Assessing conservation of alternative splicing with evolutionary splicing graphs

Abstract

Understanding how protein function has evolved and diversified is of great importance for human genetics and medicine. Here, we tackle the problem of describing the whole transcript variability observed in several species by generalising the definition of splicing graph. We provide a practical solution to construct parsimonious evolutionary splicing graphs where each node is a minimal transcript building block defined across species. We show a clear link between the functional relevance, tissue-regulation and conservation of alternative transcripts on a set of 50 genes. By scaling up to the whole human protein-coding genome, we identify a few thousands of genes where alternative splicing modulates the number and composition of pseudo-repeats. We have implemented our approach in ThorAxe, an efficient, versatile, robust and freely available computational tool.

Exploring Multi-Tissue Alternative Splicing and Skeletal Muscle Metabolism Regulation in Obese- and Lean-Type Pigs

“…Additionally, upon consideration, we can specifically tally the number of microexons within SE events when conducting alternative splicing analysis, for instance, counting the microexons involved in differential SE events between the two pig breeds. Through transcriptomic analyses of several species and organs, microexons were found to have the highest evolutionary conservation of sequence and inclusion levels relative to other classes of alternative splicing elements [3,80]. Finally, in our study, the fusion transcripts, full-length mRNAs and APA (alternative polyadenylation) sites [81] of two pig breeds have not been well characterized due to the lack of full-length transcripts, so single-molecule long-read sequencing (PacBio Iso-seq) can be used to directly obtain full-length transcripts without further assembly, thus overcoming the above-mentioned limitations [76,[82][83][84].…”

“…Alternative splicing (AS) is a prevalent and evolutionarily conserved biological process in which splice sites are differentially selected within pre-messenger RNAs, leading to the generation of diverse mRNA and protein isoforms [1][2][3]. The growing body of evidence suggests that the precise regulation of AS plays a crucial role in determining tissue types and developmental stages [4].…”

Conservation assessment of human splice site annotation based on a 470-genome alignment

“…However, only a few methods currently use this information directly either for annotation or splice site prediction [Rose et al, 2011]. A common data structure used in RNA assembly called splice graph was generalized to integrate sequence homology information between species [Zea et al, 2021], but it was used for finding clusters of orthologous exons and yet to be employed for RNA-seq assembly. As higher-quality genomes along with their alignments become available, conservation-based methods have the potential to be a powerful aid in constructing functional annotations.…”

Building alternative splicing and evolution-aware sequence-structure maps for protein repeats

“…Recent works have highlighted the importance of alternative splicing (AS) in modulating the number of protein repeats and their amino acid composition (Osmanli et al, 2022;Martinez Gomez et al, 2021;Zea et al, 2021). AS, along with alternative promoter usage and alternative polyadenylation can produce multiple mature mRNA transcripts from a single gene (Ast, 2004).…”

“…These transcripts may lead to different protein isoforms with distinct shapes (Birzele et al, 2008), interaction partners (Yang et al, 2016), and functions (Baralle and Giudice, 2017;Kelemen et al, 2013). Over the human coding fraction, a couple of thousand genes, mainly involved in cell organization, muscle contraction, and inter-cellular communication, show evidence of evolutionary conserved AS patterns modulating the usage of similar exonic sequences (Zea et al, 2021). Alternative transcripts tend to contain less tandem repeats than canonical ones and the associated deletion events do not alter the overall protein 3D structure (Osmanli et al, 2022).…”