Sunday, 28 October 2007

Operons breaking the rules

ResearchBlogging.orgFor every rule in biology there is an exception. This causes problems in teaching. Do you give the rule and leave out the exception, effectively lying to the people you are teaching or do you give them the rule and exception and making rule mean much less? This is a real problem. Well I have just discovered eukaryotes have broken a golden. They have operons. I was always taught eukaryotes don’t have operons, only prokaryotes do.

For anyone needing to be reminded what an operon is it is several genes all on the same mRNA molecule. One name for this is polycistronic mRNA (cistron is an old name for what we know as a protein coding gene). Several genes have a single promoter and a terminator of transcription controlling them all. On this polycistronic mRNA are several Shine-Dalgarno sequences (bacterial ribosome binding sites) so a ribosome binds in front of each gene and translates it until it reaches a stop codon and falls off. The classic example is the lac operon. It makes 3 proteins used by E. coli to break down the sugar lactose. The reason why you would want a single promoter to control the expression of several proteins is because if they have related function like in the lac operon you want them all to be turned on at the same time and at the same level of expression therefore making the same number of proteins.

Classically eukaryote have monocistronic mRNA (one gene per mRNA) but their is more to this story. Strange transcripts have been found in animals from the simple nematodes to complex mammals such as us. One type of mRNA that has been called operons by some people in C. elegans uses something called trans-splicing. A gene is expressed with one promoter but contains 2 protein coding regions. But this does not mature into a polycistronic mRNA but during RNA processing the introns are removed and the two coding regions are separated. But how does the downstream RNA resist degradation by RNases? It has a SL-exon from another transcript trans-spliced onto it. This way one ‘gene’ makes 2 mRNA (see diagram). This is not a conventional operon like those found in bacteria. This is not a minor thing in the nematodes genome – 15% of all genes in C. elegans are found in operons of this type. We still have monocistronic mRNA here so eukaryotes are behaving fairly well so far.

But in Drosophila and higher organisms dicistronic mRNAs have been found. No trans-splicing involved what so ever. This is definitely breaking one of the golden rules in biology. Here a promoter causes the transcription of 2 genes onto the same transcript. Each one of these gets translated. It is unclear at the moment if both genes have there own ribosome intonation site are if the ribosome that translates the first gene also translates the second one by not falling off at the stop codon of the first gene. One example (that is conserved between man and mouse) is the dicistronic mRNA coding the growth and differentiation factor 1 (GDF-1) and a membrane protein of unknown function (UOG-1). Whether they are co-transcribed because they have related function is obviously unknown.

Living creates are strange. We think we understand a bit about them, create rules that we think life follows so we can understand life better. But life doesn’t always follow the rules we think it does. So the best we can do is make rules or models up and test them as this is how science works. I just hate it when something I thought I new turned out to be wrong.

T. Blumenthal (2004). Operons in eukaryotes Briefings in Functional Genomics and Proteomics, 3 (3), 199-211 DOI: 10.1093/bfgp/3.3.199


Menelaos Symeonides said...

Great post! Very interesting. I was actually thinking about this topic a couple of weeks ago when I found out about bidirectional promoters, and I thought that it always seemed a bit strange that there were no operons in eukaryotes because they are so useful.

I think the question is when did bacteria evolve operons? Was it before the prokaryote/eukaryote split? If not, then this is an example of convergent evolution, well at least as far as the Drosophila one is concerned. Actually it is not that simple because you can't really say when the first operon evolved because it may have broken up a long time ago and we will never know about it!

The other thing is, doesn't this really depend on what our definition of a gene is? Once again it shows what a fuzzy word it is. Can we call them two genes if they are controlled by one promoter?

Anyway, can you post the paper you read this in?

James Lloyd said...

I have a question for you – are operons related? Think about it. An operon is simply functionally related (sometimes) genes that are co transcribed. So within an operon there is relationship in function but is there a phylogenetic relationship between operons, I find it hard to picture. I think of operons as arising independently. I think operons were the norm in the RNA world ie many protein coding genes on the same RNA molecule before DNA came about and a single chromosome was created. I also think operons have evolved independently multiple times. I do not know if eukaryotes and bacteria share homologues operons but I find it hard to believe and I think the paper would have said something if they were. In the case of operons like the trp operon it appears to be conserved between both bacteria and archaea!!! Therefore operons went down the archaea/eukaryotic branch of the tree of life but if eukaryotes kept them is unknown?

A gene is a strange concept. Defining it is difficult. (simon once told me he doesn’t bother anymore). I actually had problems during the post with the definition lol.

Menelaos Symeonides said...

Yeah you're right, the concept of operons does not really require any special machinery that needs to evolve, it is just something that we perceive as special even though to the genome it is just another coding sequence. I wonder how you would use bioinformatics to look for broken or "dead" operons, it would be very interesting if we found any in our genome. I might look this up in fact.

Catarina Vicente said...

That is really interesting! But in some way, it rings a bell (at least the C.elegans part), I wonder if Simon talked about it in a tutorial...?

The definition of a gene is indeed confusing, but it becomes even more when you try to describe it to a lay person. For example, to describe my project to my family, I had to start all over from what a gene is. My definition was: a piece of DNA that codes for a protein. It is a generalization, and it is not accurate, but is the only way you can get people to start thinking about it. So I guess that is the reason why at uni we are normally only told the rules, rather than the exceptions.

James Lloyd said...

One thing that bothers me with the definition of a gene is how do you relate it to the nucleotide of a piece of DNA your are cloning. eg is it just the ORF or does it include the regions around it like restriction sites you add in during PCR? Therefore I almost never refer to what I am cloning as my gene but the PCR product...
The best bit is the 3rd type of operons the paper I referenced discussed but I don’t think are operons. If a gene is alternatively spliced to give 2 completely different products only using one (or so) exon(s) the same between (sometimes non-coding exons) then is it essentially 2 genes (2 different products) but still one gene giving 2 different alternatively spliced products.
At the end of the day we only use definitions to help understand what is going on but I give up with definitions and only are about the fine print. Who cares what you call it – what is it doing is the important part. I advise you to read the paper for the end look at the horridness of this sort of thing.
PS Melly maybe eukaryotes need a special way to translate dicistronic mRNA, just one thing in the paper suggested it but I didn’t have time to look into it.