). The mouse gene ASPM is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis (Bond, 2002). The ASPM gene encodes a 10,434 bp long coding sequence (CDS). ASPM gene contains four distinguishable region: a putative N terminal microtubule - binding domain, a calponin-homology domain, an IQ repeat domain containing multiple IQ repeats (calmodulin binding motifs), and a c terminal region (Bond, 2002). Though the exact function of the human ASPM in the brain needs to be clarified, the homologues in the fruit fly, Drosophila melanogaster, abnormal spindle (asp), is localized in the mitotic centrosome and is known to be essential for both the organization of the microtubules at the spindle poles and the formation of the central mitotic spindle during mitosis and meiosis. Mutation in asp causes dividing neuroblasts to arrest in metaphase, resulting in reduced central nervous system development (Riperbelli et al. 2001).
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Prior sequence based evidence for positive selection on ASPM is persuasive, as is evidence that truncating mutations of these genes result in microcephaly. Nevertheless, as ASPM is expressed widely in many different tissues (Kouprina et al. 2005), it remains plausible that any one of its functions in these tissues might have been the subject of adaptive evolution rather than its proposed centrosomal participation in neurogenesis (Bond, 2002; Bond, 2003; Bond, 2005). Analysis of primate ASPM sequence shows that human and gorilla, but not chimpanzee, lineages exhibits significance and pronounced levels of adaptive evolution. Thus, accelerated evolution of ASPM began well before the threefold brain size increase separating early hominids from modern humans (Wood and Collard 1999). Moreover gorilla and chimpanzee lineages, within which brain sizes have failed relatively constant, have experienced adaptive and non adaptive evolution respectively. If ASPM evolution did lead to brain size increases, it would appear that this first occurred approximately 7 to 8 millions years ago, prior to the last ancestors of gorillas, chimpanzees and humans, rather than during more recent hominid brain enlargement (Wood and Collard 1999).
ASPM gene within the MCPH5 critical region on 1q31. The ASPM gene contains 28 exons and spans 62 kb of genomic sequence. ASPM gene is concentrated at mitotic spindle poles in mouse neuroepithelial cells, the primary stem and progenitor cells of the mammalian brain (Fish et al. 2006). ASPM proteins encode systematically larger numbers of repeated IQ domains between flies, mice, and humans. One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. The brain size is controlled in the part through the modulation of mitotic spindle activity in neuronal progenitor cells. Humans with autosomal recessive primary microcephaly show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex (Bond, 2005; Fish et al. 2006).
FIG 1: LOCATION OF ASPM GENE ON CHROMOSOME 1
ASPM expression was downregulated during the switch from proliferative to neurogenic cell divisions. Upon RNA interference in telencephalic neuroepithelial cells, ASPM mRNA was reduced, mitotic spindle poles lacked ASPM protein, and the cleavage plains was less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation increased the probability that the cells underwent asymmetric division, i.e. the apical plasma membrane was inherited by only one of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a large proportion of neuroepithelial cell progeny was found in the neuronal layer, implying in the reduction in the number of neuroepithelial progenitor cells upon ASPM knockdown (Fish et al. 2006). ASPM is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative divisions of neuroepithelial cells during brain development (Fish et al. 2006). ASPM as a highly connected 'hub' gene within a module of cell cycle genes that are co-expressed in glioblastoma compared to normal tissues (Horvath et al. 2006). ASPM expression was also high in fetal murine neural stem cells, and its expression decreased during differentiation. Knockdown of ASPM by small interfering RNA inhibited proliferation in both a human glioblastoma cell line and murine neural stem or progenitor cells (Horvath et al. 2006).
