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I am trying to understand if there are known genes in the human genome where copy-number should be stable at a diploid level for the carrier cell to live.

I.e., are there lethal deletions or duplications of specific genes in the human genome? I would imagine "house-keeping" genes might be needed for the regular processes within a cell, but I could not find any reference online on specific studies on the matter. House-keeping genes defined as in this article.

E.g., when looking for "lethal heterozygous deletion genes human allele copy number", I mostly found articles regarding tumor-suppressor genes, so I'm not sure I am using the right keywords.

The genes I am looking for should be exclusively from the human genome.

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  • $\begingroup$ Why "exclusively from the human genome"? $\endgroup$
    – Bryan Krause
    Commented May 12, 2022 at 2:07
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    $\begingroup$ To make the question more specific. I am currently working on the human genome and, even if genes conserved across different organisms might be interesting, this would be out of scope for this specific question, I think. $\endgroup$
    – gc5
    Commented May 12, 2022 at 6:22
  • $\begingroup$ Would you consider a translocation/insertion event as a candidate? Say a specific gene (geneA) is reverse transcribed and inserted into a different location of the genome, disrupting an essential gene (geneB). This would result in geneA having a copy number of +1 and it would be deleterious since it disrupts geneB, but it wouldn't strictly be a case where the fact of a change in copy number in and of itself is deadly, it's only because of the specific place where the copy was inserted. For deletions, the answer is trivially yes, house keeping genes being a prime example. $\endgroup$
    – terdon
    Commented May 13, 2022 at 12:46
  • $\begingroup$ @terdon, thanks. Regarding the translocation/insertion event, I believe this is interesting but not exactly what I'm looking for, since I'm looking for genes where disruption in their copy number is deleterious. Regarding house-keeping genes, is there a validated set of genes that can be used in this case? For example, where the disruption of a gene copy number is verified by different methodologies? $\endgroup$
    – gc5
    Commented May 13, 2022 at 16:06
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    $\begingroup$ I don't know, but I would guess you should be able to find things at least from mouse knockout studies and you could then translate to human. For obvious ethical reasons that sort of experiment is frowned upon on human subjects and you'll never find actual cases in the wild since any embryo carrying this wouldn't have been born in the first place. $\endgroup$
    – terdon
    Commented May 13, 2022 at 16:16

2 Answers 2

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A gene is defined as "essential" if its complete loss of function results in a complete loss of fitness (Hart et al., 2014). In practice, a prenatal lethal phenotype is typically the criterion for essentiality.

Homozygous deletion ($CN = 0$) is one of the copy number states that can lead to complete loss of function for a gene, therefore, in theory, if a cell undergoes homozygous deletion on one or more "essential" genes, this CN state might be lethal for the cell.

Some useful resources for "essential" genes are at:

I am not sure how different CN states can be assessed for cell lethality.

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  • $\begingroup$ Why the downvote? $\endgroup$
    – gc5
    Commented May 17, 2022 at 17:15
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    $\begingroup$ Completely lost means homozygous deletion, which is copy number alteration. This was the only case that I found described in the literature - probably because is more easy to assess with currently available orthogonal assays. I agree that the answer is not complete, but it is the best that I could find in the literature, so I still don't understand the downvote (which implies that the answer is not useful - or out of scope - which in my opinion is not in this case). I am open to choose another, more complete, answer - if that exists. I removed the acceptance to the answer if it helps. $\endgroup$
    – gc5
    Commented May 19, 2022 at 16:31
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    $\begingroup$ I get your point and agree. Removed my downvote. Sorry for that! $\endgroup$
    – gaspanic
    Commented May 19, 2022 at 20:10
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    $\begingroup$ No worries, I totally understand your point-of-view. Just I know that questions with downvotes are usually ignored by the reader even if they are reasonable, and I wanted to share and learn about this topic :) $\endgroup$
    – gc5
    Commented May 19, 2022 at 21:12
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    $\begingroup$ Btw, I don't have an answer to your question, but you might want to read about gene dosage. The Wikipedia article is short, but seems to have some relevant references that could be a good start. Not sure how much you will find for human genes though... $\endgroup$
    – gaspanic
    Commented May 20, 2022 at 0:55
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There is some evidence that even in a heterozygous null state some essential human genes are haploinsufficient, e.g. it is lethal when fewer than two functional copies is present.

For example, this paper pooled cells after introducing knockout edits in a variety of genes, and measured relative growth in the pool, identifying a number of genes that are quite intolerant of loss of one copy (~600 according to one expansive estimate).

Additionally, this paper abstract notes that there are some 3,000 haploinsufficient genes, which is somewhat more expansive than the previous estimate. I don't have access to the paper so I am not sure where that number comes from. This paper screened mice and humans for various flavors of essentiality, coming up with various estimates for haploinsufficiency, mostly on the order of a few hundred genes.

I would expect that some of this extends to the full loss of one gene copy, but I don't have direct evidence for a "copy number" type genomic alteration yielding essentiality-haploinsufficiency. This paper does comment somewhat on haploinsufficiency in CNVs, but does not appear to consider essentiality.

This paper also considers haploinsufficient and "triploinsufficient" genes with notable phenotypes in humans, though again I think that they are more interested in disease phenotypes than in essentiality.

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