The adaptive significance of unproductive alternative splicing in primates

Abstract

Alternative gene splicing is pervasive in metazoa, particularly in humans, where the majority of genes generate splice variant transcripts. Characterizing the biological significance of alternative transcripts is methodologically difficult since it is impractical to assess thousands of splice variants as to whether they actually encode proteins, whether these proteins are functional, or whether transcripts have a function independent of protein synthesis. Consequently, to elucidate the functional significance of splice variants and to investigate mechanisms underlying the fidelity of mRNA splicing, we used an indirect approach based on analyzing the evolutionary conservation of splice variants among species. Using DNA polymerase b as an indicator locus, we cloned and characterized the types and frequencies of transcripts generated in primary cell lines of five primate species. Overall, we found that in addition to the canonical DNA polymerase b transcript, there were 25 alternative transcripts generated, most containing premature terminating codons. We used a statistical method borrowed from community ecology to show that there is significant diversity and little conservation in alternative splicing patterns among species, despite high sequence similarity in the underlying genomic (exonic) sequences. However, the frequency of alternative splicing at this locus correlates well with life history parameters such as the maximal longevity of each species, indicating that the alternative splicing of unproductive splice variants may have adaptive significance, even if the specific RNA transcripts themselves have no function. These results demonstrate the validity of the phylogenetic conservation approach in elucidating the biological significance of alternative splicing.

Constant Splice-Isoform Ratios in Human Lymphoblastoid Cells Support the Concept of a Splico-Stat

“…Our comparison of human and chimpanzee splicing expands previous knowledge of AS species specificity (Calarco et al 2007;Skandalis et al 2010). Although the sequences of the evaluated genes GNAS and WT1 were highly conserved between human and chimpanzee, we found significant interspecies differences in spliceisoform ratios.…”

“…However, for most alternative transcripts, and in particular for those of low abundance, it is not obvious. Moreover, their formation often lacks phylogenetic conservation (Skandalis et al 2010). Isolated cases indicate, however, that low abundance of an alternative transcript and seemingly missing conservation are not sufficient criteria to discard an identified alternative transcript as being nonfunctional.…”

“…Even in a comparative analysis of AS patterns in humans and chimpanzees, hominid species separated by a relatively short period of evolutionary time and having very similar genome sequences, it turned out that 4-6% of genes show differences in splicing of orthologous exons (Calarco et al 2007). This indicates that AS may contribute to phenotypic differences between humans and chimpanzees (and more generally between all species) by diverged regulation of the splicing process of primary transcripts from genes that are very similar in their sequences (Skandalis et al 2010). Moreover, aberrations in splicing are also found as a cause of the development or progression of various diseases (Barbaux et al 1997;Valentonyte et al 2005), and splice mutations are suspected of contributing significantly to a variety of diseased states (Krawczak et al 1992).…”

Genome-wide determination of poly(A) sites in Medicago truncatula: evolutionary conservation of alternative poly(A) site choice

“…This suggests that the process of intronic APA itself may play roles in gene expression, but that the specific outcomes (which tend to vary for orthologous genes in the two species) are not as important. A similar proposal has been made for alternative splicing outcomes in primates [36]. Thus, although the alternative splicing of transcripts from the DNA polymerase beta locus in primates shows little conservation in terms of specific events, there is nonetheless extensive alternative splicing leading to unproductive transcript isoforms throughout the primate lineage.…”

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

“…Molecular analyses over subsequent decades have demonstrated that alternative splicing influences intracellular localization, protein stability, enzymatic activity, and posttranslational modification (27,28). However, alternative splicing variants are often divided into two classes: productive or functional, wherein splice variants have biological functions; and unproductive or aberrant, representing transcripts with no known functions (29)(30)(31). Studies also have shown that unproductive splicing events prevent mRNA translation (e.g., no-go, non-sense-mediated, and nonstop decay) (32)(33)(34).…”