Synonymous Snps Not So Synonymous At All

Question

[Stephan]

I've heard that even novel human synonymous snps could even be important because of the way the codons are read and/or instability of rna folding. because of the nucleotide change some codons would be more difficult to translate.

Is there someone experienced with these kind of snps?

Are there any prediction tools available?

Answer 1

[Larry_Parnell]

Here are some articles on this topic:

Bratati Kahali, Surajit Basak, Tapash Chandra Ghosh. Reinvestigating the codon and amino acid usage of S. cerevisiae genome: A new insight from protein secondary structure analysis. Biochemical and Biophysical Research Communications 354 (2007) 693–699

Chava Kimchi-Sarfaty, Jung Mi Oh, In-Wha Kim, Zuben E. Sauna, Anna Maria Calcagno, Suresh V. Ambudkar, Michael M. Gottesman. A “Silent” Polymorphism in the MDR1 Gene Changes Substrate Specificity. Science 315:525-8.

A. G. Nackley, S. A. Shabalina, I. E. Tchivileva, K. Satterfield, O. Korchynskyi, S. S. Makarov, W. Maixner, L. Diatchenko. Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure. Science 314:1930-3.

Danxin Wang and Wolfgang Sadée. Searching for Polymorphisms That Affect Gene Expression and mRNA Processing: Example ABCB1 (MDR1). The AAPS Journal 2006; 8 (3) E515-E520.

I use the human codon frequency table at KEGG to ascertain allele-specific differences in codons of synonymous SNPs. The above papers then give some idea of effect size of the alleles.

Edit 1 Feb 2011: adding a new paper that has just come to my attention as this seems very neat. The synonymous SNP alters binding of a microRNA such that the protective allele is downregulated by the microRNA and the risk allele does not support binding of that microRNA. See details in this paper by Brest, Hofman, et al. on MIRN196, IRGM expression and Crohn's disease.

Edit 14 Dec 2011: There is a very nice news feature at Nature Medicine on this topic, written by Alla Katsnelson. The theme is "synonymous DNA changes can trigger disease in a number of ways."

[Mutated_Dater]

I don't have an example off hand but synonymous snps can also affect the target sequences of intron splicing machinery and hence cause aberrant splicing. That might well be mentioned in the paper by Danxin Wang above as that mentions mRNA processing but I thought i'd mention it as another example just in case

[Khader Shameer]

Larry, thanks a lot for the articles.

[Stephan]

thank you for the articles

[Larry_Parnell]

Indeed. There are exonic splice enhancers and intronic splice enhancers, either of which can be disrupted by a polymorphism like a SNP. Obviously, it is the ESEs that could be altered by a synonymous SNP.

Answer 2

[Pierre Lindenbaum]

See the well documented article in wikipedia: http://en.wikipedia.org/wiki/Silent_mutation

Answer 3

[Khader Shameer]

Not specifically based on the mechanism that you explained, but a recent paper from Butte Lab showed that both synonymous and non-synonymous SNPs share similar likelihood and effect size of human disease associations. See the paper here.

[Larry_Parnell]

Yes, this is an important point - effect size in terms of phenotype.