Genomic cold fusion? Part III. Gene mapping: when minnows are whales

In the first two parts of this series we tried to outline the actual logic underlying the search for genes that affect a trait, disease or otherwise, that we might be interested in.  We titled this series ‘genomic cold fusion’ in response to a comment on a tweet made about our course Logical Reasoning in Human Genetics whose most recent offering was given by us a week or so ago in Helsinki, Finland.  The characterization was about the idea of ‘linkage analysis’—that is, in known pedigrees—to find genetic causal factors for complex traits. 

We tried to explain that evolutionary (population) history lies behind the logic of both family-based linkage and population-sample-based association approaches to genomewide mapping (such as in GWAS).  When causes are strong and not too numerous, mapping works in large families.  That’s because if something is genetic it must be familial—that in a sense is what ‘genetic’ means in this context—and one can trace transmission, following Mendelian principles, explicitly.

If causes are individually rare and there are many, pooling families doesn’t work very well, because getting large enough families to map individually is difficult and costly, but that is just what GWAS does in its implicit, unconstrained pooling of different families, where the family connections aren’t even known!

In the end, however, we concluded that if there were too many different causes, and they are weak or rare, and environmental factors are important, then the trait is basically the result of a mix of contributors, differing among individuals both within and between families.  Individually, we suggested, the causes are minnows, and fishing in a pond of minnows, no matter how it’s done, will only find minnows.  But there is more to the issues than this, and it deserves to be recognized.

When a minnow is a whale

There are tons of results in which a known genetic mutation identified as having a major effect is found to have lesser effects in some people.  Even family members sharing the variant may have different effects (more or less severe, for example, in regard to disease).  Some may have an essentially lethal phenotype, while others are only mildly affected.

The reason is that a variant’s causal effects depend fundamentally on its context.  This is true for environmental risk factors as much as genetic ones.  A causal minnow—a minor causal effect—can be major in some contexts.  Any approach to genetics that fails to take this basic fact seriously into account is, in a sense, amateurish.

A good illustration of this is that when a disease-causing genetic change is engineered into a laboratory mouse, it may or may not mimic the human trait.  Sometimes, perhaps most of the time, it will have a roughly similar effect in one strain of lab mice, but very different, or even no effect, in other strains.  Indeed, while this is very well-known to mouse workers (including ourselves when we were doing that sort of experiment), it is rarely taken seriously into account.  A transgenic effect is reported, but not checked in other strains of lab mice, or in other animal models, such as rats or dogs.  The reasons, especially for other species than mice, is that such testing is quite costly.  The bottom line is that we learn about the biology of the effect in one of its contexts, but extrapolate to other contexts, even humans, at our peril.  This, too, is well known.

This is why, among humans within or between populations, a mapping minnow can be a causal whale in some people, and vice versa.  It’s something that needs to be recognized more widely, but for which there really is no generic explanation.  It’s why risk estimates given for a genetic variation—such as by companies essentially practicing shell-game medicine without a license by advising customers about their ‘risk’ based on DNA analysis—are often not worth the electrons needed to send them.  Some risk factors are often very strong (one thinks of BRCA variation and breast cancer) but most are not, and some are very weak to start with and only strong in rare contexts.  Again, conscientious geneticists know this very well, or should.  It’s not secret.

Indeed, the fact that minnows can grow up to be whales or whales can shrink to minnows depending on the genomic and environmental pond they’re swimming in, is one of the important things genomicists should be directly addressing, rather than making the rather bold and expensive promises that they are making.

This isn’t an argument against doing genetics, but it is a reason to think differently, or at least carefully, before making very expensive promises that often are not very different from what preachers promise you if you’ll put some coin in the plate being passed.

Genetics is fundamental biology, and its challenges are great from the ground up.  At present, those challenges are typically whales, but are just as typically, and expediently, treated as if they are minnows.