We tend to wax rather cynical about mapping studies (GWAS and the like) that find many miniscule effects and only an occasional major, replicable one. We feel that this approach has played out (or been spent out) and that better, more thoughtful and focused science is in order these days.
One typical daily fact is the breathless announcement of finding a gene 'for' some trait or other, be it disease or even whether you voted for Romney or were one of the misguided bearers of the 'liberal' gene. Extra! Extra! Read all about it! New gene for xxxx discovered!!!
We, too, are guilty!
Well, we must confess: we are also involved in gene mapping. Though, in fact we've confessed this before (here, e.g.), if in an MT sort of way. In our work, we are using head shape data on a huge set of baboons who are deceased members of a huge and completely known genealogy housed in Texas, and a large study of over 1000 mice from a well-controlled cross between two inbred parental strains. Now these data sets are about as well-controlled as you can get. In each case, marker loci across the genome were typed on all animals and the GWAS-like approach was taken to identify markers in genome areas in which variation was associated with various head dimensions (as shown in the figure). These are then regions that affect the trait, and are worth exploration.
We regularly see proclamations of discoveries of genes 'for' craniofacial shape dimensions. Two recent papers report Bmp genes, thought to be involved in head development, and many others have reported FGF (fibroblast growth factor) results of major shapes. These findings have been so casually, or even perhaps carelessly, accepted as to have become part of the standard lore.
But based on our large, very well-controlled study of two species we beg to differ!
But, no--this time Extra! Extra! We really mean it: NO!!
After careful examination of signals from our mapping of baboons, and separately of the inbred mouse cross, we have come to the startling finding, with high levels of statistical significance rarely matched by other GWAS on this subject, that neither Bmp nor FGF genes are involved in head-shape development!
Scanning the genome markers separately in both large data sets shows clearly that there is no effect of these genes on any head shape dimension. None!
In fact, this is not so unusual a finding, as many studies simply fail to find even what were thought to be clear-cut causal genes. Yet, these findings are not eagerly sought nor published by Nature, Science, The New York Times (the leading scientific outlets these days--we do not include People in our list, despite its typically similar level of responsible fact-reporting).
We are using lots of exclamation points, but we are totally serious. Though we shout from the rooftops that we have found no evidence for these genes' involvement in head shape, we will have no hearers. It seems just not in anyone's interest to see their previous, hard-won findings debunked.
Or is there a different kind of lesson here?
What evolution leads us to expect
The lack of reporting of negative results is something of a scandal,
because negative evidence tends to disprove previous findings by not
supporting them. That seems important, but even to skeptics like us
there are important issues that should be understood.
A widely proclaimed tenet of modern science is called 'falsificationism'. The idea is that all the positive findings in the world don't prove that something is true, but a single failure to find it proves that the idea was just plain wrong. Just because the sun has risen every day so far does not by itself prove it will rise tomorrow. Night does not cause day!
But some negative findings don't really falsify previous positive findings. There can be sampling issues or experimental failure and so on. So our not finding FGF effects on head shape doesn't falsify previous findings. We could be wrong.
But even if we are wholly right, as we're pretty sure we are, this does not in any way whatsoever undermine prior findings, that seemed quite solid, that these genes are in fact involved. This is because standard ideas like falsification are based on a kind of science in which repeat experiments are expected to give statistically similar results: rolling dice, working out planetary orbits or chemical reactions are examples of things that follow natural laws and are reliable.
Here, however, we're dealing with life, and life is not replicable in that sense! Each sample really is different: different sets of people have different sets of genotypes. A negative finding is not a refutation of a prior assertion. Negative findings are expected in this area of science!
The reason we did not find FGF effects in our baboon or mouse studies is not that the FGF genes were uninvolved in head shape during development but that there was no relevant variation in those genes in our particular sample. Neither of our inbred mouse strains carried variants at those genes that affect head traits. But they did both use FGF genes in making their own heads, and the intercross animals did, too.
Even if a gene is involved in a trait in a functional way, there is no reason to expect that the same gene varies in a given study at all, or enough to have a detectable effect. Indeed, sometimes such genes are so central that they aren't free to vary without deleterious or fatal consequences. It's one of the problems of mapping that it is not a direct search for function. Instead it is just a search for variation that may lead us to function. If by bad luck our sample has no variation in a particular gene, it can't lead us to those genes by case-control kinds of statistical comparisons.
Dang it! Despite how important and under-appreciated these points are, this means that our negative findings aren't really negative and won't be of any interest to the Times.
However, this doesn't mean that mindless GWASing is OK after all. We've explained our view on this many times before.
But it does mean we need to contact the Editor at People.
No comments:
Post a Comment