Comment by dekhn | Hacker News Reader

Comment by dekhn | Hacker News Reader

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Genetics is complicated enough that both things can be true without circular reasoning.

I've studied genotype to phenotype mechanisms for a very long time (but from the lens of molecular biology, biochemistry, and biophysics, rather than genetics). The language of genetics- especially in the popular press- is extremely loose and ambiguous, and people trying to understand the genetics of autism using the popular press (or even 8th grade biology genetics) are going to be very confused.

Basically in medicine and biology in general it's best to be flexible- avoid using logical reasoning, instead adopt probabilistic mindset, and assume that the entities you're reasoning about are extremely complex and you only have a small amount of noisy, partial information that is in a highly encoded feature space. You can often measure relationships or statistical linkages that appear significant (even after multiple test correction) but rarely discern the true causal relationship between the feature vector (genome) and the outcome (autism).

One of the biggest surprises in modern genetics is that many phenotypes are determined by the sum of effects of many gene products, including many complex interactions between those gene products. Some phenotypes are linked to 1000+ genes, and there are "only" ~25K genes in the human genome. The whole thing is just crazy and our ability to test for complex phenotypes continues to be very limited.

Indeed. Thanks for the great explanation. Honestly, the complexity would be very annoying if it wasn’t also invigorating and fascinating.

The interconnections between genes has led to proposals of “omnigenic” models, the idea that all genes expressed in a cell affect every given trait of the cell, to some extent.

When it comes to something like autism, it’s a word covering a vast number of traits and behaviors of many different cells that gives rise to that set of effects as seen from outside.

And the issue with genetic testing is, we often only look at specific regions of the genome. Even when we do whole genome tests, and compare whole genomes of autistic folks, what we find is no single origin but many overlapping patterns. No definitive set is found because we are looking at complex processes that have many nodes where mutations can mildly tweak the function. Many such functionally relevant mutations can chain together to give you the signatures of autism, and no two are the same.

All these reasons also point to why we are increasingly realizing autism isn’t a “disease” with a “cure”. It’s a way in which people can be people. It’s time society accepted that and expands itself to accommodate.

It seems only natural for nature to have it like this. It’d be hard for evolution to optimize things if the genotype to phenotype mapping was sharp, with phase transitions and such

How do geneticists go about identifying alleles associated with autism? Seems like the effect size would be very small for most of them, and given the relatively small sample population of humans that can be practically sequenced for this, it seems difficult to separate true signal from statistical noise.

Also is it actually just “a sum of cumulative effects of these alleles crossing a threshold causes autism” or more complex like “Allele A and B together has a very significant effect, A and C has a moderate effect but A, B, and C together is has no effect”

What's an allele? There is no real answer to that question. Or rather, the concept of allele is highly abstract and does not correspond well to actual genomic sequences.

Predicting phenotypes is not a linear function of the genome. It's a highly nonlinear function, affected by complex generative processes, feedback control, homeostasis, and many other active control mechanisms. With that said, you could come up with a proxy score that was a function of the genome and had predictive value for autism (ideally better than binary, with a description of the predicted autistic traits somebody showed).

Biology is the only field I've worked in where both "necessary but not sufficient" and "sufficient but not necessary" can both be the case at the same time.

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