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Cited by 28RNA Research and SplicingGenetic Associations and EpidemiologyGenomics and Rare Diseases

Expression changes confirm genomic variants predicted to result in allele-specific, alternative mRNA splicing

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Mucaki, Eliseos J., Shirley, Ben C., Rogan, Peter K.·2020·Frontiers in Genetics
DOI 10.3389/fgene.2020.00109PMC PMC7066660

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Abstract

Splice isoform structure and abundance can be affected by either noncoding or masquerading coding variants that alter the structure or abundance of transcripts. When these variants are common in the population, these nonconstitutive transcripts are sufficiently frequent so as to resemble naturally occurring, alternative mRNA splicing. Prediction of the effects of such variants has been shown to be accurate using information theory-based methods. Single nucleotide polymorphisms (SNPs) predicted to significantly alter natural and/or cryptic splice site strength were shown to affect gene expression. Splicing changes for known SNP genotypes were confirmed in HapMap lymphoblastoid cell lines with gene expression microarrays and custom designed q-RT-PCR or TaqMan assays. The majority of these SNPs (15 of 22) as well as an independent set of 24 variants were then subjected to RNAseq analysis using the ValidSpliceMut web beacon (http://validsplicemut.cytognomix.com), which is based on data from the Cancer Genome Atlas and International Cancer Genome Consortium. SNPs from different genes analyzed with gene expression microarray and q-RT-PCR exhibited significant changes in affected splice site use. Thirteen SNPs directly affected exon inclusion and 10 altered cryptic site use. Homozygous SNP genotypes resulting in stronger splice sites exhibited higher levels of processed mRNA than alleles associated with weaker sites. Four SNPs exhibited variable expression among individuals with the same genotypes, masking statistically significant expression differences between alleles. Genome-wide information theory and expression analyses (RNAseq) in tumor exomes and genomes confirmed splicing effects for 7 of the HapMap SNP and 14 SNPs identified from tumor genomes. q-RT-PCR resolved rare splice isoforms with read abundance too low for statistical significance in ValidSpliceMut. Nevertheless, the web-beacon provides evidence of unanticipated splicing outcomes, for example, intron retention due to compromised recognition of constitutive splice sites. Thus, ValidSpliceMut and q-RT-PCR represent complementary resources for identification of allele-specific, alternative splicing.

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  • The majority of noncoding variants are involved in the production of aberrant transcripts through exon skipping, cryptic site use, or intron retention.

    “The majority of noncoding variants are involved in the production of aberrant transcripts through exon skipping, cryptic site use, or intron retention [44].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [44]

    The Introduction says the majority of mutations in a set of validated splice-variant predictions were associated with exon skipping, cryptic site use, or intron retention. It does not extend that finding to the majority of all noncoding variants, and it classifies some resulting isoforms as alternative rather than aberrant. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Mucaki, E. J., Shirley, B. C., & Rogan, P. K.
Affiliations
Western University (CA)
Corresponding author
Rogan, Peter K.
ORCID
Venue
Frontiers in Genetics
Publisher
Frontiers Media SA
Published
2020-03-05
Volume
11
Pages
109-109
ISSN
1664-8021 (ISSN-L)
DOI
10.3389/fgene.2020.00109
PMC
PMC7066660
OpenAlex
W3009285026
Cited by
28
References
2
Citations by year
2026: 1 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 3 · 2020: 2 · 2019: 2
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Scholarship@Western (Western University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-06290)
  • Canada Research Chairs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
single nucleotide polymorphisms, cryptic splice site, splice site strength, exon inclusion, intron retention, gene expression, splice variants

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