Báo cáo khoa học: Alternative splicing: good and bad effects of translationally silent substitutions

MINIREVIEW

Alternative splicing: good and bad effects of

translationally silent substitutions

M. Raponi and D. Baralle

Academic Unit of Genetic Medicine, Human Genetics Division, University of Southampton, Southampton General Hospital, UK

Introduction

Splicing is an important part of a post-transcriptional

mechanism where introns are removed and exons are

joined together, allowing the resulting mature mRNA

to be translated into a specific protein product. This

mechanism is supported by the spliceosome machine,

which recognizes the well-characterized splicing con￾sensus sequences at the exon–intron junctions (donor

and acceptor sites) and their proximities (branch

points). Other cis-acting elements involved in the deter￾mination of the splicing outcome are recognized by

trans-acting factors that can either act as splicing

silencers or enhancers.

Alteration of splicing may occur whenever cis varia￾tions alter the recognition of splicing regulatory

sequences [1,2]. This could result in altered isoform

proportions, activation of a control mechanism such as

nonsense-mediated decay, as well as the creation or

loss of splicing variants. As this process has a signifi￾cant impact on protein abundance and ⁄ or functional￾ity, it follows that sequence variants in translationally

silent exonic positions that modify splicing are crucial

in genetic diagnosis and their role as a possible cause

of disease cannot be ignored. Equally important is the

role that these silent sequences may have in evolution.

For example, many algorithms used to calculate evolu￾tionary distances are normalized against the transla￾tionally ‘silent’ sequence variants, which until recently

were considered evolutionarily neutral. We now know

that many so-called neutral substitutions are instead

causative, as they produce the skipping of the exon or

Keywords

minigene; NF1; pre-mRNA; silent; splicing;

translation

Correspondence

D. Baralle, Academic Unit of Genetic

Medicine, Human Genetics Division,

University of Southampton, Duthie Building

(Mailpoint 808), Southampton General

Hospital, Tremona Road, Southampton

SO16 6YD, UK

Fax: +44 2380794346

Tel: +44 2380796162

E-mail: [email protected]

(Received 26 August 2009, revised 4

November 2009, accepted 17 November

2009)

doi:10.1111/j.1742-4658.2009.07519.x

Nucleotide variations that do not alter the protein-coding sequence have

been routinely considered as neutral. In light of the developments we have

seen over the last decade or so in the RNA processing and translational

field, it would be proper when assessing these variants to ask if this change

is neutral, good or bad. This question has been recently partly addressed

by genome-wide in silico analysis but significantly fewer cases by laboratory

experimental examples. Of particular relevance is the effect these mutations

have on the pre-mRNA splicing pattern. In fact, alterations in this process

may occur as a consequence of translationally silent mutations leading to

the expression of novel splicing isoforms and ⁄ or loss of an existing one.

This phenomenon can either generate new substrates for evolution or cause

genetic disease when aberrant isoforms altering the essential protein func￾tion are produced. In this review we briefly describe the current under￾standing in the field and discuss emerging directions in the study of the

splicing mechanism by integrating disease-causing splicing mutations and

evolutionary changes.

Abbreviations

Ka, ratio of nonsynonymous substitutions; Ks, ratio of synonymous substitutions.

836 FEBS Journal 277 (2010) 836–840 ª 2010 The Authors Journal compilation ª 2010 FEBS