What is the difference between a paralog and an isoform?

Question

I am reading a journal paper about the protein kinase GSK3 and I have come across the following statement:

Although commonly referred to as isoforms, GSK3α and GSK3β are
actually paralogs, homologous proteins derived from different genes.

I am not sure what the difference is between an isoform and a paralog. I have Googled both definitions and paralogs refer to 'genes that derive from the same ancestral genes'.
Whereas isoforms refer to 'any of two or more functionally similar proteins that have a similar but not identical amino acid sequence and are either encoded by different genes or by RNA transcripts from the same gene which have had different exons removed'
These definitions seem quite similar to me so I was wondering if there are any significant differences between paralogs and isoforms? Any insights are appreciated.

Guest · Accepted Answer

I think the confusing thing here is that the two terms come from different fields of biology. While describing something similar, they emphasise different aspects.
The term paralog is mostly used in evolutionary biology, when one wants to find out how genes developed. Paralogs are, as you correctly found out, genes that originate from the same ancestral gene which duplicated. Thus, you would use this word when you want to emphasise the evolutionary relationship.
The term isoform on the other hand is not interested in evolutionary origin, and in fact it is not perfectly defined. This word is used when people studying the molecular biology of an organism discover that there are proteins in this organism that have a very similar amino acid sequence. Here, the interesting question is what differences in function these similar, but slightly different proteins might have. The evolutionary origin is not asked for, and thus there are two different definitions of isoforms:

Some people define isoforms only as variants of the same gene that underwent different post-transcriptional modifications (e.g. English Wikipedia), thus, paralogs would not be isoforms.

Other people also allow paralogs in addition (e.g. German Wikipedia).

In your paper, I guess that the author wants to emphasise that the proteins are not the results of different splicing but encoded by two different genes.

What is the difference between a paralog and an isoform?

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