Of Yeast and Men

Nature reports on the Dissection of genetically complex traits with extremely large pools of yeast segregants.


Ehrenreich et al have a new way of mapping the genetic basis of complex traits in yeast, "complex" being what geneticists call anything which isn't controlled by one single gene. They dub their approach "Extreme QTL mapping". This suggests images of geneticists running experiments atop Everest, or perhaps collecting blood samples from lions with their bare hands, but actually

Extreme QTL mapping (X-QTL) has three key steps. The first is the generation of segregating populations of very large size. The second is selection-based phenotyping of these populations to recover large numbers of progeny with extreme trait values. This can be accomplished, for example, by selection for drug resistance or by cell sorting. The final step is quantitative measurement of pooled allele frequencies across the genome.

The basic idea is to cross breed two strains of yeast to generate lots of different hybrid strains each with a random selection of DNA from each "parent". Then, you put all the hybrids under some kind of selective pressure - for example, by adding the toxin 4-NQO to their dish.

Some yeast are more or less resistant to 4-NQO, and this trait is largely determined by genetics. So after a while, the vulnerable hybrids will die out and only the most highly resistant strains will be left in the 4-NQO dish to reproduce. It's a quick and dirty form of selective breeding. Finally, you can compare the genetics of the 4-NQO resistant hybrids to a control group of hybrids who didn't get any toxins, using a GWAS. Any genetic differences are likely to represent 4-NQO resistance genes.

Using this method, Ehrenreich et al found no less than 14 4-NQO resistance variants. That includes two replications of previous findings, and 12 new ones. Collectively, the genes explained

59% of the phenotypic variance in 4-NQO sensitivity in an additive model. Because we measured the heritability of this trait to be 0.84, the loci explained 70% of the genetic variance, indicating that we have explained most of the genetic basis of this trait with the loci detected by X-QTL.

In other words, they've found most of the genes with a substantial effect on 4-NOR resistance, but not all of them. (They then did the same thing for several other toxins). About 30% of the heritability is "missing". Compare that to most human complex traits, where the missing heritability is more like 95%-99% at the moment. For example, twin studies and similar find human height to have a heritability of about 0.8, and more than 40 genetic variants have been associated with height, but together they only explain 5% of the heritability.

Why is Neuroskeptic posting about yeast? Well, partly because we live in a yeast-based society. Without yeast, we would have no alcoholic drinks. I think it's important to acknowledge their contribution to our lives. But mainly because there's a lesson here for people interested in the genetics of complex traits in humans, like, say, personality, IQ, and mental illness.

Yeast resistance to toxins is about the most straightforwardly "biological" trait you could imagine. Finding its genetic basis ought to be easy. But it wasn't. It was...extreme. Ehrenreich et al had to breed and select yeast with extreme traits (e.g. extremely high resistance to toxins), and compare them to control yeast of the same ancestry, to find the genes, and they still had a good deal of missing variance.

If they'd had to work on a random bunch of yeast from the wild, they'd have had a lot more trouble. That's why previous yeast GWAS studies didn't get results as good as these. Yet when it comes to humans, we're indeed forced to use a random bunch of people from the wild. You can't selectively breed people.

You can breed, say, mice, but it takes a lot longer than with yeast. I think there have been a few studies breeding mice for a certain trait and then looking at their genetics but not with a great degree of success, even though the first thing every mouse researcher learns is that different strains of mice are very different (C57BL/6 mice, for example, are notoriously hard to handle and love biting people.)

This is bad news for human genetics, where the interesting traits are clearly a lot more complex, ill-defined, and hard to measure than in yeast. On the other hand, though, it's perhaps also rather reassuring, as it suggests that our failure to explain more than a few % of the heritability so far reflects technical limitations rather than because these traits just aren't as genetic as we think after all...

Ehrenreich IM, Torabi N, Jia Y, Kent J, Martis S, Shapiro JA, Gresham D, Caudy AA, & Kruglyak L (2010). Dissection of genetically complex traits with extremely large pools of yeast segregants. Nature, 464 (7291), 1039-42 PMID: 20393561