Code inside the codon: The role of synonymous mutations in regulating splicing machinery and its impact on disease

Sarkar, Avik; Panati, Kalpana; Narala, Venkata Ramireddy

doi:10.1016/j.mrrev.2022.108444

Cited by 19 publications

(10 citation statements)

References 164 publications

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“…Synonymous mutations usually do not alter the encoded amino acids and are easily overlooked in studies of the genetic basis of phenotypic variations. However, more and more studies have shown that synonymous mutations affect gene expression by altering mRNA stability, mRNA secondary structure, splicing processes and translation dynamics (Sarkar et al., 2022). In this study, screening for this synonymous mutation was found to determine the skeletal MM of pigeons, suggesting a potential causal mutation site, although further analyses are needed to elucidate the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of growth traits and validation of key mutations (MSTN c.C861T) associated with the muscle mass of meat pigeons

Hou,

Wang,

et al. 2023

Animal Genetics

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Selective breeding of meat pigeons is primarily based on growth traits, especially muscle mass (MM). Identification of functional genes and molecular markers of growth and slaughter traits through a genome‐wide association study (GWAS) will help to elucidate the underlying molecular mechanisms and provide a theoretical basis for the selective breeding of meat pigeons. The phenotypic data of body weight (BW) and body size (BS) of 556 meat pigeons at 52 and 80 weeks of age were collected. In total, 160 434 high‐quality single nucleotide polymorphism sites were obtained by restriction site‐associated DNA sequencing. The GWAS analysis revealed that MSTN, IGF2BP3 and NCAPG/LCORL were important candidate genes affecting the growth traits of meat pigeons. IGF2BP3 and NCAPG/LCORL were highly correlated to BW and BS, which are related to overall growth and development, while MSTN was associated with pectoral thickness and BW. Phenotypic association validation with the use of two meat pigeon populations found that the MSTN mutation c.C861T determines the MM. These results provide new insights into the genetic mechanisms underlying phenotypic variations of growth traits and MM in commercial meat pigeons. The identified markers and genes provide a theoretical basis for the selective breeding of meat pigeons.

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Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of growth traits and validation of key mutations (MSTN c.C861T) associated with the muscle mass of meat pigeons

Hou,

Wang,

et al. 2023

Animal Genetics

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“…2a) [37,48,[97][98][99]. The splice mutation is associated with multiple cancers and plays a crucial role in the regulation of pre-mRNA splicing [100][101][102]. The G870A mutation has been identified as a crucial splice mutation contributing to the production of CCND1a and CCND1b (Fig.…”

Section: Ccnd1 Isoforms Caused By G870a Mutationmentioning

confidence: 99%

“…Additionally, BAF57 (SMARCE1) [122], MYF5 [123], SNIP1 [124], Brm (SMARCA2) [125], and other regulatory factors had also been reported to be involved in the splicing of CCND1 and summarized in Table 2. CCND1 splice mutation Mutation of the splice region is associated with multiple cancers and plays a crucial role in the regulation of pre-mRNA splicing [100,101]. It is generally believed that splice mutation result in recognition of ectopic splice sites through pre-mRNA spliceosome, thereby changing splicing patterns, such as exon jumping and intron retention, and finally modulating the risks of cancer development and outcome [48,126].…”

Section: Trans-acting Factorsmentioning

confidence: 99%

Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation

Wang

Zhang

et al. 2023

Cell Death Dis

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Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.

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“…Remarkably, approximately 22% of disease-associated missense variants have been recognized as having the capacity to modulate pre-mRNA splicing [ 1 , 2 ]. This influence goes beyond missense variants and includes synonymous and nonsense variants [ 3 , 4 ]. These findings have far-reaching implications for our understanding of disease pathogenesis and the advancement of precision medicine.…”

Section: Introductionmentioning

confidence: 99%

Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1 coding variants

Wu,

Lin,

Tang

et al. 2024

Hum Genomics

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Background Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length gene splicing assay (FLGSA) in conjunction with SpliceAI to prospectively interpret the splicing effects of all potential coding SNVs within the four-exon SPINK1 gene, a gene associated with chronic pancreatitis. Results Our study began with a retrospective analysis of 27 SPINK1 coding SNVs previously assessed using FLGSA, proceeded with a prospective analysis of 35 new FLGSA-tested SPINK1 coding SNVs, followed by data extrapolation, and ended with further validation. In total, we analyzed 67 SPINK1 coding SNVs, which account for 9.3% of the 720 possible coding SNVs. Among these 67 FLGSA-analyzed SNVs, 12 were found to impact splicing. Through detailed comparison of FLGSA results and SpliceAI predictions, we inferred that the remaining 653 untested coding SNVs in the SPINK1 gene are unlikely to significantly affect splicing. Of the 12 splice-altering events, nine produced both normally spliced and aberrantly spliced transcripts, while the remaining three only generated aberrantly spliced transcripts. These splice-impacting SNVs were found solely in exons 1 and 2, notably at the first and/or last coding nucleotides of these exons. Among the 12 splice-altering events, 11 were missense variants (2.17% of 506 potential missense variants), and one was synonymous (0.61% of 164 potential synonymous variants). Notably, adjusting the SpliceAI cut-off to 0.30 instead of the conventional 0.20 would improve specificity without reducing sensitivity. Conclusions By integrating FLGSA with SpliceAI, we have determined that less than 2% (1.67%) of all possible coding SNVs in SPINK1 significantly influence splicing outcomes. Our findings emphasize the critical importance of conducting splicing analysis within the broader genomic sequence context of the study gene and highlight the inherent uncertainties associated with intermediate SpliceAI scores (0.20 to 0.80). This study contributes to the field by being the first to prospectively interpret all potential coding SNVs in a disease-associated gene with a high degree of accuracy, representing a meaningful attempt at shifting from retrospective to prospective variant analysis in the era of exome and genome sequencing.

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Code inside the codon: The role of synonymous mutations in regulating splicing machinery and its impact on disease

Cited by 19 publications

References 164 publications

Genome‐wide association study of growth traits and validation of key mutations (MSTN c.C861T) associated with the muscle mass of meat pigeons

Genome‐wide association study of growth traits and validation of key mutations (MSTN c.C861T) associated with the muscle mass of meat pigeons

Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation

Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1 coding variants

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