MICROCEPHALIN GENE: Microcephalin 1 (MCPH 1) is one of the most important gene causing primary microcephaly, this condition is characterized by a severely diminished brain. Hence it is assumed that normal variants have a role in brain development, but no effect on mental ability. MCPH 1 is expressed in the fetal brain, in the developing forebrain and on the walls of the lateral ventricles. Cells of this area divide, producing neurons that migrate to eventually from the cerebral cortex (Trimborn, 2004). A derived form of MCPH 1 called haplogroup D appeared about 37000 years ago and has spread become the more common form throughout the world except sub Saharan Africa. The timing of its emergence may have closely preceded the upper Paleolithic, when people started colonizing Europe, although the margin of error is substantial and there is evidence that the transition to the upper Paleolithic occurred in Africa before spreading to Europe. The modern distributions of chromosomes bearing the ancestral forms of the MCPH 1 and MCPH 5 coincide with the incidence of tonal languages, although the nature of the relationship can only be guessed at haplogroup D may have originated from a lineage separated from modern humans approximately 1.1 million years ago and later entered into in humans (Trimborn, 2004).
FIG 2: LOCATION OF MICROCEPHALIN ON CHROMOSOME 8
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MCPH1 encodes an 835 amino acid which was named Microcephalin. MCPH1 mutations are a rare cause of primary microcephaly. It has been shown that MCPH1 primary microcephaly is allelic to premature chromatin condensation syndrome (PCC) which led to the identification of Microcephalin as a negative regulator of condensin II, a protein complex involved in chromatin packaging (Trimborn, 2006). Clinically, patients with mutations in MCPH1 display an increased number of prophase like cells on standard cytogenetic analysis - a clinically useful discrimination unique to MCPH1 microcephaly. Microcephalin contains three BRCA1 C-terminal (BRCT) domains, also found in DNA repair and cell cycle checkpoint proteins. These domains seem to bind phosphoproteins to control DNA damage-induced cell cycle checkpoints. Three functions have so far been reported for Microcephalin (Trimborn, 2006).
Small-interfering- RNA (siRNA) mediated depletion of MCPH1 identified a role in regulating chromosome condensation during the cell cycle (hence PCC) (Trimborn, 2006).
A role in DNA damage response through the regulation of BRCA1 and Chk1 (Trimborn, 2006).
MCPH1 was identified as a negative regulator of the catalytic subunit of telomerase (Trimborn, 2006).
Autosomal recessive primary microcephaly is the term used to describe a genetically determined form of microcephaly previously referred to as microcephaly. It is clinically diagnosed using the following guidelines - 1. Microcephaly is present at birth. 2. Degree of microcephaly does not progress throughout lifetime. 3. Mild to severe mental retardation without other neurological findings. The brains of affected individuals are characterized significant reduction in the size of the cerebral cortex. There is also a smaller general reduction in the rest of the central nervous system (CNS), although the architecture is preserved (Trimborn, 2004; Trimborn, 2006).
ROLE OF MICROCEPHALIN SUBTYPES IN BRAIN EVOLUTION:
MCPH1 encodes an 835 amino acid protein which was named as Microcephalin (Woods et al. 2005). MCPH1 mutations are a rare cause of primary microcephaly, and affected individuals display a broader phenotype than reported for other forms of MCPH (Jackson, 1998). It has been shown that MCPH1 primary microcephaly is allelic to premature chromatin condensation syndrome, which led to the identification of Microcephalin as a negative regulator of condensin II, a protein complex involved in chromosome packaging. Clinically patients with mutations in MCPH1 display an increased number of prophase like cells on standard cytogenetic analysis. Microcephalin contains three BRCAI C-terminal (BRCT) domains, also found in DNA repair and cell cycle checkpoint proteins. These domains seem to bind phosphoproteins to control DNA damage induced cell cycle checkpoints. Three functions have so far been reported for Microcephalin: small interfering RNA (siRNA) mediated depletion of MCPH 1 identified a role in regulating chromosome condensation during the cell cycle a role in DNA damage response through the regulation of BCRAI and Chk 1; and MCPH 1 was identified as a negative regulator of the catalytic sub unit of telomerase (Jackson, 1998).
