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Methods to Evaluate the Effects of Synonymous Variants

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Single Nucleotide Polymorphisms

Abstract

Degeneracy of the genetic code enables a majority of amino acids to be encoded by multiple codons, called synonymous codons. Synonymous variants are single nucleotide changes that result in synonymous codon substitutions without changing the underlying amino acid sequence. For a long time, synonymous variants were assumed to be functionally neutral and were commonly referred to as “silent variants”. Under the same assumption, it was considered safe to employ synonymous variants in recombinant proteins and gene therapy designs using a technique called codon optimization to primarily improve protein expression. However, there is a critical mass of evidence in the last two decades showing that synonymous variants are not always silent and can affect encoded protein’s expression and quality through multiple mechanisms at both transcriptional and translational level. A large number of synonymous variants are implicated in several diseases as well as altering drug responses. Misclassification of synonymous variants as neutral or silent could result in failure to recognize disease-causing variants or failure to properly regulate recombinant therapeutic products harboring synonymous variants. Therefore, a careful evaluation of the functional effects of synonymous variants is critical. A plethora of in-vitro, ex-vivo and in-silico tools are currently available to assess functional effects of one or more co-occurring synonymous variants. The current chapter reviews methods frequently employed to study functional effects of synonymous variants.

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  1. Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, MD, USA

    Brian C. Lin, Katarzyna I. Jankowska, Douglas Meyer & Upendra K. Katneni

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  1. Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Zuben E. Sauna

  2. Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Chava Kimchi-Sarfaty

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Lin, B.C., Jankowska, K.I., Meyer, D., Katneni, U.K. (2022). Methods to Evaluate the Effects of Synonymous Variants. In: Sauna, Z.E., Kimchi-Sarfaty, C. (eds) Single Nucleotide Polymorphisms. Springer, Cham. https://doi.org/10.1007/978-3-031-05616-1_7

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