Evolutionary dynamics of gene and isoform regulation in mammalian tissues

By J. Merkin, Caitlin Russell, Ping Chen, C. Burge. Science, 2012

936 citations recorded by the source corpus.

Whence Species Variation? Vertebrates have widely varying phenotypes that are at odds with their much more limited proteincoding genotypes and conserved messenger RNA expression patterns. Genes with multiple exons and introns can undergo alternative splicing, potentially resulting in multiple protein isoforms (see the Perspective by Papasaikas and Valcárcel). Barbosa-Morais et al. (p. 1587) and Merkin et al. (p. 1593) analyzed alternative splicing across the genomes of a variety of vertebrates, including human, primates, rodents, opossum, platypus, chicken, lizard, and frog. The findings suggest that the evolution of alternative splicing has for the most part been very rapid and that alternative splicing patterns of most organs more strongly reflect the identity of the species rather than the organ type. Species-classifying alternative splicing can affect key regulators, often in disordered regions of proteins that may influence protein-protein interactions, or in regions involved in protein phosphorylation. Messenger RNA alternative splicing is highly variable among vertebrates and links to kinase signaling pathways. Most mammalian genes produce multiple distinct messenger RNAs through alternative splicing, but the extent of splicing conservation is not clear. To assess tissue-specific transcriptome variation across mammals, we sequenced complementary DNA from nine tissues from four mammals and one bird in biological triplicate, at unprecedented depth. We find that while tissue-specific gene expression programs are largely conserved, alternative splicing is well conserved in only a subset of tissues and is frequently lineage-specific. Thousands of previously unknown, lineage-specific, and conserved alternative exons were identified; widely conserved alternative exons had signatures of binding by MBNL, PTB, RBFOX, STAR, and TIA family splicing factors, implicating them as ancestral mammalian splicing regulators. Our data also indicate that alternative splicing often alters protein phosphorylatability, delimiting the scope of kinase signaling.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8400b0f4bd1740b54b574975fe0041992eb38558

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Citations in the corpus

Mechanisms and Regulation of Alternative Pre-mRNA Splicing (2015, background): “Indeed, although the mouse and human genomes contain similar numbers of genes, alternative pre-mRNA splicing occurs in >95 to 100% of human genes, compared with ∼63% of mouse genes (Table 1) (5, 6).”
Enhancer Evolution across 20 Mammalian Species (2015, background): “…( Cotney et al., 2013; Xiao et al., 2012) have indicated that enhancers may change rapidly during evolution (Degner et al., 2012; Shibata et al., 2012), particularly when compared with evolutionarily stable gene expression patterns (Brawand et al., 2011; Chan et al., 2009; Merkin et al., 2012).”
Annotation-free quantification of RNA splicing using LeafCutter (2017, neutral): “When using gene expression levels, they saw clustering by organ as expected, however when using exon-skipping levels, they instead saw a clustering by species 27,28 .”
Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution. (2019, background): “Comparative vertebrate transcriptomics of a common set of organs from fish to human revealed that brain-specific alternative splicing events are among the most evolutionarily conserved (BarbosaMorais et al., 2012; Merkin et al., 2012).”
NONCODE 2016: an informative and valuable data source of long non-coding RNAs (2015, background): “In order to explore the conservation information of lncRNAs, NONCODE collected six new mammalian species (chimpanzee, gorilla, orangutan, rhesus macaque, opossum and platypus) (17).”
A highly conserved program of neuronal microexons is misregulated in autistic brains (2014, result): “This is in marked contrast to the generally low degree of evolutionary conservation of other types of AS across vertebrate species (Barbosa-Morais et al., 2012; Braunschweig et al., 2014; Merkin et al., 2012).”
Widespread intron retention in mammals functionally tunes transcriptomes (2014, background): “Similar to cassette exon AS (Barbosa-Morais et al. 2012; Merkin et al. 2012), IR has diverged rapidly in all tissues during vertebrate evolution, although to a considerably lesser extent in the brain than in organs such as testis, which shows the most divergent IR profiles (Fig.”
15 years of PhosphoSitePlus®: integrating post-translationally modified sites, disease variants and isoforms (2018, background): “Alternative isoform usage plays important roles in many biological processes (26,27).”
Complexity of the Alternative Splicing Landscape in Plants[C][W][OPEN] (2013, methodology): “Global studies in metazoans using computational and experimental methods investigating tissuespecific splice variants suggest that their protein products may rewire protein–protein interaction networks and impact signaling pathways (Buljan et al., 2012; Ellis et al., 2012; Weatheritt et al., 2012;…”