Friday, October 25, 2013

The genetics of olfaction: In evolution, where there's one, or one thousand....there's more. But how much more? Part I.

The way we're taught genetics in school, we have two copies of every gene and both are expressed in their appropriate tissues.  That expression is based on regulatory sequences near to the gene, and when specific proteins (call them Transcription Factors, or TFs) stick to those sequences, the nearby gene is transcribed into messenger RNA which is then used to make the protein the gene codes for.

Thus, like the pair-by-pair march onto Noah's Ark, your two sets of globin genes march on--are expressed--in red blood cells, your digestive enzyme genes in the gut, neurotransmitter genes in brain cells, and so on.  So if you have an 'aa' genotype both 'a' alleles are expressed, but if you're 'Aa' your cells get a comparable dose of each....just as Mendel told us.

Well, not exactly!  Each copy is expressed at a level determined by its nearby regulatory DNA sequences.  These could be very different (due to inherited variation in their sequence details, among other things), so even if both copies are being used, they may not be being used as much.

But that's not all.  Sometimes we find monoallelic expression: only one of the two copies is being used!  Our knowedge of this once-strange exception to the rule has been growing rapidly in recent years.  Now we know there's nothing exceptional about it.....but how 'nothing' is that?

X marks the un-used: monoallelic expresssion and sex determination
Female humans and other mammals are specified by having two X chromosomes.  Since males have only one X and a very different Y chromosome, one might expect the delicate cell environment to be impaired in males,  with only a single dose of all the X-linked proteins, when for the rest of their genes on all the 22 other chromosomes they had a double dose.  But instead, it has been found that in females, for about 85% of the genes on the X-chromosomes, only one of the copies that she carries is actually used.  The other is silenced.  Early in a female embryo's development each cell picks one of its X's to use, and inactivates the other (except for about 15% of genes, when both are used).  Thereafter, descendent cells express only the chosen X.  Since this is random, about half a female's cells use a gene on one X chromosome, the other half genes on the other X.  The use of only one of two available genes in a given cell is known as monoallelic expression (the two copies being 'alleles' of the same gene).

The patchy distribution of color on tortoiseshell cats results from the random inactivation of one X chromosome in females. Scitable, by NatureEducation,

Monoallelic expression, beyond the X
A specific mechanism for this was worked out, starting decades ago, and today much is known about how it works.  It was long thought to be a unique random-selection-inactivation phenomenon. But things in evolution seem to pop up again and again, sometimes in very different guises.  For example, some decades ago it was found that the antibody genes that are expressed in white blood cells and work against microbial infections have something similar to X-inactivation....but also quite different.  Each white cell selects from a large array of possible gene sections, chains them together to form the messenger RNA for an antibody protein, then cuts the un-used sections from the DNA and discards them from the cell.  Not only that, but the other of the two copies of this entire gene is inactivated.

The protein coded by the activated genecopy is shepherded to the surface of the white blood cells, and as the cell circulates in the blood or lymph, it bumps into whatever is around.  If it happens to bind to something it recognizes, like a nasty virus particle, a cascade of events is triggered.  Among other things, the excited white cell divides rapidly, making more of its kind (that remember and continue to express the chosen antibody gene), so they can detect other copies of the infecting villain that are in the body.  When successful, this triggers a cascade of hunt-and-destroy activities that rid the body of the infection.
B Cell development; Weiss and Buchanan; Genetics and the Logic of Evolution, 2004

I've omitted many details, but it is in this basic way that you fight the kinds of infection your inheritance can't have directly predicted--that is, that you didn't evolve specifically to be able to ward off. It works because basically every white blood cell lineage is using a somewhat different antibody molecule, and this  diversity makes it possible to molecularly 'recognize' unpredictable foreign molecules.  There are several gene complexes, located on different chromosomes, that are used in essentially the same way in the formation of various white blood cell types. How these choices are made and the antibody gene regions identified is not fully known.

A given pathogen or alien substance, pollen, virus, bacterium etc., has its molecular surface characteristics.  If one or (usually) more than one part of its surface can be recognized by at least one lineage of immune system cells because of the particular variant receptor they have on their surface, then the pathogen can be grabbed and surrounded by such cells or antibody molecules, and destroyed.

Is that all there is to monoallelic expression?  By no means!

Olfactory receptors: monoallelic expression big-time
How do you smell?  We're not talking about your BO or your Chanel No. 5 sex appeal.  No, we mean how can you smell?  How can you tell it's bananas, lemons, or a dead rat you smell when you walk into a dark room?

The world is drenched in molecules wafting through the air, all around us, and of an essential infinity of different structures.  If detecting food or predators has always been important, one would expect the system to be quite specific, or at least quite sensitive.  In fact, while there may be some specific smell senses (see, pheromones, in Monday's post), in animal evolution it has apparently been generally safer to generate a large array of more or less random odorant detector molecules so that your chances that at least one of them would be sensitive to any odor molecule you may come across, and be sensitive to, and able to remember and discriminate among such molecules.   Your ancestors needed to be able to tell if they smelled a rat or a ratatoulle.

As with the unpredictability of potential sources of infection, you can't know what odors you may be exposed to or want to identify--and remember.   In fact, this has been achieved in mammals and even in insects by a kind of combinatorial mechanism very similar to that used in immune defenses.....but with entirely different mechanism!  We'll talk about that next week.

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