Sunday, July 8, 2007

Evolving regulation

For the latest installment of my Sunday Journal Club, I had initially thought of summarising this paper, but half of the internet seems to have been there before me. All I will contribute to the debate is to say that a Canadian male of my acquaintance thinks the study can not be extrapolated outside of the United States as American males are such well-known girly men.

Luckily, my weekly reading also included two other papers that complement each other very well and are unlikely to provoke a cross-border incident. The first is “Fast-evolving non-coding sequences in the human genome”, by Christine Bird and colleagues from the Sanger Institute, the University of California Santa Cruz, and Penn State University. Open access at Genome Biology.

The vast majority of the human genome does not code for proteins. While large stretches of this non-coding DNA have no known function, certain non-coding sequences have been shown to contribute to processes such as the regulation of gene expression. As I have mentioned before (see post and comments), altering the patterns of gene expression can have dramatic effects on embryonic development and other essential processes. Not surprisingly, therefore, mutations within some specialised non-coding DNA sequences are thought to have made major contributions to human evolution.

Bird and colleagues looked at non-coding regions that were previously found to be very similar in many vertebrate species. These conserved non-coding (CNC) sequences are found throughout the human genome, and their sequences can be compared in human, chimpanzee and macaque. This technique allows you to identify species-specific changes; a sequence that is identical in macaque and chimpanzee, but different in human, must have mutated within the human population, after the split from the chimpanzee lineage. The research group looked specifically for CNC sequences that have mutated in the human lineage. Around 10% of the qualifying sequences displayed evidence of a human-specific accelerated rate of mutation.

So why might a CNC sequence suddenly start to change in humans? One possible explanation is that a region that was once important for normal function, and therefore not allowed to mutate without disastrous consequences (this is known as negative selection), is freed from negative selective constraint when the function it serves becomes non-essential. The other possibility is that the human-specific mutation was beneficial, increased the reproductive success of individuals that carried the mutation, and started to spread in the population (this is known as positive selection and is much rarer). Bird et al. distinguished between these possibilities by looking at the general rate of change between human and chimpanzee Accelerated CNC (ANC) sequences. Regions that are under positive selective pressure will tend to mutate faster than regions that have merely lost their negative selective constraint. Around 15 - 19% of the observed ANCs were found to have mutation rates consistent with positive selection.

As I mentioned in a previous post, gene duplication is an important driver of evolutionary change. The genome essentially acquires a back-up copy of the gene, freeing the other copy from negative selective constraint and allowing it to evolve new functions. More of the putative positively-selected ANC sequences were mapped to recently duplicated regions than would be expected by chance. ANC sequences also frequently overlapped with regions of the human genome that are thought to be evolving under positive selection.

For me, the most interesting result was the correlation between ANC regions and gene expression. Mutations within ANC sequences were more likely to correlate with changes in gene expression levels than were mutations in other regions. The three genes that were affected the most by ANC sequence mutations will no doubt be the subject of future studies on the importance of gene expression regulation to human evolution. The paper concludes by suggesting that the likelihood of a particular gene's expression being affected by changes within an ANC sequence depends on the type of function the gene performs.

The second paper of the day starts where Bird's paper leaves off. “Genetic Properties Influencing the Evolvability of Gene Expression”, by Christian Landry and colleagues from Harvard and the University of Utah, is another example of the kind of study that is possible when you work with yeast. The study set out to determine whether certain kinds of gene are more likely than others to be affected by mutations within their regulatory regions. I'm afraid a subscription to Science is needed to view this paper in its entirety.

The group took a population of genetically identical yeast, and developed from it four independent lineages. Four randomly chosen offspring of the original yeast population were separated from each other, and each one was grown for 4,000 generations, enough time for the four parallel lineage to accumulate multiple independent mutations. The four resulting populations were then screened for differences in gene expression levels; 2,031 affected genes were identified and studied further.

As also suggested by the results of Bird's study, genes with certain cellular functions were less likely than average to have evolved differences in gene expression. Genes with an essential role, in processes such as cell growth, display negative selective constraint and are less likely to tolerate mutations that affect gene expression.

Landry and colleagues also investigated other factors that might contribute to the evolvability of gene expression. Genetic regulation is a very complex process, with multiple genes often contributing to the control of another. The more genes it takes to regulate the expression of a particular gene, the more likely it is that that gene's expression will evolve. This is expected, as a more complex network presents a larger target for mutation, with changes to the expression level of one gene having a knock-on effect on other members of the network. Possession of a certain type of regulatory sequence, common in genes that are known to be more diverged between different species, also makes a gene more susceptible to evolutionary change.

These two papers contribute to the growing body of evidence that changes to gene expression are important drivers of evolutionary change. As every good study should, both papers identify interesting candidates for further study. The availability of whole-genome sequences and information about the regulatory interactions between different genes is enabling many similar studies. The post-genome era really is a golden age of evolutionary biology.


  1. No-one seems to dare to use the word 'chromatin', or suggest that control of gene expression is most likely to be effected through DNA topology. We have known for a few years that many transcription factors operate in this way - unpacking histones, freeing up regions of DNA from compacted storage.
    I bet that there is a pattern to be found in ANC's, corresponding to histonal footprints - or rather, the presentation of a distinct 'face' of heterochromatic co-proximal elements, which may span a small number of histones (in order to lie together in vivo).
    How much would I bet ? - all the sportsmen in the world.

  2. Hello and welcome!

    I don't think it's a matter of no-one dares, more that no-one knows how to read the histone code well enough yet. I guess if 2 sequences are identical then they should have very similar, if not identical, histone patterns associated with them, and mutation might be expected to alter the pattern of histone binding and / or modifications. So the results of these 2 studies could still be valid even if the primary mechanism is via histone modification.

    I followed this field very closely during my PhD research, which actually involved moving transcription factor binding sites to the opposite face of the DNA helix, but not since - is there anything recent I should be reading?

    BTW, in my experience, betting on scientific outcomes usually results in students and postdocs relinquishing money to their supervisors. Best avoided if you ask me.


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