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October 10th, 2006


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11:49 pm - Biology Blogging: Gene Duplication

Alright, I'm going to write about an interesting review article on gene duplication that I just read, on the grounds that I don't have anything better to write about, so I might as well node blog my homework.

So, traditionally evolution is considered to progress by small mutations accumulating over time, with beneficial mutations being subject to positive selection and harmful mutations being subject to negative selection. A problem arises, however, if we consider how it is that a new function is supposed to arise in a gene by such stepwise mutations: any mutation that confers some new function is likely to abolish the old function. Hence, it would seem that new functions could not arise from genes responsible for the production of essential proteins, since the arising of these new functions would abolish the old, essential functions, and therefore would be selected against.

Enter gene duplication. This is a process where some error in recombination (or some other process, such as the function of a retrotransposon) results in the duplication of a gene, some section of a chromosome, an entire chromosome, or an entire genome becoming duplicated. This resolves the above problem because there are now two copies of the gene present, one of which can retain the original function while the other can accumulate mutations without harming the organism.

Now, mutations are much more likely to abolish the function of the gene than to result in new function. Therefore, in the majority of gene duplication events, we would expect that one copy would be preserved while the other copy becomes nonfunctional due to the accumulation of deleterious mutations, thereby becoming a pseudogene. In some rare cases, we would expect that one copy would be preserved while the other copy acquires a mutation that confers some new, beneficial function, leading to both copies of the gene being subjected to positive selection. Wikipedia says as much:

This is because with two copies of a gene present, mutations in just one copy of the gene often have no deleterious effect on the organism; thus, the second copy is free to "explore" the sequence space by mutating randomly. The duplicate gene may either (a) acquire mutations that lead to a gene with a novel function or (b) acquire deleterious mutations and become a pseudogene.

However, when we examine the prevalence of preserved duplicate genes in extant genomes, we find that duplicate genes are preserved at a rate much higher than would be predicted based upon the assumption that most duplicated genes will become pseudogenes. This is because it is mistaken to consider genes as being composed of only a single unit, and, as such, there is actually a third possibility for the fate of a duplicated gene which the traditional model (and Wikipedia) omit.

The article Preservation of Duplicate Genes by Complementary, Degenerative Mutations by Force et al. [Genetics. 1999 Apr; 151(4): 1531-45] demonstrates this third possibility in this figure:

fates of duplicated genes

The gene in this figure has a large coding region and 4 small regulatory regions that control expression in different tissues. The two possible fates discussed above are shown in the two leftmost columns in the figure: nonfunctionalization, or the loss of function of one copy whereby it becomes a pseudogene, and neofunctionalization, or the gain of new function of one copy. The third possibility is subfunctionalization, whereby the loss of some discrete subfunction in one copy of the gene is accompanied by the loss of some different discrete subfunction in the other copy. By this mechanism, both copies become necessary for retention of the original function. This process could explain why we observe preservation of both copies at a higher rate than would be predicted when taking only nonfunctionalization and neofunctionalization into consideration.

Another interesting thing about this hypothesis is that, in the example above, different versions of the duplicated gene are expressed in different tissues. This could allow for changes to occur which are specific to those tissues; therefore, this process could be a mechanism whereby developmental changes might evolve.

Anway... it's an interesting paper.


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[User Picture]
From:gdwatson
Date:October 14th, 2006 04:27 am (UTC)
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This is way over my head, but: how could such a necessary duplicate survive more than one generation? It seems that for at least the first few generations, the offspring's chance of survival is nil.

Does the subfunctionalization take place in a later generation from the copying, and I just missed it?
[User Picture]
From:nchaimov
Date:October 14th, 2006 05:06 am (UTC)
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Yeah, each stage takes place in a different generation, and to get to the point where a preserved duplicated gene is fixed in a population would take many hundreds of generations. (Which is why all of the experiments are done in bacteria and fruitflies; otherwise you'd have to wait too long to get results.)
[User Picture]
From:gdwatson
Date:October 15th, 2006 10:46 pm (UTC)
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But then how does is the copy prevented from becoming a pseudogene before subfunctionalization preserves it? Won't the copied gene be intermixed in generation two with whatever happens to occupy that "space" in the mate's DNA?

It makes sense that subfunctionalization (so long to type...) would preserve a gene, but how does the gene survive intact even that long?
[User Picture]
From:nchaimov
Date:October 15th, 2006 11:37 pm (UTC)
(Link)
The copy isn't prevented from becoming a pseudogene before subfunctionalization; only afterwards, but it is more probable than neofunctionalization. Most duplicated genes become psuedogenes; according to this paper, between 50% and 90% of all duplicated gene pairs become pseudogenes.

So the answer to your question is: it doesn't happen very often.
[User Picture]
From:nchaimov
Date:October 15th, 2006 11:46 pm (UTC)
(Link)
And I suppose another question that might arise is why we would suspect that subfunctionalization might be an important mechanism given its apparent rarity. The answer to that is that we can see evidence of it in actual preserved duplicated gene pairs. E.g, in this comparison of two duplicated genes in zebrafish:



The dots show regions with high identity between the two copies; the colored regions show known regulatory elements. Eng2a lacks the first such regulatory element, which is preserved in Eng2b, while Eng2b lacks the third element, which is present in Eng2a.
[User Picture]
From:nchaimov
Date:October 15th, 2006 11:55 pm (UTC)
(Link)
It would be nice if LiveJournal let you edit comments, since I just realized that I explained that figure incorrectly; it shows the percent similarity between the two duplicated Zebrafish genes and the single, nonduplicated version of the gene in humans, not between the two Zebrafish genes.

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