Theory Suggests That All Genes Affect Every Complex Trait

The original paper is https://www.cell.com/cell/fulltext/S0092-8674(17)30629-3 There was a nice follow up last week https://www.cell.com/cell/abstract/S0092-8674(18)30714-1 There's a lot of good theoretical biology to be done here. I don't think any of us systems biologists are surprised about this result, but pinning down exactly the structure of the genetic basis for complex traits is going to be an interesting enterprise.

Having studied biology and genetics this is common sense to me. Genetic systems are probabilistic chemical systems where everything influences everything to varying degrees in parallel. They are nothing like the linear assemblies of modules that humans prefer to engineer.

Which explains why gene regulatory network inference by expression patterns is garbage. My first time in graduate school I worked on it, and the model worked just as well using random genes instead of annotated transcription factors.

There was no science in it, so I took a master’s, worked in industry, and am now doing real science in a CS PhD program.

This is a paper that I'm glad was published (maybe not Cell, but somewhere), because it presents an interesting and pretty clear theory.

At the same time, it seems like it's fairly clearly falsifiable almost on its face, because there are many genetic disorders involving clear, substantial mutations (in a chromosomal topography sense) that are circumscribed in their effects, at least to one extent or another.

I think some variant of this might be true, where traits are influenced by a very very large number of genes (like thousands or hundreds of thousands or more), possibly interacting or in more complex chaotic effects. But this is basically a variant of the polygenic hypothesis, which has been a major paradigm for years. This model seems like the dominant paradigm pushed to its limit, rather than something fundamentally new.

Maybe I'm misrepresenting my sense of the field, but I doubt that many people doing GWASes believe in a relatively limited number of genes affecting traits. I think this has been true for several years now at least. I've been wrong in my assumptions about the field before though.

There's a couple of things that are slowly changing in the thinking of biologists related to this:

1. Genes are not loci. The "one gene = one protein" dogma of molecular biology (expanded: "one trait selectable in breeding experiments = one compact locus of the chromosome") was a priori wrong, but it's taken us decades to undo the damage. We were led astray because there are traits that do map to a single locus, or single mutations that were found to be able to control a trait, which is not the same thing as the trait.

2. Distributed representation. If I point to a sentence and ask "where is the sarcasm?" (assuming the sentence is sarcastic), there is no answer. It's certainly a trait of the sentence, just as, say, being red headed is a trait of the organism. But a linear model showing each word's contribution to sarcasm isn't helpful.

3. Perhaps a corollary of (2), humans have the concept of abstraction. There are many situations where you can get something like an abstraction from evolution. If a human engineered it, we'd call it a leaky abstraction, but please don't get caught up on that. Evolution doesn't abstract. But there are structures that emerge that can have similar properties, especially from repeated exaptation. Consider the MAP kinase pathways. Lots and lots of cell responses involve them, in all kinds of subtly different ways. We don't try to claim that a MAP kinase is the gene for anything in particular, any more than we would claim that the interrupt for triggering a system call on 32 bit Linux is the cause of certain behavior that a program is supposed to have in a particular domain.