”These are all fairly obvious” (says Sewall Wright)

I was checking a quote from Sewall Wright, and it turned out that the whole passage was delightful. Here it is, from volume 1 of Genetics and the Evolution of Populations (pages 59-60):

There are a number of broad generalizations that follow from this netlike relationship between genome and complex characters. These are all fairly obvious but it may be well to state them explicitly.

1) The variations of most characters are affected by a great many loci (the multiple factor hypothesis).

2) In general, each gene replacement has effects on many characters (the principle of universal pleiotropy).

3) Each of the innumerable possible alleles at any locus has a unique array of differential effects on taking account of pleiotropy (uniqueness of alleles).

4) The dominance relation of two alleles is not an attribute of them but of the whole genome and of the environment. Dominance may differ for each pleiotropic effect and is in general easily modifiable (relativity of dominance).

5) The effects of multiple loci on a character in general involve much nonadditive interaction (universality of interaction effects).

6) Both ontogenetic and phylogenetic homology depend on calling into play similar chains of gene-controlled reactions under similar developmental conditions (homology).

7) The contributions of measurable characters to overall selective value usually involve interaction effects of the most extreme sort because of the usually intermediate position of the optimum grade, a situation that implies the existence of innumerable different selective peaks (multiple selective peaks).

What can we say about this?

It seems point one is true. People may argue about whether the variants behind complex traits are many, relatively common, with tiny individual effects or many, relatively rare, and with larger effects that average out to tiny effects when measured in the whole population. In any case, there are many causative variants, alright.

Point two — now also known as the omnigenetic model — hinges on how you read ”in general”, I guess. In some sense, universal pleiotropy follows from genome crowding. If there are enough causative variants and a limited number of genes, eventually every gene will be associated with every trait.

I don’t think that point three is true. I would assume that many loss of function mutations to protein coding genes, for example, would be interchangeable.

I don’t really understand points six and seven, about homology and fitness landscapes, that well. The later section about homology reads to me as if it could be part of a debate going on at the time. Number seven describes Wright’s view of natural selection as a kind of fitness whack-a-mole, where if a genotype is fit in one dimension, it probably loses in some other. The hypothesis and the metaphor have been extremely influential — I think largely because many people thought that it was wrong in many different ways.

Points four and five are related and, I imagine, the most controversial of the list. Why does Wright say that there is universal epistasis? Because of physiological genetics. Or, in modern parlance, maybe because of gene networks and systems biology. On page 71, he puts it like this:

Interaction effects necessarily occur with respect to the ultimate products of chains of metabolic processes in which each step is controlled by a different locus. This carries with it the implication that interaction effects are universal in the more complex characters that trace such processes.

The argument seems to persists to this day, and I think it is true. On the other hand, there is the question how much this matters to the variants that actually segregate in a given population and affect a given trait.

This is often framed as a question of variance. It turns out that even with epistatic gene action, in many cases, most of the genetic variance is still additive (Mäki-Tanila & Hill 2014, Huang & Mackay 2016). But something similar must apply to the effects that you will see from a locus. They also depend on the allele frequencies at other loci. An interaction does nothing when one of the interaction partners are fixed. If they are nearly to fixed, it will do nearly nothing. If they’re all at intermediate frequency, things become more interesting.

Wright’s principle of universal interaction is also grounded in his empirical work. A lot of space in this book is devoted to results from pigmentation genetics in guinea pigs, which includes lots of dominance and interaction. It could be that Wright was too quick to generalise from guinea pig coat colours to other traits. It could be that working in a system consisting of inbred lines draws your attention to nonlinearities that are rare and marginal in the source populations. On the other hand, it’s in these systems we can get a good handle on the dominance and interaction that may be missed elsewhere.

Study of effects in combination indicates a complicated network of interacting processes with numerous pleiotropic effects. There is no reason to suppose that a similar analysis of any character as complicated as melanin pigmentation would reveal a simpler genetic system. The inadequacy of any evolutionary theory that treats genes as if they had constant effects, favourable or unfavourable, irrespective of the rest of the genome, seems clear. (p. 88)

I’m not that well versed in pigmentation genetics, but I hope that someone is working on this. In an era where we can identify the molecular basis of classical genetic variants, I hope that someone keeps track of all these A, C, P, Q etc, and to what extent they’ve been mapped.

Literature

Wright, Sewall. ”Genetics and the Evolution of Populations” Volume 1 (1968).

Mäki-Tanila, Asko, and William G. Hill. ”Influence of gene interaction on complex trait variation with multilocus models.” Genetics 198.1 (2014): 355-367.

Huang, Wen, and Trudy FC Mackay. ”The genetic architecture of quantitative traits cannot be inferred from variance component analysis.” PLoS genetics 12.11 (2016): e1006421.

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Yours truly outside the library on Thomas Bayes’ road, incredibly happy with having found the book.

