Next to ... meaningless

We posted a few weeks ago about a gene mapping project we're involved in, and the myriad difficulties in identifying genes that could be responsible for the variation in craniofacial shape in two strains of mice.   I'm still slogging through map intervals, though I am willing to say out loud that I can now see the end.

Brca1 expression, developing mouse
embryo. Image from GenePaint

I haven't revised my sense of what this all means: The function of many genes is still unknown -- indeed, most genes are expressed in multiple tissues throughout the body, so often it's surely true that a gene's multiple functions are still unknown.  And, because many genes are named for a disease they have been discovered to be associated with, or for a single tissue in which they are expressed at a specific time, even though they can have many other functions, it's hard to know if they are relevant or not (e.g., a gene in one of the intervals I was characterizing last week was named for its involvement in follicle maturation, but it turns out it's expressed in many tissues in the developing mouse embryo, including the head, so it's hard to rule it out as possibly contributing to the development of traits we are interested in).

I also found the Brca1 gene in one of the intervals I was looking at, the "breast cancer 1" gene.  Candidate?  This is one of the genes that, when mutated, is associated with high risk of early onset breast cancer.  But, in spite of its name, it's not a gene 'for' breast cancer.  It's a DNA repair gene, and it's expressed in a variety of organs in the body, at various developmental stages.  In the picture to the left, the darker stain in the section of mouse embryo represents Brca1 expression; it's in the brain, the facial region, the liver, the intestine, the lungs, and so on.

And it's bad enough to be named after a function that you only have when you're mutated, that ignores your major purpose in life.  But, here's the height of indignity for a poor gene: the gene that sits next to Brca1 on mouse chromosome 11 is called Nbr1, which is short for "next to BRCA1" gene.  What a way to go through life!  This gene was first identified in the mid 1990s, and was of interest because of its chromosomal proximity to Brca1.  But its function is still not known.  If you look it up in GeneCards, which is a compendium of what's known about tens of thousands of genes, you find this:

The protein encoded by this gene was originally identified as an ovarian tumor antigen monitored in ovarian cancer. The encoded protein contains a B-box/coiled coil motif, which is present in many genes with transformation potential, but the function of this protein is unknown. This gene is located on a region of chromosome 17q21.1 that is in close proximity to tumor suppressor gene BRCA1. Three alternatively spliced variants encoding the same protein have been identified for this gene. (provided by RefSeq)

And, listed under "Function":

Acts probably as a receptor for selective autophagosomal degradation of ubiquitinated targets.

That is, it may be involved in the recycling of proteins within cells.  Maybe.

This in itself has nothing whatever to do with breast cancer, nor with being 'near' to breast cancer whatever that might mean!  Clusters of genes near to each other on their respective chromosome often comprise gene families -- that is, genes that arose by miscopying of an existing gene so that in the descendant cell there are two adjacent copies of the ancestral gene.  This kind of thing is a regular if rare occurrence and is, indeed, a major way that genomes evolve:  duplicate genes can initially provide redundancy for the parent gene's functions, but one of the two can then diverge through mutational changes to take on a new function.  But the functions need not be relevant even to the same tissue.

And unrelated genes that happen to be nearby on a chromosome can sometimes, but certainly need not, be expressed in the same cell types nor involved in the same functions.  So being 'near' to  a 'breast cancer' gene and hence even mildly suspected of being related to breast cancer, or any cancer, is a nefarious case of guilt by association!

Too often we are driven by labels rather than using them in a neutrally informative way.  There are pressures to coin a name for a gene you've discovered, just as there are incentives to give a new species name to a fossil you've discovered.  Our reward system that is too often based on publicity and marketing is to some extent responsible, along with the normal everyday vanity to which we are perhaps all subject.

But it's not good for science.

These are but two examples of why identifying candidate genes for traits of interest is difficult.  And, these are genes we know something about.  When nothing's known, neither where a gene is expressed or what it does, that gene can't be considered a candidate for anything, even though it certainly does something.  And that's true for a lot of genes.