Mutational bias and the protein code shape the evolution of splicing enhancers

Rong, Stephen; Buerer, Luke; Rhine, Christy L.; Wang, Jing; Cygan, Kamil J.; Fairbrother, William G.

doi:10.1038/s41467-020-16673-z

Cited by 19 publications

(15 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our result confirms the prediction that purifying selection generally restricts the ability of sequence to evolve to a lower mutability state. A similar pattern was simulated by Rong et al (2020) when modeling the evolution of splice sites. The fact that coding sequence had higher mutability was not solely driven by the highly mutable CpG trinucleotides as simulations removing CpG trinucleotides produced a qualitatively similar result.…”

Section: Resultssupporting

confidence: 54%

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

Oman

Alam

Ness

2022

Genome Biology and Evolution

View full text Add to dashboard Cite

The rate of mutations varies >100-fold across the genome, altering the rate of evolution, and susceptibility to genetic diseases. The strongest predictor of mutation rate is the sequence itself, varying 75-fold between trinucleotides. The fact that DNA sequence drives its own mutation rate raises a simple but important prediction; highly mutable sequences will mutate more frequently and eliminate themselves in favour of sequences with lower mutability, leading to a lower equilibrium mutation rate. However, purifying selection constrains changes in mutable sequences, causing higher rates of mutation. We conduct a simulation using real human mutation data to test if (1) DNA evolves to a low equilibrium mutation rate and (2) purifying selection causes a higher equilibrium mutation rate in the genome’s most important regions. We explore how this simple process affects sequence evolution in the genome, and discuss the implications for modelling evolution and susceptibility to DNA damage.

show abstract

Section: Resultssupporting

confidence: 54%

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

Oman

Alam

Ness

2022

Genome Biology and Evolution

View full text Add to dashboard Cite

show abstract

“…It is conceivable that once the pyrimidine content in the 3PT increased due to avoidance of the 3’ splice signal, splicing factors co-evolved with this pattern to develop higher binding specificity to pyrimidines. In a similar manner, it has also recently been shown that mutation bias together with purifying selection created precursor exonic splicing enhancers (pre-ESEs), to which trans-acting factors adapted later (Rong et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Purifying selection against spurious splicing signals contributes to the base composition evolution of the polypyrimidine tract

Yıldırım

Vogl

2022

Preprint

View full text Add to dashboard Cite

Among eukaryotes, the major spliceosomal pathway is highly conserved. Long introns may contain additional regulatory sequences, but those in short introns seem to be nearly exclusively related to splicing. While regulatory sequences involved in splicing are well-characterized, little is known about their evolution. At the 3' end of introns, the splice signal nearly universally contains the dimer AG, which consists of purines. The polypyrimidine tract upstream of the 3' splice signal is characterized by over-representation of the pyrimidine bases cytosine and thymine. We hypothesize that the over-representation of pyrimidines in the polypyrimidine tract is caused by avoidance of a premature splicing signal- AG should be most under-represented dimer. DNA-strand asymmetry patterns in fruit flies of the genus Drosophila confirm this prediction. In short introns of Drosophila, a region between the 5' splice signal and the branch point, which at least contains the nucleotides 8-30, is considered to evolve neutrally. Comparing this presumably neutrally evolving region to the polypyrimidine tract, we infer a moderate scaled selection strength below four against 3' splicing signals. Patterns of asymmetry in other eukaryotes indicate that avoidance of premature splicing similarly affects the nucleotide composition in their polypyrimidine tracts.

show abstract

“…In particular, prior analyses ( 55 ) detected no evidence for selection operating on the candidate ( 110 ) ESS motifs when in exons. The motifs also don’t show avoidance of stop codons, despite CDS exonic motifs being motifs that should (by definition) have low stop codon density ( 40 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

“…ESEs may also exist in a sequence space that is especially prone to disruptive nonsense mutations. Despite the purine enrichment of both ESEs and stop codons, ESEs have a low density of TAA, TGA and TAG motifs ( 40 ) (see also 50 ). This may well reflect the fact that, while such motifs need only avoid nonsense mutations in one frame, they tend to be employed in all frames ( 51 ).…”

Section: Introductionmentioning

confidence: 99%

Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption

Abrahams

Savisaar

Mordstein

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

Transcripts containing premature termination codons (PTCs) can be subject to nonsense-associated alternative splicing (NAS). Two models have been evoked to explain this, scanning and splice motif disruption. The latter postulates that exonic cis motifs, such as exonic splice enhancers (ESEs), are disrupted by nonsense mutations. We employ genome-wide transcriptomic and k-mer enrichment methods to scrutinize this model. First, we show that ESEs are prone to disruptive nonsense mutations owing to their purine richness and paucity of TGA, TAA and TAG. The motif model correctly predicts that NAS rates should be low (we estimate 5–30%) and approximately in line with estimates for the rate at which random point mutations disrupt splicing (8–20%). Further, we find that, as expected, NAS-associated PTCs are predictable from nucleotide-based machine learning approaches to predict splice disruption and, at least for pathogenic variants, are enriched in ESEs. Finally, we find that both in and out of frame mutations to TAA, TGA or TAG are associated with exon skipping. While a higher relative frequency of such skip-inducing mutations in-frame than out of frame lends some credence to the scanning model, these results reinforce the importance of considering splice motif modulation to understand the etiology of PTC-associated disease.

show abstract

Mutational bias and the protein code shape the evolution of splicing enhancers

Cited by 19 publications

References 64 publications

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

Purifying selection against spurious splicing signals contributes to the base composition evolution of the polypyrimidine tract

Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption

Contact Info

Product

Resources

About