We Are All Special

A study in yeast finds that rare mutations have outsize influence on traits.

The word "mutation" is frowned upon in these politically correct days. While we may have a human reference genome sequence derived from some guy from Buffalo, New York, all genomes are equal, and thus differences between them and the reference are now termed "variations" rather than mutations.

After the first human genome was cranked out, the natural question was- How do we differ, and what do those differences say about our medical futures and our evolutionary past? This led to the 1000 genomes project, and much more, to the point that whole genome sequencing is creeping into normal medical practice, along with even more common panels of a smattering of genes analyzed for specific issues, principally cancers. Well, we differ a lot, and this data has been richly rewarding, especially in forensic and evolutionary terms, but only somewhat in medical terms. The ambition for medical studies has been extremely high- to interpret from our code why exactly we are the way we are, and what our medical fate will be. And this ambition remains unfulfilled. It will take decades to get there, and our code is far from controlling everything- even complete knowledge of our sequences and their impact on our development and medical issues will leave a great deal to accidents of fate.

The first approach to mining the new genomic information, especially variations among humans, for medically useful information was the GWAS study. These put the 1000 genomes (or some other laboriously accumulated set of sequences, which came tagged with medical information) into a blender and asked which variations between people's sequences correlated with variations in their diseases. Did diabetes correlate with particular genes being defective or altered? Despite huge resources and high hopes, these studies yielded very little.

The reason was that the notion of variation (or mutation) and especially the intricate field of evolutionary population genetics, was, among these researchers, in a somewhat primitive state. They only accepted variations that occurred a few times, so that they could be sure they were not just random sequencing mistakes. In a population of, say, 1000, any variation that occurs a few times has a particular nature, which is to say that it must be somewhat stable in the population and have a long history, to allow it to rise to such a (modest, but significant) level of prevalence. This in turn means that it can not have a severe effect, in evolutionary terms, which would otherwise have cut its history in the population rather short. So it turned out that these researchers were studying the variations least likely to have any effect, and for all the powerful statistics they brought to bear, little fruit turned up. It was a very frustrating experience for all concerned.

A recent paper recapitulated some of these arguments in the setting of yeast genetics. The topic remains difficult to approach in humans, because rare variations are, by definition, rare, and hard to link to diseases or traits. Doing so in a clinical study requires statistical power, which arises from the number of times the linkage is seen- a catch-22 unless one can find an obscure family pedigree or a Turkish village where such a trait is rampant. In yeast, one can generate lineages of infinite size at will, and the sequencing is a breeze, with a genome 1/250 the size of ours. The only problem is that the phenotypic range of yeast is slightly impoverished compared to ours(!) Yet what variety they can display is often quantifiable, via growth assays. The researchers used 16 yeast strains from diverse backgrounds as parents, (presumably containing a wide variety of distinctive variations), generated and sequenced 28,000 progeny, and subjected them to 38 growth conditions to elicit various phenotypes.

The major result, graphing the frequency of variations against their phenotypic effect. The effect goes up quite strongly as the frequency goes down.

These researchers claim that they can account for 73% of phenotypic variation from their genetic studies- far higher the rate seen for any complex human trait. They see on average 120 loci affecting each trait across the study, and 12 loci affecting each trait in any one mating. Based on past work with libraries of yeast strains, they could also classify the mutations, er, variations they saw coming from these diverse parents as either common (similar to what was analyzed in the classic GWAS experiments in humans, occurring at 1% or more) or rare. Sure enough, the rarer the allele, the bigger its effect on phenotype, as shown below. In rough terms, the rare variants accounted for half the phenotypic variation, despite comprising only a quarter of the genetic variation.

In an additional analysis, they compared all these variants to their relatives in a close relative of this yeast species, in order to judge which allele (variant / mutant or the reference / normal version) was ancestral, i.e. older. As expected, the rare variations that led to phenotypic effects were mostly of recent origin, and more so the stronger their effect.

"Strikingly, no ancient variant decreased fitness by more than 0.5 SD units, whereas 41 recent variants did."

The upshot is that to learn about the connection between genotype and phenotype, one needs significant (and typically deleterious) mutations, as geneticists have known since the time of Mendel and Morgan. Thus the use of common variants (with small effects) to analyze human syndromes and diseases has yielded very little, either medically or scientifically, while the study of rare variants has been a gold mine. And we all have numerous rare variants- they come up all the time, and are likewise selected out of existence all the time, due to their significant effects.

The scale of the experiments done here in yeast allow high precision genetic mapping. Here, one trait (growth in caffeine) is mapped against correlating genomic variations. The correlations home in on variations in the TOR1 gene, a known target of caffeine and a master regulator of cell growth and metabolism.

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