Annonser

From Lisbon, part 2

ESEB 2013 is over. I’ve had a great time, met with a lot of cool people and actually coped reasonably well with the outdoor temperature. As a wimpy Swede, I find anything above 30 degrees Celsius rather unpleasant. There have been too many talks and posters to mention all the good stuff, but here are a few more highlights:

Trudy Mackay’s plenary on epistasis in quantitative traits in D. melanogaster: Starting with the Drosophila Genetic Reference Panel and moving on to the Flyland advanced intercross population, Mackay’s group found what appeared to be extensive epistasis in several quantitative traits. Robert Anholt spoke later the same day about similar results in olfactory behaviour. While most of the genetic variance on the population level is still effectively additive, there seems to be a lot of interaction at the level of gene action, and it hinders QTL detection. The variants that did show up appeared to be involved in common networks. Again, we ask ourself how big these networks are and how conserved they might be among different species.

How did all this epistasis come about then? Mackay’s answer is phenotypic buffering or canalisation (as we say in the Nordic countries: a beloved child has many names). That is, that the organism has a certain buffering capacity against mutations, and that the effect of many of them are only revealed on a certain genetic background where buffering has been broken. See their paper: Huang et al (2012). Mackay mentioned some examples in answer to a question: potentially damaging exonic mutations travelled together with compensatory mutations that possibly made them less damaging. It would be really fun to see an investigation of the molecular basis of some examples.

(Being a domestication genetics person, this immediately brings me to Belyaev’s hypothesis about domestication. Belyaev started the famousic farm fox domestation experiment, selecting foxes for reduced fear of humans. And pretty quickly, the foxes started to become in many respects similar to dogs. Belyaev’s hypothesis is that ‘destabilising selection’ for tameness changed some regulatory system (probably in the hypothalamus–pituitary–adrenal axis) that exposed other kinds of variation. I think it’s essentially a hypothesis about buffering.)

Laurent Excoffier about detecting recent polygenic adaptation in humans. Very impressive! The first part of the talk presented a Fst outlier test applied to whole pathways together instead of individual loci. This seems to me analogous to gene set enrichment tests that calculate some expression statistic on predefined gene sets, instead of calculating the statistic individually and then applying term enrichment tests. In both cases, the point is to detect more subtle changes on the pathway as a whole. As with many other enrichment methods, particularly in humans, it is not that obvious what to do next with the list of annotation terms. Even when the list makes good biological sense — really, is there a gene list that wouldn’t seem to make at least a bit of biological sense? The results do (again) imply epistasis in human immune traits, and that is something that could potentially be tested. Though it would be a heroic amount of work, I hope someone will use this kind of methods in some organism where it is actually possible to test the function and compare locally adapted populations.

Alison Wright’s talk on Z chromosome evolution. She works with Judith Mank, and I’ve heard a bit about it before, but sex chromosomes and the idea that you can trace the ‘strata’ of chromosome evolution are always fascinating. Wright also presented some interesting differences in the male hypermethylated region between birds with different mating systems.

William Jeffery on blind cavefish: I’ve been thinking for ages that I should blog about the blind cavefish (for popular/science and in Swedish, that is), because it’s such a beautiful example. The case for eye regression as an adaptive trait rather than just the loss of an unnecessary structure seems pretty convincing! Making an eye regress at the molecular level seems at once rather simple — removal of the lens (by apoptosis in the blind cavefish) seems to be all that is needed — and complex (it’s polygenic and apparently not achieved the same way in all blind cavefish populations).

Virpi Lummaa’s plenary about using parish records from preindustrial Finland to investigate hypotheses about reproduction, longevity and menopause. I heard about the Grandmother hypothesis ages ago, so I knew about it, but I didn’t know to what extent there was empirical support for it. Unfortunately, that many of the cases where I’ve heard a nice hypothesis but don’t know the empirical support turn out to be disappointments. Not this time, however! On top of all the good stuff in the talk, Lummaa had very pretty slides with old photos and paintings by Albert Edelfelt. The visual qualities were surpassed only by Rich FitzJohn’s slides.

Edelfelt_Larin_Paraske

(Larin Paraske by Albert Edelfelt)

Two things that were not so great:

The poster sessions. Now my poster session on Friday turned out very well for me, but many others weren’t so lucky. I don’t know why half of the posters were hung facing the wall with hardly enough space for people to walk by the poster board, but it was a terrible idea and must have stopped a lot of people from seeing more posters.

The gender balance. According to Julia Schroeder only 27% of invited speakers were women. I don’t know how it worked behind the scenes and what the instructions to symposium organisers were, and there might not be an easy fix, but this urgently needs fixing.

Of course, there were many more good talks and posters than the handful I’ve mentioned, and apart from them, the twitter feed and tweetup, the social gatherings and the fact that there were actually several interesting people that came to my poster to chat were highlights for me. I come home with a long list of papers to read and several pages of things to try. Good times!

lisbon