scholarly journals Mutations primarily alter the inclusion of alternatively spliced exons

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Pablo Baeza-Centurion ◽  
Belén Miñana ◽  
Juan Valcárcel ◽  
Ben Lehner
Keyword(s):  
Genome Sequence ◽  
Sequence Variation ◽  
Common Mechanism ◽  
Genetic Analyses ◽  
Exon Inclusion ◽  
Alternatively Spliced ◽  
In Trans ◽  
Alternatively Spliced Exons ◽  
Mature Mrnas

Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.

scholarly journals Mutations primarily alter the inclusion of alternatively spliced exons

2020 ◽  
Author(s):  
Pablo Baeza-Centurion ◽  
Belén Miñana ◽  
Juan Valcárcel ◽  
Ben Lehner
Keyword(s):  
Genome Sequence ◽  
Sequence Variation ◽  
Common Mechanism ◽  
Genetic Analyses ◽  
Exon Inclusion ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons ◽  
Mature Mrnas

AbstractGenetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.

scholarly journals Genome sequence variation analysis of two SARS coronavirus isolates after passage in Vero cell culture

2004 ◽  
Vol 49 (17) ◽  
pp. 1824-1827 ◽  
Author(s):  
Weiwu Jin ◽  
Liangxiang Hu ◽  
Zhenglin Du ◽  
Qiang Gao ◽  
Hong Gao ◽  
...  
Keyword(s):  
Cell Culture ◽  
Vero Cell ◽  
Genome Sequence ◽  
Sequence Variation ◽  
Variation Analysis ◽  
Sars Coronavirus ◽  
Vero Cell Culture

scholarly journals Positive Selection in Alternatively Spliced Exons of Human Genes

2008 ◽  
Vol 83 (1) ◽  
pp. 94-98 ◽  
Author(s):  
Vasily E. Ramensky ◽  
Ramil N. Nurtdinov ◽  
Alexei D. Neverov ◽  
Andrei A. Mironov ◽  
Mikhail S. Gelfand
Keyword(s):  
Positive Selection ◽  
Human Genes ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons

Elements regulating an alternatively spliced exon of the rat fibronectin gene

1993 ◽  
Vol 13 (9) ◽  
pp. 5301-5314 ◽  
Author(s):  
G S Huh ◽  
R O Hynes
Keyword(s):  
Splice Sites ◽  
Cell Type ◽  
Long Distance ◽  
Sequence Elements ◽  
Alternatively Spliced ◽  
A Cell ◽  
Cell Type Specific ◽  
Alternatively Spliced Exons

We have investigated the regulation of splicing of one of the alternatively spliced exons in the rat fibronectin gene, the EIIIB exon. This 273-nucleotide exon is excluded by some cells and included to various degrees by others. We find that EIIIB is intrinsically poorly spliced and that both its exon sequences and its splice sites contribute to its poor recognition. Therefore, cells which recognize the EIIIB exon must have mechanisms for improving its splicing. Furthermore, in order for EIIB to be regulated, a balance must exist between the EIIIB splice sites and those of its flanking exons. Although the intron upstream of EIIIB does not appear to play a role in the recognition of EIIIB for splicing, the intron downstream contains sequence elements which can promote EIIIB recognition in a cell-type-specific fashion. These elements are located an unusually long distance from the exon that they regulate, more than 518 nucleotides downstream from EIIIB, and may represent a novel mode of exon regulation.

scholarly journals Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts

2020 ◽  
Author(s):  
Jennifer E. Hurtig ◽  
Minseon Kim ◽  
Luisa J. Orlando-Coronel ◽  
Jellisa Ewan ◽  
Michelle Foreman ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Low Frequency ◽  
Common Mechanism ◽  
Duplicate Genes ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Functional Consequences ◽  
Alternatively Spliced ◽  
Mammalian Genes

AbstractMany eukaryotes use alternative splicing to express multiple proteins from the same gene. However, while the majority of mammalian genes are alternatively spliced, other eukaryotes use this process less frequently. The budding yeast Saccharomyces cerevisiae has been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. We have recently shown that the alternative splicing of SKI7/HBS1 is widely conserved, but that yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated unspliced genes as part of a whole genome doubling (WGD). Here we show that other examples of alternative splicing that were previously found to have functional consequences are widely conserved within the Saccharomycotina. We also show that the most common mechanism by which alternative splicing has disappeared is by the replacement of an alternatively spliced gene with duplicate genes. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently than S. cerevisiae. This suggests that the WGD is a major reason for the low frequency of alternative splicing in yeast. We anticipate that whole genome doublings in other lineages may have had the same effect.

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