How do synonymous mutations affect fitness?

While it has often been assumed that, in humans, synonymous mutations would have no effect on fitness, let alone cause disease, this position has been questioned over the last decade. There is now considerable evidence that such mutations can, for example, disrupt splicing and interfere with miRNA binding. Two recent publications suggest involvement of additional mechanisms: modification of protein abundance most probably mediated by alteration in mRNA stability and modification of protein structure and activity, probably mediated by induction of translational pausing. These case histories put a further nail into the coffin of the assumption that synonymous mutations must be neutral. (c) 2007 Wiley Periodicals, Inc.