Demethylating our minds
From the abstract of the melanoma paper, published in Nature Genetics on 3 March, 2013:
In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity."The existing paradigm." Let's think this through.
We recently blogged about the problem of genes 'for' some disease or normal function being surprisingly found to be associated with some other often unrelated trait. It's bad enough when a gene is assigned a single function, but when it's a disease, it's even more misleading. For one thing, why would we have a gene for disease, never mind multiple diseases? How could such a deleterious gene evolve?
Just for fun, let's check out where this disease gene is expressed in the developing embryo. If it's a gene for obesity or developmental delay or T2d or melanoma, then we'd not expect it to be expressed at all in the normally developing mouse embryo, right? But, a quick search on GenePaint, a database that has archived the results of over 20,000 gene expression studies on the developing mouse, shows it to be so widely expressed that it clearly has some widespread 'normal' function/s as well.
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| FTO expression, E14.5 mouse, GenePaint |
But what? Let's see if we can track that down. There are a number of bioinformatics databases that collate information about genes, so we'll turn to those.
GeneCards is a good place to start. The Entrez Gene summary here says:
This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes.They note the disease-related findings, but also tell us what type of gene it is, as a member of the 2-oxoglutarate-dependent oxygenase superfamily, though its exact function (or even inexact function) is unspecified.
Wikipedia has extensive information about some genes, though not all. Let's see how it does with FTO. Ah, here for FTO, we find a little more information. It seems that FTO codes for an enzyme, alpha-ketoglutarate-dependent dioxygenase, "that shows high homology with the enzyme AlkB which oxidatively demethylates DNA". That is, what's known about the normal function of this gene is an educated guess, which can be made because of the similarity of the protein it codes for with one that's better understood.
One of the modifications of DNA that affects gene expression but doesn't affect the DNA sequence itself is methylation, the addition of a methyl group to a nucleotide, which silences gene expression --epigenetic modification. The normal function of the FTO protein, then, seems to be to demethylate DNA, to then, presumably, allow the affected gene to be expressed again. Why the gene is so ubiquitously expressed during development is a puzzle, at least to us, and may suggest that it has yet a further function as well, because it seems unlikely that so much DNA all over the place needs demethylation.
But this seems to be the best we can do, without a huge amount of searching the literature, to get some sense of what FTO does when it's not causing obesity or diabetes, or now melanoma. And that doesn't even touch the question of how it causes obesity and its sequelae. This is probably known at least to some extent but, again, not by us.
The influence of FTO on diabetes is pretty strong, and repeatedly observed in genomewide searches for diabetes-related variation. But FTO is not found in searches for variation affecting diabetes-related traits, again showing its non-specificity. It wasn't found in a very big study of waist-hip ratio, a measure of obesity, nor in a study of obesity-related traits in Samoans (Polynesians). So, what are we to think this gene is 'for'?
This example brings up, again, the issue of what we understand about genes and how. Historically, it has been easiest to figure out a gene's function when it breaks, and when the breakage has a large effect. And, the quest to understand disease was invested in earlier and more heavily than the quest to understand development and normal gene function, which in part explains why so many genes are known because of their association with disease, and named accordingly.
But, that the normal function of a gene that has been investigated for so long is not yet understood says a lot about the state-of-the-art. It's still early days, and gene mapping -- trying to identify genes 'for' traits based on what we know about genes -- is hampered as a result, even if that's not always acknowledged (and it rarely is). And, it belies the idea that once we know which genes are involved in a disease, it will be a snap to develop drugs to interrupt the pathways.
The 'gene for' view of genetics is so much easier than a broader view, which would take into account things like the complexity of FTO, and the multitude of functions it seems to have, broken and not. The difficulty of documenting and understanding that complexity inhibits a broader understanding of genes and traits.
Maybe what we need is an FTO gene to demethylate our thought processes, to allow us to see the broader picture.
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** Actually, to compound the felony, this was first named for 'Fused Toes', the trait in mice that led to its discovery!
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