Positive selection in alternatively spliced exons of human genes

Abstract

Alternative splicing is a well-recognized mechanism of accelerated genome evolution. We have studied single-nucleotide polymorphisms and human-chimpanzee divergence in the exons of 6672 alternatively spliced human genes, with the aim of understanding the forces driving the evolution of alternatively spliced sequences. Here, we show that alternatively spliced exons and exon fragments (alternative exons) from minor isoforms experience lower selective pressure at the amino acid level, accompanied by selection against synonymous sequence variation. The results of the McDonald-Kreitman test suggest that alternatively spliced exons, unlike exons constitutively included in the mRNA, are also subject to positive selection, with up to 27% of amino acids fixed by positive selection.

Figure 1

Substitution Rates in Constitutive, Major and Minor Alternatively Spliced Exons of Human Genes (A) Nonsynonymous (Ka) and synonymous (Ks) substitution rates for SNPs (SNP) and human-chimpanzee divergence substitutions (Div). The Ka values are lower and the Ks values are higher in the minor exons. (B) Same as (A), but only neutral SNPs (with frequency > 5%) are considered. (C) The Ka/Ks ratios in the minor exons are consistently higher for SNPs and divergence in the total sample and when only neutral SNPs are considered.