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Silent mutations speak up

Overlooked genetic changes could impact on disease.

Biologists have realized that the genetic code harbours a layer of information that they have largely ignored. Again.

Read the story here.

Posted by Helen Pearson on December 21, 2006 08:22 PM |

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It would seem that "silent" genes having an impact would make them visible to natural selection, which would make them less useful as gene markers. Are there still truly silent genes that can be used as neutral markers? What impact (if any) will this have on estimating the date for the last common ancestor of two organisms.

Posted by: David Elm | December 21, 2006 09:12 PM

It's funny that people are holding their hands up and going woo, silence is no longer golden. I have always thought of silent mutations as not silent at all but speaking perhaps at a frequency inaudible to human ears. (That sounds mystical, it's not meant to be.) The same is true in other parts of biology, perhaps all scientific analyses: take gene knockouts as an example, just because there is no phenotype doesn't mean there is no phenotype, and the gene has no function. It's merely down to asking the right questions and having the right assays.
I for one have always worried when other lab workers having sequenced their clones say "oh well it has a few silent point mutation, it will be ok". This new evidence might make a few PIs ask for other clones to be analysed. Poor Ph.D students!

Posted by: geneticus | December 22, 2006 01:54 PM

As the article pointed out, one major dimension of this is the effect of synonymous mutations (not "silent"!) on splicing and especially alternative splicing. The CFTR example mentioned in the article is a nice experimental demonstration of this, but it's just the tip of the iceberg. Genome-wide studies have shown that tissue-specific alternative exons (alternatively spliced exons that are only included in transcripts in a specific tissue) have a 3 - 4 fold reduction in Ks (synonymous mutation density) relative to constitutive exons, suggesting that the tissue-specific exons have a stronger requirement for RNA sequence motifs that regulate their splicing. In other words, these exons appear to display strong negative selection against most synonymous mutations during their recent evolution. Genome-wide studies show that minor-form alternative exons (i.e. that are only included in a minority of transcripts for that gene, averaged over all tissues) have 6 - 7 fold lower Ks than neighboring constitutive exons in the same gene. One analysis (Lopez-Bigas et al. FEBS Lett. 2005) indicates that splicing mutations could potentially be the biggest source of human disease mutations. If you're interested in details, we wrote a review about this area recently in Nature Reviews Genetics:
http://dx.doi.org/10.1038/nrg1896

Posted by: Christopher Lee | December 23, 2006 02:36 AM

Looking everywhere, under the microscope, behind the mirror, in the looking glass, everyday we find more and more dimensions to inheritance and the mechanisms of evolution. Genetic information can grow into organisms from the exterior, genes thought deleted are found to have only been sleeping or reacquired from the environment, patterns of the observable, trait behaviors are not always comprehendible from models and theory. New theories are created with the notion that the information of inheritance may have to do to do with more than spelling, sentence structure, but the shape of the page itself. Computers are capable of modeling signals and switches with respect to this notion but it obviously does not imply that nature proceeds in a similar manner. This is on a very different track from the DNA helix-gene enzyme ideas that even physicists who review these notions have to rethink what is meant by a point in time. In the raising the blinders we employ in our lines of investigation, in the knowing of a thousand new turns we must take to fit all our new information together in an explainable form, I do not think it is wise to advertise medical cures and new understanding, especially step by step in public news. It is a shame that that the funds to support these academic pursuits depend on pubic health related sources when we do not really have sufficient understanding to attempt to make apply our results, offer promises of better medical prognosis’s that might not materialize. With the suffering of cancer, for example, we have done remarkable things, but we are now contemplating making genetic changes.
A less depressing scenario... shape of a persons' head, in this approach, could possibly be related as 'information coding' for the structure of molecular membrane nutrient transport systems secondarily connected with limb size in heart rate functions-or the latter changing place with the former on additional investigation-or unsuspected orders and connections found---but the bottom line is that all that would be need to treat such a related illness would be a plastic surgeon. Even that could be disastrous if it found that a changed head shape or limb dimensions could be "acquired" through whatever mechanisms.
'Wholism', in contrast to 'Partism' leaves us, perennially, in an uncertain state of
confidence, that we should ask ourselves about, and dissect in long range, the exact economics of our pursuits. Should we pursue the cure for a rare disease, for instance, because it will add to our total understanding, thinking we will have both the benefit of a cure AND a new understanding. In reality this is a very extravagant approach as well as risky that we do not accomplish a surprise change in the shape of our heads or limb dimensions in advance to asking, or creatively questioning the existence of such a possibility.

http://www.marvinekirsh.com
http://www.authorsden.com/marvinelikirsh

Posted by: Marvin E. Kirsh | December 26, 2006 05:39 AM

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