Tuesday, March 5, 2013

Demethylating our minds

FTO - Fat Mass and Obesity Associated gene.  Another gene named for something it screws up.**  And, not only does it screw up body weight, but it has found to be associated with developmental delay, type 2 diabetes, brain volume, whatever that implies, end-stage renal disease, heart disease, Alzheimer's disease, osteoarthritis, and mortality risk in general, all apparently through its association with body mass. And now it turns out that this 'obesity' gene also apparently causes melanoma, but this time it's a different part of the gene, having nothing to do with FTO's association with body mass index.  Old bad gene, new bad function.

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.

FTO expression, E14.5 mouse, GenePaint
The darker blue in this picture is where the gene is expressed -- strongly, in the brain and spinal cord, the developing jaw and upper face, the vertebrae and other bone, limbs, intestines, and so on.  Just about the only places it's not expressed is the liver and heart.  So, this is pretty strong evidence that FTO must have a function not related to obesity or disease.  

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.

** Actually, to compound the felony, this was first named for 'Fused Toes', the trait in mice that led to its discovery!


ebieb said...

As you said, we are in early days... characterization of genes and genetic pathways is like groping around a dark room, and finding phenotype changing (i.e. disease causing) mutations is like having a flashlight- it lets us shine a small area of light on the subject. No, the entire story is not illuminated, but it's a starting point.
Don't you think the fact that a gene originally associated embryonic development, and then characterized as having mutations associated with fused toes, obesity and T2DM, and more recently melanoma, demonstrates an openness to the complexity of this particular gene/pathway, i.e, knowing its association with one disorder has not prevented it from being explored as important in other seemingly unrelated disorders/pathways?

As far as the name of the gene... You are mistaken about the origin of "FTO"- The original description comes from Peters et al, who called the gene "Fatso" because of it's size (>250kb), and they knew nothing about its correlation with obesity; they characterized it as being important in embryonic development- how's that for irony :)

Anne Buchanan said...

Ah, thanks for the history lesson. My point still stands, I think -- for a gene with such a long history, primarily due to its association with abnormalities, fundamentals are still unknown. And that's true of many genes, of course.

Yes, it's good that people remain open to new gene functions, but a testament to our lack of humility that finding those new functions can become a big story. I think we should keep in mind just what you say -- we're groping around in a dark room with a flashlight. Or too often, like the drunk under the lamppost -- looking for his keys there because that's where the light is.

Ken Weiss said...

My source was Wikipedia, for the origin of FTO and it says it goes back to 1999 and implies that Fatso is a derivative. I didn't read either paper, but a point would be that gene names often are inappropriate for the range of functions later discovered.

Your main point arguing that once a gene is discovered, is it worthwhile following it up to see what else it does, certainly has merits. But it can be used for open-ended reasons--or excuses--to keep pursuing something when more weighty things are there to be pursued.

The obesity story illustrates the issues. With infinite funding and infinitely many quality investigators, one could hardly object. With limited funding, going to predictably incremental work when more important, and more clearly focused problems exist, I am personally far less sanguine. Even FTO has rather modest predictive value (or is that to be kind?). Too often, we talk about complexity but really are just example-collecting.

I'm not casting stones (only)! With collaborators, we're working on fibroblast growth factor receptors in problems that have little if anything to do with fibroblasts. In the past I worked with 'distal-less' (Dlx) genes in tooth development, but the name came from leg segments.

ebieb said...

I had to re-visit this post, as I was just reading a paper about long non-coding RNAs, and they make this conclusion about moving away from the "protein-centric" paradigm of gene annotation relevant to your point: "...invert the functional genomics paradigm of annotating 'genes' as discrete entities by the product(s) they produce. Instead, RNAs could be annotated by their genomic origin, genomic environment and what is known of their function, including open reading frame content and interactions with other molecules. In effect, this would circumvent the issue of gene definition (including its boundaries) by consigning it to obsolescence." Mattick JS, Taft RJ, Faulkner GJ. Trends Genet. 2010 Jan;26(1):21-8

Anne Buchanan said...

I like that. Thanks. I would probably add expression profile, too, though then we're in the realm of Louis Wolpert's remark about knockout mice with "no phenotype" -- "But, did you take it to the opera?" Expression would vary by embryonic stage, age, environment and so forth.

ebieb said...

Ha! Yes, context too, the complexity is unending...