Thursday, February 26, 2015

Digesting yeast's message

A new paper in Nature by Levy et al. reports on the genomic consequences of large-scale selection experiments in yeast.  Yeast reproduce asexually and clones can be labeled with DNA 'barcode' tags and followed in terms of their relative frequency in a colony over time.  This study was able to deal with very large numbers of yeast cells and because they used barcodes the investigators could practicably follow individual clones without needing to do large-scale genome sequencing.  Prior to this, this sort of experiment was prohibitively costly and laborious.  So the authors add to findings in selection experiments using bacteria or flies and so on, where mostly aggregate responses could be identified.

In this case, nutrient stress was imposed, and as beneficial mutations occurred and gave their descendant cells (identified by their barcode) an advantage, the dynamics of adaptation could be followed.  The authors showed, in essence, that at the beginning the fitness of the overall colony increased as some clones, bearing advantageous mutations, rose rapidly in relative frequency.  Then, the overall colony fitness stabilized and subsequent advantageous mutations were largely kept at low frequency (most eventually went extinct).  But overall, the authors found thousands of colonies with different advantageous variants; most fitness effects were of only a small (or, for the majority, very small) percent.  Once a set of large numbers of 'fit' variants had become established, new ones had a difficult time making any difference, and hence staying around very long.

This study will be of value to those interested in evolutionary dynamics, though I think the interpretation may be rather more limited than it should, for reasons I'll suggest below.  But I would like to comment on the implications beyond this study itself.

Who cares about yeast (except bakers, brewers, and a few labs)?  You should!
This is interesting (or not) you might say, depending on whether you're running a yeast lab, or in the microbrew or bakery business. But there are important lessons for other areas of science, especially genomics and the promises being made these days.  Of course, the lesson isn't a pleasant one (which, you might correctly assume, is why we're writing about it!).

This study has important implications for basic evolutionary theory perhaps, but also for much that is going on these days in human biomedical (and also evolutionary) genetics, where causal connections between genomic genotypes and phenotypes are the interest.  In evolution, selection only works on what is inherited, mainly genotypes, but if causation is too complex, the individual genotype components have little net causal effect and as a result are hardly 'seen' by selection, and evolve largely by chance.  That's important because it's very different from Darwin's notions and the widespread idea that evolution is causally rather simple or even deterministic at the gene level.

Put another way, genomic causation evolved via the evolutionary process.  If natural selection didn't or couldn't refine causation to a few strong-effect genes, that is, to make it highly deterministic at the individual gene level, then biomedical prediction from genome sequences won't work very effectively.  This is especially true for traits, disease or otherwise, that are heavily affected by the environment (as most are) or for late-onset traits that were hardly present in the past or arose post-reproductively and hence didn't affect reproductive fitness and are not really 'specified' by genes.

There was considerable genomic variation between the authors' two replicate yeast experiments.  As one might say, meta-analysis would have some troubles here.  Likewise, from cell lineage to cell lineage, different sets of mutations were responsible for the fitness of the lineage in this controlled, fixed environment. This means that even in this very simplified set-up, genomic causation was very complex.  No 'precise' yeastomic prognostication!

In real biological history, even for yeast and much more so for sexually reproducing species in variable environments, selection has never been unitary or fixed, and genomes much more complex. Human populations have been until very recently very much smaller than 10^8 in the yeast experiments, and recent population expansion will make the number of low-frequency variants much greater, and with recombination, vastly more genomically unique.

The bottom line here is that our traits should be much less predictable from genotypes than traits in yeast. We have not reached, nor did our ancestors ever reach, the kind of fitness equilibrium reached in the yeast study under controlled selection, and fixed environments.

Somatic mutation
The authors also compare the large numbers of cells whose evolution they were able to follow with their barcode-tagging method, to the evolution of genetic variation in cancer and microbial infections, where there are even larger numbers of cells in an affected person and, importantly, clones expanding because of advantageous mutations. From the yeast results, these clonal advantages may not generally be due to one or two specific mutations (with perhaps, hopefully, exceptions when chemotherapy or antibiotics exert far stronger selection than was imposed in the yeast experiment). But the general complexity of such clonal expansions present major challenges, because they may end up with descendant branches distributed throughout the body where even in principle the responsible variation can't be directly assessed.

But the implications go far beyond cancer.  As we've recently posted, cancer is a clear but perhaps only a single manifestation of a more general phenotypic relevance of the accumulation of somatic mutations, that occur in body cells during life and can in aggregate have systemic or organismal-level implications.  The older we get the more likely we are to generate such clones, all over the body, and it seems likely that they can become manifest not just as individually ill-behaving cells, but as disease for the whole person.

But it's not just late onset implications that the yeast work may forebode.  There are already huge numbers of cells in the early embryo and fetus whose even huger descendant clades of cells during life grow many, many fold by adulthood.  There is no reason not to expect that each of us will carry clades that include differently-than-normal functioning cells in our tissues.  Let age, environmental exposure, and further mutations add to this and disease or age-related degeneration can result.  Yet none of this can be detected in the usual individual's 'genome' as currently viewed.  This is a potentially important fact that, for practical reasons or what one might call reasons of convenience, is ignored in the wealth of mega-sequencing projects being lobbied for based on genome sequencing (precision prediction being the most egregious claim).

So a bit of brewer's yeast may be telling us a lot--including a lot that we don't want to hear. Inconvenient facts can be dismissed.  Oh, well, that's just yeast!  They evolve differently!  That was just a lab experiment!  Brewers and bakers won't even care!

So let's just ignore it, as if it only applies to those rarefied yeast biologists.  Eat, drink, and be merry!

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