1. Genoscope (CEA), 2 rue Gaston Crémieux CP5706, 91057 Evry, France
2. CNRS, UMR 8030, 2 rue Gaston Crémieux CP5706, 91057 Evry, France
3. Université d'Evry, 91057 Evry, France
4. École Normale Supérieure, Laboratoire de Génétique Moléculaire, 46 rue d'Ulm, 75005 Paris, France
5. CNRS, UMR 8541, 46 rue d'Ulm, 75005 Paris, France
6. CNRS, Centre de Génétique Moléculaire, UPR 2167, 91198 Gif-sur-Yvette, France
7. Université Paris-Sud, 91405 Orsay, France
8. Université Pierre et Marie Curie – Paris 6, 75005 Paris, France
9. CNRS, Laboratoire de Biométrie et Biologie Évolutive, UMR 5558, Université de Lyon, Université Lyon 1, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne, France
10. These authors contributed equally to this work.

Correspondence to: Eric Meyer^4,5 Correspondence and requests for materials should be addressed to E.M. (Email: emeyer@biologie.ens.fr).

Most eukaryotic genes are interrupted by non-coding introns that must be accurately removed from pre-messenger RNAs to produce translatable mRNAs¹. Splicing is guided locally by short conserved sequences, but genes typically contain many potential splice sites, and the mechanisms specifying the correct sites remain poorly understood. In most organisms, short introns recognized by the intron definition mechanism² cannot be efficiently predicted solely on the basis of sequence motifs³. In multicellular eukaryotes, long introns are recognized through exon definition² and most genes produce multiple mRNA variants through alternative splicing⁴. The nonsense-mediated mRNA decay^{5, 6} (NMD) pathway may further shape the observed sets of variants by selectively degrading those containing premature termination codons, which are frequently produced in mammals^{7, 8}. Here we show that the tiny introns of the ciliate Paramecium tetraurelia are under strong selective pressure to cause premature termination of mRNA translation in the event of intron retention, and that the same bias is observed among the short introns of plants, fungi and animals. By knocking down the two P. tetraurelia genes encoding UPF1, a protein that is crucial in NMD, we show that the intrinsic efficiency of splicing varies widely among introns and that NMD activity can significantly reduce the fraction of unspliced mRNAs. The results suggest that, independently of alternative splicing, species with large intron numbers universally rely on NMD to compensate for suboptimal splicing efficiency and accuracy.

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