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Wed, Sep. 26th, 2007, 06:26 pm
Microarrays in evolutionary neuroscience

ResearchBlogging.org Todd M. Preuss, Mario Cáceres, Michael C. Oldham, Daniel H. Geschwind (2004). Human brain evolution: insights from microarrays Nature Reviews Genetics, 5 (11), 850-860 DOI: 10.1038/nrg1469


In a recent post, I commented on article by Todd Preuss' research group, and compromised myself to a further attempt to describe his research programme here. As I said then, nyuanshin pointed me to Preuss' homepage, and I downloaded a few articles – including one review paper that appeared in Nature Reviews Genetics on the insights that were obtained from microarray studies to theories of brain evolution [1]. Of course, no article can be published in Nature Reviews Something if it does not involve speculations on something that is relevant to human beings, and thus this particular paper is called Human brain evolution: Insights from microarrays. Even though I do not support such “anthropocentric” attitude from high-impact journals, it is indeed a very good review, and I shall sum it up and digest it for the few of you who read this.
 
   
Most comparative genetic studies in the primate lineage – specially the clade that includes humans, chimpanzees and macaques – have concentrated on the identification of genes that underwent significant changes in terms of sequence or in terms of the rate of nucleotide changes. The recent fuzz are the genes microcephalin [2] and ASPM [3], which seem to regulate brain sizes, whose evolution seem to have been driven by strong positive selection. Microarray studies of those genes demonstrated that there is an unusual pattern of amino-acid substitution in both genes in humans, when compared to both chimps and macaques, which implies large sequence changes in the human lineage. Brain size is, as postulated in my precisof Striedter's “Principles of Brain Evolution”, a variable that is related to many secondary physiological and behavioral consequences, the chief consequence here being that “as regions phylogenetically increase in size, they tend to fractionate in more subdivisions, nuclei, or areas” and tend to “invade” other areas. The interest in those genes arose also from observations that both ASPM and microcephalin seem to still be undergoing adaptive evolution [4-5]; also, there are some suggestions that microcephalin was introgressed in the human lineage from an archaic Homo lineage(paraphrasing the title of the article), probably Neanderthals [6].
Exciting as these results could be, they are not without contradiction. Yu et al. [7] criticized the ASPM analysis on the basis that, even though computer simulations indicate that ASPM showed an unusual pattern of variation within the last 500 to 14,100 years, an empirical comparison of ASPM with other loci does not ensue evidence for positive selection on the abnormal spindle-like microcephaly associated (ASPM) gene in European populations in the past 6000 years, as postulated by Mekel-Bobrov et al. [4]. In the same direction, Currat et al. [8] suggested that the demographic histories examined by Lahn's crew [4] were only a small subset of all possible demographic histories; as such, other computational models of such demographic histories could (and indeed, do) generate the observed patterns of variation without appeal to the inferred positive selection. The obvious problem here is that Mekel-Bobrov et al.'s [4] and Evans et al.' [5] studie used computational models to estimate variation without considering alternative models or other empirical data. The evidence for the “ongoing adaptive evolution” of ASPM and microcephalin, thus, is not enough to reject the “null-hypothesis” that the observed variation can be explained by other, non-selectional variables.
This does not mean that those genes did not present evolutionary change in the human clade, though. Evans et al. [2] and Zhang [3] postulated that those genes were positively selected in the human lineage, even if there is no evidence of ongoing selection. As such, those oligonucleotide array studies demonstrated that ASPM and microcephalin underwent either large sequence changes or acceleration in the rate of nucleotide changes when Homo sapiens appeared. As Preuss et al. [1] review, however, evolutionary change occurred in other genes, as well. In the previous post on Preuss' group's work, I commented that there seems to be an increase in the expression of the THBS4 and THBS2 genes in cortex and caudate nucleus of humans when compared to chimpanzees and macaques. Another example is the FOXp2 gene – related to a human speech and language disorder [9] –, which encodes a protein that contains two human-specific amino-acids in positions that are conserved in other species [10]. FOXp1 and FOXp2 are also expressed in the brain of songbirds [11], and, as I recently learned in a FeSBE symposium held by Constance Scharff, knocking off FOXp2 in specific songbird pallial areas (HVC and area L) seriously impair the animals' capacity to learn new songs. In fact, as Butler and Hodos [12] put it, “[t]he avian vocalization pathways have evolved independently of those in mammals, with many similarities and some differences”. It seems, however that, among primates, a unique pattern of protein structure of the products from FOXp2 is found among humans. Preuss [13] argued that there is no evidence that new cortical areas evolved in the human lineage for language processing; “indeed, a reasonable case can be made that classical language areas have homologs in nonhuman primates”.
Down-regulation of gene expression is also seen in humans, in relation to other primates. The most striking change in this sense (pun unintended) is the loss of “a substantial fraction” of genes that encode olfactory receptor proteins [14]. It is probable that an enlarged olfactory system is linked to the feeding habits of carnivores [15,16], and, as such, should be diminished in herbivores and omnivores, including here Homo sapiens. It is interesting to notice that, even though prior theorists doubted the existence of a vomeronasal (accessory) olfactory system in some mammals – including human beings –, it has been demonstrated that this trait is probably retained in all mammals [17].
Cáceres et al. [18], using gene ontology classification [19], demonstrated that the genes that were in excess in human brains were those that were included in the categories of cell growth and/or maintenance and metabolism. Uddin et al. [20] did a similar gene-ontology analysis, and identified expression changes in transcription, translation and mRNA-processing genes. One should be directed to Preuss et al.'s [1] table 2 to take the full impact of those gene-ontology analyses.
What are the functional consequences of such elevated expression levels? Let the authors speak:
The elevated expression levels of many genes in the human brain, and their relationship to energy metabolism, indicates that the general level of physiological activity in the adult cerebral cortex might be higher in humans than in chimpanzees [[18, 20]]. Additionally, the upregulation in gene expression could be the result of an accumulation of mRNA molecules in human cells to allow for rapid responses to external stimuli. The human brain might also have adapted to the damaging effects of maintaining high rates of neural activity over the course of a long lifetime by increasing the expression of chaperones and other genes with neuroprotective functions [[18]].
The issue of what differences exist between human and nonhuman primate brains is a long-standing one. Human brains have been structurally reorganized during evolution, producing proportionately larger cortices, more direct projections from neocortex to the medulla, and enlarged lateral prefrontal cortices [21], as well as a meshwork pattern in the V1 visual cortex [22]. According to Striedter [21], those changes can be traced back to changes in brain size. It is only recently that the genes that are responsible for those evolutionary changes were identified, and their evolutionary history told, mainly due to those microarray studies. An exciting possibility – that of reconciling morphological and cladistic studies with molecular studies – begins to unfold in evolutionary neuroscience, thanks to those studies. Preuss' effort to review those microarray studies is helping to shape the future of evolutionary developmental neuroscience.
That's it for now. Go away, now. Go do something useful.
 
