Why a gene with amplification in copy number shows downregulation in transcriptome level?

Question

[Zahra]

Hi.

I have some genes that have amplification in copy number but show downregulation or non-significant changes in transcriptome level. What happened with these genes?

Thanks for any idea.

Answer 1

[Shred]

Assuming you're studying a mammal ('cause you know, you don't specify and any organism is the same.. )

TL;DR

The correlation isn't 1:1 because of dosage-compensation mechanisms. Indeed, given a chromosomal or segmental duplication you'd expect an higher expression for most of the genes. So, in your case, for some genes this may be explanable by some regulatory mechanism under the hood: if you see this behavior systematically, there's something strange.

From "Gene Copy-Number Alterations: A Cost-Benefit Analysis":

"[..] Before considering the biological impact of changes in gene copy number, it is important to address the question of whether such changes are translated into corresponding changes in gene expression or whether mechanisms are in place that ensure wild-type levels of expression irrespective of gene copy number. Such mechanisms, collectively called dosage-compensation mechanisms, exist for sex chromosomes, which naturally vary in copy number between sexes. With the exception of Drosophila and some plant species [..], dosage-compensation mechanisms do not exist for autosomes. Gene copy-number proportional expression of whole chromosomal or segmental aneuploidies has been observed in fission yeast, budding yeast, Arabidopsis, trisomic mouse embryonic fibroblasts (MEFs), partially trisomic mouse tissues, and human trisomies. CNVs also typically result in a corresponding change in gene expression. In humans and mice, 85%–95% of CNVs are associated with changes in expression of the affected genes (Henrichsen et al., 2009; Stranger et al., 2007). "

From Hernichsen et al, 2009:

"[..] genes that vary in copy number, and thus seem to be less dosage-sensitive, may generally not be very tightly regulated and, consequently, might show high expression variance among individuals from the same strain despite invariant copy numbers."

[Zahra]

Thanks for your informative comment.