Evolution of Gene Expression
Compared to brains of other animals, the human brain is characterized by a number of “higher functions” including language and abstraction. Like our genetic similarity, the internal structures of our brains have few differences when compared to chimpanzees. Caceres et al. propose that the differences in size and function between our brains and the brains of chimps and other primates can be attributed to differences in the regulation of genes. Using a variety of methods I vaguely understand, they found that asymmetries in gene expression between humans and other primates are greater in brains than in other tissues such as the liver and heart. They propose that changes in gene regulation may be an adaptation to maintain neuronal functions over a greater period of time. Some questions: Does this explanation make sense when accounting for the “natural” life-span that characterized human evolution? Eg, Humans live longer in the present than they did hundreds of years ago and neuro-degenerative diseases, which generally affect older individuals, may not have had fitness consequences. Caceres et al. also propose that genes may be up-regulating metabolic processes in the human brain. Is this up-regulation characterized by a greater number of mitochondria? If so, how is the amount of mitochondria in different tissues regulated?
Uddin et al. conducted a similar study, also involving methods I don’t understand. They also found an up-regulation of genes that are involved in metabolism and neural functions. In contrast to Cacerres et al., Uddin et al. found that chimpanzees have gene regulation profiles more similar to humans than to gorillas. This demonstrates that chimpanzees are the sister group to humans. The similarity of gene regulation between chimps and humans could help elucidate the molecular mechanisms that associated with “higher” brain functions.
Uddin et al. conducted a similar study, also involving methods I don’t understand. They also found an up-regulation of genes that are involved in metabolism and neural functions. In contrast to Cacerres et al., Uddin et al. found that chimpanzees have gene regulation profiles more similar to humans than to gorillas. This demonstrates that chimpanzees are the sister group to humans. The similarity of gene regulation between chimps and humans could help elucidate the molecular mechanisms that associated with “higher” brain functions.
posted by Ondi at 9:39 PM
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The Cáceres et al. and Uddin et al. papers (published within 6 months of each other) give slightly differing views in the differential levels of gene expression in brain tissues of humans versus non-human primates. Cáceres et al. report up-regulation of 90% of identified genes in humans compared to chimps and macaques (in cerebral cortex tissue) while Uddin et al. report more or less equal gene expression profiles between chimpanzees and humans in anterior cingulated cortex (ACC) tissue. One issue influencing the results of both studies is whether changes in level of gene expression are really due to evolutionary changes in expression or to interspecific differences in transcript nucleotide sequences, a consequence of using human microarrays to identify genes in non-human primates. Cáceres et al. confirm their results through RT-PCR and cDNA arrays (54 of 169 genes were confirmed to have higher expression levels in humans through these independent procedures). Additionally, they find that human brain tissue shows higher gene expression compared to primates but heart and liver tissues do not. Both studies find substantial up-regulation in humans (and chimps in Uddin et al.) suggesting that neuronal activity and cerebral metabolism is quite high in humans, although, the two papers don’t report any of the same genes as allowing increased neuronal activity (maybe finding the same genes with microarrays is improbable anyway?)…
So, these techniques are Greek to me—how exactly is a level of gene expression measured in the microarrays? Also, are there any differences between the tissues that were utilized in the two studies (cortex tissue vs. anterior cingulated cortex tissue)? From the descriptions in the papers, it seems like the ACC is only a small portion of the cortex. Is this true, and if so, does examination of the ACC give a narrower scope of genes to be scrutinized for differential expression?
In the Caceres study, gene expression was measured in the cortex of humans, chimpanzees, and macaques. The cortex was chosen because it is associated with many complex brain functions including memory, attention, perceptual awareness, "thinking", language, and consiousness.The majority of the genes with a differential in expression between humans and the other primates showed an up-regulation of expression in the humans. Interestingly enough, when comparing the gene expression of tissues from the heart and liver of humans and chimps it was found that there was an almost equal amount of up-regulation and down-regulation. Although the study does not explicitly say that the genes that are up-regulated in the human brain lead to a greater amount of higher level function, I think it can assumed. These results suggest that the human brain evolved to increase neuronal activity becoming “superior”, yet other tissues remained static in terms of superiority.
The problem I had with the study, as was argued in the discussion, is that human arrays were used to measure gene expression in non-humans. We have no idea if the genes the non primates express but don’t share with humans are as important to higher level function as the shared genes.
Uddin et. al 2004.
This paper examine the relative abundance of transcribe messages of different expressed genes in the anterior cingulated cortex (ACC; that is involved in cognition) among Humans, Chimpanzee, Gorilla and Macaque. They also use Spindle cells (which are a specific class of neurons that participate in signal transmission in the nervous system, and are characterized by a large spindle shaped soma) to compare brain evolution among these primates. The show that humans are not very different from the close relatives in the number of probe sets detected in the ACC. One of the main result show that human and chimpanzee are close relatives. Another important result is that several electron transport chain (ETC) genes show apparent expression differences as well suggesting that this pathway has been subject to both gene regulation and protein sequence evolution during the descent of catarrhines. Looking at table one I was wonder if sample size matters? and how much intra-specific variation exist in the different groups in the gene expressed in the ACC. Also, does gene expression change with age?
Cáceres et. al 2003.
This paper used oligonucleotide arrays to identify genes differentially expressed in the brain of humans or chimpanzees. The authors found that most of the genes used in the study show high signal intensity in humans compared with chimpanzees. They said that this finding was unexpected, I don’t know why?. Base on this result the author wanted to explore if this patterns was unique to the brain or it occurred in other organs, to know this they explore up-regulation of gene expression in the heart and liver. They found that they gene regulation in these to organs was similar between humans and chimpanzees. Another interesting finding that is related with the topics mention in previous classes was that gene expression change related to energy metabolism. In addition, they use previous studies to show that human brain have higher metabolic rate compare to macaques, and that this have important consequences in cognitive and behavioral capacities. Although this paper have interesting new ideas, there was one that call my attention an is the one where the authors said that because of the great life-span potential of humans our neural cells could possess biochemical adaptations that enable them to function longer than those of other primates.
Finally, The authors made the arguments that this study may help to understand degenerative brain disease that are rare in other primates, I was wonder if any one knows if primates brain disease are well known.
To follow up on Gustavo's point on primate brain disease, another interesting study could look for the differences in the abundance and level of expression of endogenous neuroprotective antioxidants among primates. Uddin et. al. demonstrate that the most parsimonious tree shows that humans and chimpanzees are more closely related than either species to gorillas. Further data suggests that both species, humans and chimps, have up-regulation of neuronal-funciton genes as well as aerobic metabolism genes, specifically in the Electron Transport Chain. It is conjectured that the up-regulation of ETC and neuron function genes in the human and chimpanzee are signs of increased demand of these genes relative to other species; evidence which may account for higher cognitive ability. Could a next step include looking for intra-human cognitive gene differences? [1]
Caceres et. al. picture a slightly different scenario. They find that a key difference in inter-species brain function resides in the level of gene expression, and not necessarily sequence differences. Specifically, genes responsible for neuronal acitivity were up-regulated in humans, when compared to other non-human primates. It was also clear that the greatest differences, in support of last weeks reading, of gene expression occured in the brain, as opposed to the heart, liver, etc. Areas that had near-equal expression of regulation.
[1] See: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11807284&query_hl=10&itool=pubmed_docsum
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