Positive Selection and Alternative Splicing in Humans

Alternative splicing is an important mechanism of generating protein diversity and accelerated genome evolution. The mode of the selection acting in constitutive, major alternative and minor alternative regions of human genes is different. Whereas constitutive and major alternative regions tend to evolve under negative (stabilizing) selection, alternatively spliced exons from minor isoforms experience lower selective pressure at the amino acid level accompanied by weak selection against synonymous sequence variation. The McDonald–Kreitman test uses the nucleotide variation for a gene or a set of genes between and within species to detect the positive Darwinian selection in the presence of negative selection. The results of the test suggest that alternatively spliced exons are also subject to positive selection, with up to 27% of amino acids fixed by positive selection. Key concepts Alternative splicing is an important mechanism of generating protein diversity and accelerated genome evolution. Alternatively spliced regions are often evolutionarily young. There is a difference in the selection mode in constitutive, major alternative, and minor alternative regions of human genes. Constitutive and major alternative regions evolve under negative (stabilizing) selection. Up to 27% of positions in minor alternative regions may be experiencing positive selection. Keywords: alternative splicing; positive selection; human genome; molecular evolution; McDonald–Kreitman test