Of chimps and men

This is another post not related to ketosis (I have one almost finished which should be published shortly). 

The reason for this post comes after the "evidence" presented by Don Matesz in his last post. I think that my answer got a little short and I think this topic is very important for understanding certain aspects of nutrition, especially when talking about evolutionary nutrition. First of all, I have to mention that humans can adapt to almost every diet. Obviously I have my own reasons for believing that a high fat diet is better than other diets, but I don't dismiss the idea that different people can get the same results using different dieting approaches. 

Ok, back to the main topic. Don made the following assertion:

"Ninety-eight percent of the human genome is identical to the nearest primate relative, chimpanzees, who eat a 95 percent plant diet.  Recent hunter-gatherers consume up to 20 times more meat than chimpanzees on a percent energy basis, a substantial deviation from the primate baseline."

This leads us to comparative genomics. What is comparative genomics?

"Comparative genomics is the analysis and comparison of genomes from different species. The purpose is to gain a better understanding of how species have evolved and to determine the function of genes and noncoding regions of the genome."

But ultimately, the genome tells us nothing about how genes are transcribed and/or translated which is what in the end is physiologically relevant. The fact that two genomes from different species have the same genes doesnt mean that a. they are equally expressed, b. they are equally translated or c. they yield the same final product (protein or RNA). The collection of all transcripts present in a cell, at a given time and condition is called the transcriptome. The set of expressed proteins in a given cell type, time and condition is called the proteome. Further, another area of research is the metabolome. 

Copyright © 2002, Bios Scientific Publishers.

The genome is divided in coding regions (genes) and non-coding regions (cis-regulatory elements and junk DNA). Briefly, transcription of a gene is performed by RNA polymerase II, which is the polymerase that synthesizes mainly mRNAs, which are then translated into functional proteins. This is a dynamic and highly regulated process, which means that the merely presence of a gene in a genome gives us no information about the importance of this gene in a particular cell type at a given time, or for that matter, for an organism. Gene expression can be regulated in multiple ways. For most eukaryotic protein-coding genes, the binding of RNApolII and general transcription factors depend on the binding of several proteins (activators and repressors) to transcription-control elements, such as promoters, promoter-proximal elements and enhancers. The binding of transcription factors to these elements in turn depend on the energy status of the cell, as well as activation of different signaling pathways activated by different stimuli (ie. hormones). Another important aspect of this process of activation/repression (or on/off status of a particular gene) is its location within the chromosome (heterochromatin vs. euchromatin) and histone modifications (methylation, acetylation and phosphorylation being the most characterized). The condensation of chromatin regulates the binding of proteins and RNApolII to DNA, thereby regulating transcription initiation, which is the main mechanism in the control of gene expression. 

Another level of gene expression control are post-transcriptional modifications. After the transcription of a gene, the initial product (primary transcript) has to be processed to yield a mature RNA. This gives us high variability in the final product given that a particular gene can yield different proteins by alternative splicing (the process of removal of introns and splicing of exons). 

Schematic representation of alternative splicing. Exons are colored while introns are represented by lines. (Source: designmatrix.wordpress.com)

During and after the translation of mRNAs, proteins can be further modified (post-translational modifications). A detailed review of these processes can be found here. 

The overall effect of these modifications explain why the number of actual proteins greatly exceeds the number of predicted proteins by DNA and RNA analysis. 

But what is the relationship between the transcriptome and the proteome? One can assume that the transcriptome is directly related to the proteome, the amount and specificity of mRNAs present in the cell determines the amount and specificity of proteins being synthesized. But, as complex as multicellular organism are, this is not the case. Recent integrative analysis of the transcriptome and proteome has shown that there is, in general, a weak correlation between them; and mRNA levels could not be consistently relied upon to predict protein abundance (1,2). The amount of active protein is dependent on factors such as its location, half-life, post-translational modifications or interaction with other proteins to become effective. These might be some of the reasons for the differences observed between the transcriptome and proteome. 

So if we want to compare two species for making physiological assumptions, we must look into the transcriptome and proteome, and not only the genome. Applying this to the comparison of humans and chimpanzees, there is evidence that differences in gene regulation is a major cause of the difference in phenotype between human and chimpanzee (3). 

