Epistasis

Ewan Birney @ewanbirney

Is there a good recent review about epistasis in human genetics - both rare and common? (@leonidkruglyak @jcbarret @dgmacarthur)

Ewan Birney @ewanbirney

Or, alternatively, about review about epistasis in general (Drosophila, Mouse etc?)

Ewan Birney @ewanbirney

I can see both sides of the argument about the importance of epistasis. Case For: we know it exists (mendelian genetics, model organisms)>>

Ewan Birney @ewanbirney

but we are poorly powered to untangle epistasis in common variation of natural phenotypes, as well as this being expected to be complex.

Ewan Birney @ewanbirney

Case against. Although epistasis does exist for severe variation, in common variation one expects smoothing of interaction terms>>

Ewan Birney @ewanbirney

This is due to both environmental "noise" and evolutionary arguments. In practice we don't need invoke epistasis to have good models

Ewan Birney @ewanbirney

Hence estimates of h2 (narrow sense heritability - no epistasis) is not so different from H2 (broad sense heritability) in practice.

Ewan Birney @ewanbirney

However, I find the variance decomposition models weirdly fragile, and the out-of-sample prediction is way worse than % var explained

Ewan Birney @ewanbirney

So - I'm in the "epistasis is important, we can't find/model it well" camp I think. Love to hear other arguments.

Kevin Mitchell @WiringTheBrain

.@ewanbirney Just back from a really interesting meeting on epistais, with @moorejh. Clearly important, but systematically under-estimated

Kevin Mitchell @WiringTheBrain

.@ewanbirney Strain of human exceptionalism claims epistatic interactions not impt in human genetics, tho' seen everywhere else

Kevin Mitchell @WiringTheBrain

.@ewanbirney Only because ignoring epistasis inflates h2. But then find most of it "missing"! Hmmm....

Kevin Mitchell @WiringTheBrain

.@ewanbirney For "complex" disorders, epistasis implicit in liability-threshold model. (Otherwise, how to explain the threshold?)

Kevin Mitchell @WiringTheBrain

.@ewanbirney For "complex" disorders, epistasis implicit in liability-threshold model. (Otherwise, how to explain the threshold?)

Ewan Birney @ewanbirney

@WiringTheBrain environment (pure and GxE...)

Ewan Birney @ewanbirney

@felbalazard @BioMickWatson oh. I'd be wary of bringing out a high dimensional trainer (random forests) on case / control data

Ewan Birney @ewanbirney

@felbalazard @BioMickWatson lots of likely data quality / DNA quality / subtle population stratification for the random forest to use

Ewan Birney @ewanbirney

@felbalazard @BioMickWatson in a pure quantitative trait in one cohort ... I'd be happier ...

Ewan Birney @ewanbirney

@felbalazard the right thing is to do it on a quantitative trait ... And we've tried random forests ... I don't trust them in case / control

Ewan Birney @ewanbirney

@felbalazard @BioMickWatson far better randomisation of trait measurement to genotype measurement. Even then, got to be careful ..

Kevin Mitchell @WiringTheBrain

.@Abebab Absolutely agree on that point! High heritability *within* groups does NOT imply mean diffs b/w groups are due to genetics

Kevin Mitchell @WiringTheBrain

.@Abebab Absolutely agree on that point! High heritability *within* groups does NOT imply mean diffs b/w groups are due to genetics

Kevin Mitchell @WiringTheBrain

.@Abebab e.g. body mass index highly heritable w/in populations, yet varies massively (thank you) across populations for non-genetic reasons

Kevin Mitchell @WiringTheBrain

.@Abebab e.g. body mass index highly heritable w/in populations, yet varies massively (thank you) across populations for non-genetic reasons

Kevin Mitchell @WiringTheBrain

.@ewanbirney No - model just says when have N alleles you're fine, but N+1 (or small number) and you're diseased. Purely genetic threshold