Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans.

Area of Science:

• Evolutionary biology
• Genomics
• Molecular biology

Background:

• Alternative splicing (AS) is common in eukaryotes, but its functional significance is debated.
• Organismal complexity correlates positively with genome-wide AS rates, suggesting a role in adaptive evolution.
• An alternative hypothesis posits that higher AS rates in complex organisms reflect increased splicing errors due to weaker selection (drift barrier).

Purpose of the Study:

• To test the drift barrier hypothesis by analyzing the relationship between effective population size (Ne) and genome-wide AS rates across metazoan species.
• To investigate whether low-abundance splice variants, which dominate the repertoire, represent functional adaptations or errors.

Main Methods:

• Analysis of 3496 transcriptome sequencing samples from 53 metazoan species.
• Quantification of AS rates and correlation with proxies for effective population size (Ne).
• Characterization of low-abundance vs. abundant isoforms regarding their functional enrichment and relationship with Ne.

Main Results:

• A negative correlation was observed between Ne proxies and genome-wide AS rates across species, supporting the drift barrier hypothesis.
• Low-abundance isoforms, comprising the majority of splice variants, are depleted in functional events and likely represent errors.
• Abundant isoforms, enriched in functional events, showed lower AS rates in more complex species.

Conclusions:

• Variation in AS rates across metazoans likely reflects the constraints imposed by genetic drift on selection's ability to minimize gene expression errors.
• The observed pattern suggests that elevated AS rates in complex organisms may be a consequence of reduced efficacy of selection against splicing errors, rather than a driver of adaptive evolution.