A very long and detailed review on human-chimpanzee comparisons has been written by Kehrer-Sawatzki and Cooper (4). I will copy some relevant excerpts for this discussion (my bolds).

"It is always possible that measured mRNA levels may not reflect the actual levels of functionally active proteins synthesized by the respective genes [Gygi et al., 1999; Preuss et al., 2004]. Interestingly, parallel patterns of gene expression differences and protein divergence have been observed in comparisons of human and chimpanzee transcriptomes and proteomes [Bustamante et al., 2005; Khaitovich et al., 2005a; Nielsen, 2006; Gilad et al., 2006]. These parallel patterns indicate that significant gene expression differences correlate with extensive divergence of the encoded proteins."

"The central question remains as to the molecular basis (and its ultimate causes) of the observed gene expression divergence between humans and chimpanzees. The processes involved are likely to include the sequence divergence of regulatory regions, differences in the control of transcriptional initiation, RNA processing and translation, the modification of chromatin structure, and potentially also differences in DNA methylation. (...)

Just as gene expression diversity between individual humans is known to be influenced by multiple cis- and trans-acting factors [Morley et al., 2004; Stranger et al., 2005], so it is likely that multiple genetic differences will be found to influence expression divergence between humans and chimpanzees. Particularly interesting in the context of the expression divergence between these higher primates is the finding that transcription factors have evolved rather rapidly in the human lineage by comparison with other human proteins [Bustamante et al., 2005]. The accelerated evolution of transcription factors is indicative of how a relatively small number of genetic changes in key locations may pleiotropically affect the expression patterns of a myriad of different genes by influencing their transcription factor binding capacity. We may therefore surmise that the accelerated evolution of transcription factors in the human lineage has in all likelihood had a major impact on gene expression divergence between human and chimpanzee."

"Alternative splicing contributes very significantly to increased transcriptome and proteome diversity as well as to interspecies divergence [Boue et al., 2003]. An estimated 60% of all human genes employ alternative splicing [Mironov et al., 1999; Lander et al., 2001]. Dual coding regions in particular are characterized by alternative splicing; the same exon sequences are shared by different transcripts encoding distinct amino acid sequences in different reading frames. At least 7% of all alternatively spliced genes in the human genome contain multiple coding regions [Liang and Landweber, 2006].(...) Interestingly, 4% of human dual coding regions are not conserved in chimpanzees, as indicated by the presence of stop codons that disrupt one of the two reading frames [Liang and Landweber, 2006]. (...) When human and chimpanzee exon flanking regions were compared, a significant reduction in the nucleotide substitution rate of the flanking regions of alternatively spliced exons was observed, independent of the site-by-site variation in mutability due to different CpG contexts. Thus, increased purifying selection appears to have impacted on exon flanking regions and thus, in all likelihood, the regulation of alternative splicing in humans and chimpanzees [Xing et al., 2006]."

Other mechanisms such as gene duplications, insertions/deletions, chromatin condensation, genome rearrangements, etc. are also important but discussing all of them would make this post extremely large. Nevertheless, the difference in gene expression patterns between humans and chimpanzees has been reported in several studies (5,6,7). This pattern also seems to be influenced by diet (8), which could influence phenotypic differences between humans and chimpanzees.Thus, it seems that cis-regulation is a major mechanism by which humans and chimpanzees differ (9).

Summing up

I think is pretty clear now how invalid is to use genome comparisons as evidence of the superiority of a given diet. Although this is a valuable tool for making phylogenetic and evolutionary assumptions, as well as for identifying orthologous genes, it does not help predicting gene expression dynamics. Moreover, using the idea of parsimony (nature is lazy), mutations driving species diversification should not be observed primarily in protein-coding regions, but in cis-regulatory elements which control gene expression. This in turn influences levels and expression of transcription factors for specific genes, like the differences observed between humans and chimpanzees. Finally, differential alternative splicing can yield completely different proteins from the same gene, thus contributing to phenotypic differences between humans and chimpanzees. Overall, these processes show how two divergent species can have a great sequence identity but a completely different phenotype, and thus require different diets. 

Addendum

A very interesting review on diet and gene expression among humans and non-human primates can be found here.

Kehrer-Sawatzki H, & Cooper DN (2007). Understanding the recent evolution of the human genome: insights from human-chimpanzee genome comparisons. Human mutation, 28 (2), 99-130 PMID: 17024666