Alex Palazzo is an Assistant Professor in the Department of Biochemistry at The University of Toronto.
Yesterday Melissa Moore gave a talk at the School of Public Health here at Harvard Med School. She had lots of data - on nonsense mediated decay (how cells degrade mRNA transcripts with premature stop codons that arise through various mechanisms) and on nonfunctional ribosome decay (NRD). Here is some neat info from her intro on introns & NMD:
- Since 90% of the gene coding region is introns, exons are for all practical purposes modular. When DNA is duplication or swaped within a gene or between genes, chances are that genes will be cut and ligated at intronic sequences. (Thus the exons are moved around as modules.) This facilitates exon duplication and other gene rearrangements thus increasing the "evolvability" of genes in organisms with high intronic content. There is strong evidence that such modular changes have occurred in genes that are involved in brain development such as DsCam.
- Introns also allow for alternative splicing, so that a single gene could encode for many different types of transcripts. Again using DsCam, the types of transcripts produced from this fly gene outnumbers the amount of genes in the entire fly genome.
- Splicing marks the transcript within the nucleus. This mark is a complex of proteins called the exon junction complex (or EJC), then follows the mRNA out into the cytoplasm. The EJC communicates the nuclear history of the transcript to factors in the cytosolic compartment.
Why have NMD? This topic came up in a previous post ...
- According to Moore, 15% of all genetic disorders are due to the introduction of premature termination codons. The truncated gene products can act as "dominant negative" isoforms. NMD helps target such potentially harmful transcripts for destruction. Clearing away these genetic aberrations, especially when the non-mutated form of the gene is present in the sister chromosome, can be advantageous. Having said this, there are cases where if the cell did produce the truncated form of the protein, the organism would be better off.
- With all the alternative splicing going on in a cell, there are lots of splicing errors, upto 10% of all mRNAs are misprocessed acording to Moore. Again NMD would clear these up. (I may add that Nogo decay may clear these up as well.)
- NMD may act to fine tune expression by decreasing the half life of certain transcripts. Alternatively NMD may be activated in a context dependent manner. There may be cases where translation of silent mRNA is activated, but the translation of the mRNA would simultaniously activate NMD. Like the tape recorder in Mission Impossible, once the message is read, it self-destructs. This would generate a burst of translational product.
The second question that Moore addressed, nonfunctional ribosome decay, is interesting because ribosomes are very long lived molecules - Dr Moore's group tried to measure the half life of rRNA, but could never see a decrease over time (making it impossible to calculate a half life. As cells grow, old ribosomes get diluted out into the pool of newly made ribosomes. About the only time you degrade functional ribosomes is when cells are under starvation conditions, then they eat ribosomes. So what happens when rRNA is mutated? Well the non-functional rRNA is assembled into ribosomes but after a while is degraded. It seems like cells can recognize ribosomes that don't work well. This may actually be a major problem as there is about 10x more rRNA than DNA in a typical cell. Imagine all those nucleotide damaging agents - as Moore stated - "ribosomes would eventually become decrepit over time" somehow the cell needs to recycle these ribosomes. This is a big problem for cells that don't divide - their ribosomes would just become more and more decrepit.
OK I need to get out of here before I become decrepit.
Comments
Since 90% of the gene coding region is introns, exons are for all practical purposes modular.
While this may be true for mammals, it can't be generalized across all eukaryotic taxa. A few of the better studied genomes -- Drosophila, yeast, Caenorhabditis -- do not display this trend.
And invoking an adaptive explanation for introns is a highly speculative process. Mike Lynch argues that introns are present in eukaryotes because eukaryotic population size isn't large enough for selection to purge these slightly deleterious insertions. This makes certain predictions regarding intron size and population size (ie, they should be positively correlated), which we observe in the data.
While introns may allow for some modularity in regards to gene duplication, this may simply be a spandrel from some non-adaptive process.
Posted by: RPM | December 9, 2006 10:35 AM
RPM,
Yeah, I've seen that paper (were you the one who linked to it?) - I guess it is inconclusive whether introns are adaptive in the sense of "evolvability", yet it does seem like many genes have undergone exon duplication. This is the case for DsCam, and probably many other genes (Nesprins for example). So although introns have no short term bennefit in this aspect, modularity in the long run can provide a platform for gene experimentation. If neutral mutations are more prevelent in (and I know you don't like this next term, but I'll use it anyway) higher eukaryotes because of their lower numbers, intron/exons may not only serve to further buffer neutral/deleterious mutations but alow organisms to explore more of the genetic landscape.
Posted by: apalazzo | December 9, 2006 10:49 AM
Your or Moore's (not sure if you are still paraphrasing her at this point) third point on "why have NMD" is very interesting (control of translation, translate and destroy the mRNA). The diversity of Dscam and its role in axonal patterning creates a potentially dizzying problem insofar as you could have ~38,000 different receptors each of which is neccessary for a specific type of connection. Any evidence that NMD-mediated translational control is either local (e.g. at the growth cone) or that it is generally involved in axonal patterning?
BTW- thanks for unspamming me the other day, I'll be sure to avoid spelling out TX from now on!!
Posted by: Theodore Price | December 9, 2006 12:06 PM
"There may be cases where translation of silent mRNA is activated, but the translation of the mRNA would simultaniously activate NMD. Like the tape recorder in Mission Impossible, once the message is read, it self-destructs. This would generate a burst of translational product."
This issue gets me out of bed in the morning. I imagine a competition between polysomes translating the message while it's being degraded. That would give a burst without having to invoke a high concentration of the translationally quiescent message persisting at a given site if there were a single ribosome translating the RNA. The concept of a real digital switch is pretty amazing and would likely involve some awesome interactions. I bet the FlAsH-ReAsH system will help yield some great answers over the next couple years.
Posted by: Bartholomew Cubbins | December 9, 2006 4:01 PM