MCPH 5 mutations is the most common cause of the MCPH phenotype (Roberts, 2002). It is a large gene and encodes the human orthologue of the Drosophila gene abnormal spindle (asp) called abnormal spindle mutated in microcephaly (ASPM). The reported mutation are spread throughout the ASPM gene and result in truncated ASPM protein products ranging in size from 116 - 3357 amino acids (Cho, 2006), 81 isoleucine glutamine (IQ) repeat motifs and a C terminal region of unknown function. Structural projection and comparison with myosin suggest that when ASPM is present at the centrosome, it assumes a semi-rigid rod conformation with microtubules bound by the N terminus and the centrosomal components interacting at the C terminus. ASPM is found near the centrosome and is thought to play an essential role during neurogenic mitosis. The asp protein is required for microtubule organization of the mitotic spindle poles and the central spindle in mitosis and meiosis. In contrast ASPM mutations in humans produce a mitotic defect restricted to the brain. This may be due to a functional overlap between ASPM and Nuclear mitotic apparatus protein 1 (NuMA) another protein shown to regulate spindle dynamics (Roberts, 2002; Cho, 2006).
MCPH 3 encodes cyclin dependent kinase 5 regulatory associated protein 2 (CDK5RAP2). Little is yet known about the function of CDK5RAP2 (Bond, 2005); however it was originally identified as a negative regulator of cyclin dependent kinase 5 (CDK 5) through its inhibition of CDK 5 regulatory protein 1. CDK 5 divergent from the rest of the cyclin dependent kinase (CDK) families other members of which are ubiquitously expressed and regulate mitotic checkpoints. In contrast CDK 5 expression is restricted to the brain where it regulates the creation migration and degeneration of neurons (Cruz and Tsai 2004). The Drosophila orthologue centrosomin (CNN) has been studied and CNN mutants display reduced cell numbers in both the central and peripheral nervous system (Bond, 2005). CDK5RAP2 is located at the centrosome throughout the cell cycle and its N-terminus interacts with the tubulin ring complex, which initiates microtubule nucleation (Bond, 2005), required for spindle formation. The restriction of CDK5RAP2 mutations to MCPH and not a more widespread growth disorder is probably due to the complementary tissue expression pattern of a mammal specific homologue called Myomegalin (Bond, 2005).
The MCPH 6 gene encodes centromere-associated protein J (CENPJ, also known as CPAP, centrosomal Protein 4.1 Associated Protein). Despite its name, CENPJ is a centrosomal protein and this localization depends on non erythroid protein 4.1 splice isoform 135 (4.1R-135). Intriguingly this protein is also responsible for recruiting NuMA to the centrosome. It has been demonstrated that CENPJ associates with the tubulin ring complex and in vitro evidence suggests that CENPJ may modulate microtubule nucleation and depolymerise microtubules (Evans, 2004). This may suggest that an inverse relationship exists between CENPJ and CDK5RAP2 in regulating microtubule dynamics (Bond, 2005). RNAi depletion of CENPJ in HeLa cells resulted in a mitotic arrest with >40% of cells containing multipolar spindles a finding similar to asp mutant neuroblasts in Drosophila sp (Cho, 2006; Evans, 2004).
In summary the developmental linkage between comparative brain morphometry and the comparative processes that influence the specification of axonal connectivity suggests that what is uniquely different about human brain is not just their quantitative organization, but more importantly the consequent shifts in connectivity in brain region. For over a century scientists have studied brain evolution as a problem of gross functional morphology. ASPM and MCPH responded to natural selection and the resulting changes contributed to our large brains. But how exactly the ASPM gene produced these changes is not yet entirely clear. It seems to control how many times cells in the cerebral cortex can divide which controls how much space there is for neurons. It is known that a variant of the gene that allowed additional cell divisions gave some hominids the additional neuronal infrastructure that eventually let them develop abstract reasoning and language skills.
Nature is not democratic. Individuals' IQs vary. Instead genetic interactions with the environment suggest that enriched environments will help everyone achieve their potential, but not to quality. Our potential seems largely pre determined. That our interpretation of intelligence the brain and heritability has succumbed to a variety of political and social pressures is undeniable. Presumed functional correlates of brain size differences, theories of encephalization and the plausibility of highly modular species specific changes all must be carefully reexamined in the context of this information. Although well-accepted claims about brain evolution in our lineage may be put in question as a result the value of comparative morphological analysis takes on a new significance as a guide to more detailed development and molecular studies of brain. Achieving this new synthesis of quantitative morphology, developmental biology and genetics is key to unlocking the mystery of what makes human's brain human & therefore more detail studies in this field is required to reveal the mystery.