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Comment by gravelc | Hacker News Reader

I'm going to disagree with go with 'sometimes yes and sometimes no'.

Take a construct and transform it into a plant. Check the expression of the transgene from hundreds of different transformation events, and there'll be huge variation, from highly expressed to silenced, even though all inserted transgenes have the same promoter and terminator. Location matters.

However, if the function of gene A is redundant, or it goes to a location when expression is not affected, or it's just not a very important gene, then it probably doesn't have any great phenotypic effect.

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I would make a bet. Randomly generate 100 spots in the mouse genome, let's say maybe not in centromeric locations. Don't correct for being inside an ORF or a promoter. Pick 100 random translocations swapping these spots. 95 of them will be viable with no obvious phenotype.

In how many samples are you doing this? It’s all about effect size.

I broadly agree with your point but careful when saying “no obvious phenotype”. As my former boss likes to say about work in C. elegans: “Worms can’t talk. They seem healthy but maybe they’re extremely unhappy.” Less flippantly, we know that biological systems in general have huge plasticity to buffer environmental changes. The environment is controlled under lab conditions, so loss of robustness due to genetic changes will almost never be detected. We have no good estimate — not even a ballpark! — of how many of these 95 “no obvious phenotype” cases actually have no phenotype, and beliefs widely vary.

I couldn't agree more. Many knock-out mice for protein coding genes don't have an "obvious phenotype", but they are conserved across species. When studied in detail they often reveal an effect, be it in the response to environmental stress or subtle behavioural alterations. I can't find an updated reference, but results published in 2012 by the Mouse Genetics Project and the International Mouse Phenotyping Consortium indicate that ~20% of coding gene knock-out lines examined don't have an "obvious phenotype" [1]. The most likely explanation for their conservation is that they do have a function and a phenotype: we just don't know what to look for.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463797/

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