Friday, 9 March 2012

Opening a can of worms

Possibly the laziest title for any commentary on a C.elegans paper but why not set a low standard of cliche from the offset?
Here's a paper I found quite interesting the other week that challenges the notion of redundancy in eukaryotes.
Research has shown there appears to be a general discrepancy between the high level of conservation of genes in animals and the amount of genes with essential function. You'd think if they are highly conserved that they must be highly important but many loss-of-function screens in Drosophila and C. elegans suggest otherwise.
There are two possible explanations for this;

1) Animals have genetic networks that are robust to mutation (through redundancy or genetic buffering) so that  loss-of-function in a single gene has no observable phenotype. 

2) Loss-of-function studies often occur in a single controlled environment and that the essential function of a gene is only unmasked in a specific environment.  An example of this is that my waterproof jacket isn't essential if I'm sitting in my house but it is if I go outside and it's raining.

Explanation 1) still doesn't really answer why the genes would be so conserved when you think about it. If anyone it should mean that species accumulate mutations until synthetic lethality finally gets the better of them. The second explanation works a lot better in the sense that we are probably just missing the essential functions of genes by not trying a variety of environments. In the case of S.cerevisiae it is indeed the case that most genes have a fitness defect when impaired in at least one environmental or genetic condition. The same does not appear to be true in similar experiments in C.elegans. A recent study, in C.elegans by Ramani et al however suggests that the majority of genes are actually required for wild-type fitness.

So why do there results differ so much from previous ones?
The key difference in this study is that the authors monitor growth of C.elegans populations over several generations as opposed to recording observable changes in individuals over a single generation, This is comparable in many ways to how yeast fitness is determined as it is the population phenotype over many generations that is measured and not that of an individual yeast cell. RNAi of over 500 genes shows that the majority of genes are required for fitness in a single environment and that this difference from previous observations is due to the genes having a very subtle effect that can only be observed over populations and generations. This observation fits the high conservation of genes seen in eukaryotes.

Even more interesting for me is the observation that the proportion of worm genes required for wild-type fitness appears to be substantially higher than the proportion required for normal growth in yeast. The authors suggest the reason for this could be due to the fact that multi-cellular organisms have multiple cell types, each requiring their own genetic network to function, and essentially exist in multiple environments at any one time, whereas the yeast cell only needs to operate in a single environment and therefore requires less genes to function. This actually makes a lot of sense when you think about all the different environments and tissue types we have within our own bodies, we're bound to need more genes working at any one time than if we were just a single cell sitting in some yummy media.

To conclude I like this paper because it challenges the term "non-essential" genes. I always find these kinds of labels incredibly short-sighted and misleading much like the infamous notion of "junk DNA". Just because we don't know what it does yet doesn't mean it's useless because if it is we have to ask what the hell it's still doing here? The challenge now may be to actually work out what it is that all these genes are doing that affect general fitness and that's why I chose the cliched title! See, there was method in my madness.

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