Hhuman genetic diseases linked to synonymous single nucleotide polymorphisms

What is it about?

For a long time synonymous single nucleotide polymorphisms were considered as silent mutations. However, nowadays it is well known that they can affect protein conformation and function, leading to altered disease susceptibilities. This paper we considered 22 human genetic diseases or traits, linked to 35 synonymous single nucleotide polymorphisms in 27 different genes. We performed a local sequence context analysis in terms of the ribosomal pause propensity affected by synonymous single nucleotide polymorphisms. We found that synonymous mutations related to the above mentioned mechanisms presented small pause propensity changes, whereas synonymous mutations that were not related to those mechanisms presented large pause propensity changes. On the other hand, we did not observe large variations in the codon usage of codons associated with these mutations. Furthermore, we showed that the changes in the pause propensity associated with benign sSNPs are significantly lower than the pause propensity changes related to sSNPs associated to diseases.

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Why is it important?

These results suggest that the genetic diseases or traits related to synonymous mutations with large pause propensity changes, could be the consequence of another mechanism underlying non-silent synonymous mutations. Namely, alternative protein configuration related, in turn, to alterations in the ribosome-mediated translational attenuation program encoded by pairs of consecutive codons, not codons. These findings shed light on the latter mechanism based on the perturbation of the co-translational folding process.