References:
 
[1] Preuss TM, Cáceres M, Oldham MC, Geschwind DH (2004). Human brain evolution: Insights from microarrays. Nature Reviews Genetics 5:850-860. http://dx.doi.org/10.1038/nrg1469
 
[2] Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT (2004). Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Human Molecular Genetics 13: 1139-1145.
 
[3] Zhang J (2003). Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165: 2063-2070.
 
[4] Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA, Lahn BT (2005). Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science 309: 1720-1722. http://dx.doi.org/10.1126/science.1116815
 
[5] Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT (2005). Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309: 1717-1720. http://dx.doi.org/10.1126/science.1113722
 
[6] Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR, Lahn BT. Evidence that the adaptive allele of the brain size gene microencephaling introgressed into Homo sapiens from an archaic Homo lineage. PNAS Early Edition. http://dx.doi.org/10.1073/pnas.0606966103
 
[7] Yu F, Hill RS, Schaffner SF, Sabeti PC, Wang ET, Mignault AA, Ferland RJ, Moyzis RK, Walsh CA, Reich D (2007). Comment on “Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens”. Science 316: 370b. http://dx.doi.org/10.1126/science.1137568
 
[8] Currat M, Excoffier L, Maddison W, Otto SP, Ray N, Whitlock MC, Yeaman S (2006). Comment of “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: 172a. http://dx.doi.org/10.1126/science.1122712
 
[9] Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco APA (2001). A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413: 519-523.
 
[10] Enard W et al (2002). Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418: 869-872.
 
[11] Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA. Parallel FoxP1 and FoxP2 expression in songbirds and human brain predicts functional interaction. Journal of Neuroscience 24: 3152-3163.
 
[12] Butler AB, Hodos W (2005). Comparative Vertebrate Neuroanatomy. Second edition. Hoboken: John Wiley & Sons.
 
[13] Preuss TM (2000). What's human about the human brain? In: MS Gazzaniga (Ed.), The New Cognitive Neurosciences, Second Edition, pp. 1219-1234. Cambridge: MIT Press.
 
[14] Gilad Y, Man O, Paabo S, Lancet D (2003). Human specific loss of olfactory receptor genes. PNAS 100: 3324-3327.
 
[15] Gittleman JL (1986). Carnivore brain size, behavioral ecology, and phylogeny. Journal of Mammalogy 67: 540-554.
 
[16] Gittleman JL (1991). Carnivore olfactory bulb size: Allometry, phylogeny, and ecology. Journal of Zoology 225: 253-272.
 
[17] Eisthen HL (1997). Evolution of vertebrate olfactory systems. Brain, Behavior and Evolution 50: 222-233.
 
[18] Cáceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C (2003). Elevated gene expression levels distinguish human fro non-human primate brains. PNAS 100: 13030-13035. http://dx.doi.org/10.1073.pnas.2135499100
 
[19] Ashburner M et al. (2000). Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium. Nature Genetics 25: 25-29.
 
[20] Uddin M et al. (2004). Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain-gene expression profiles. PNAS 101: 2957-2962.
 
[21] Striedter GF (2005). Principles of Brain Evolution. Sunderland: Sinauer Press.
 
[22] Preuss TM, Coleman GQ (2002). Human-specific organization of primary visual cortex: Alternating compartments of dense Cat-301 and calbindin immunoreactivity in layer 4A. Cerebral Cortex 12: 671-691.