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Journal of Applied Genetics Aug 2018Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and... (Review)
Review
Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. This article summarizes the current knowledge about the "splicing mutations" and methods that help to identify such changes in clinical diagnosis.
Topics: Algorithms; Computational Biology; Computer Simulation; DNA Mutational Analysis; Exons; Genetic Diseases, Inborn; Humans; Introns; Mutation; Point Mutation; Pyrimidine Nucleotides; RNA Splice Sites; RNA Splicing
PubMed: 29680930
DOI: 10.1007/s13353-018-0444-7 -
American Journal of Human Genetics Mar 2000More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all...
More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, <20% represent C-->T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.
Topics: Cohort Studies; Conserved Sequence; CpG Islands; DNA Mutational Analysis; Exons; GTPase-Activating Proteins; Genes, Neurofibromatosis 1; Genetic Variation; Germany; Humans; Introns; Kinetics; Mutation; Mutation, Missense; Neurofibromatosis 1; Neurofibromin 1; Protein Structure, Tertiary; Proteins; Pseudogenes; RNA Splicing
PubMed: 10712197
DOI: 10.1086/302809 -
Nature Oct 2008Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the...
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
Topics: Adenocarcinoma, Bronchiolo-Alveolar; Female; Gene Dosage; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Male; Mutation; Proto-Oncogenes
PubMed: 18948947
DOI: 10.1038/nature07423 -
WormBook : the Online Review of C.... Sep 2005A genetic enhancer is a mutation in one gene that intensifies the phenotype caused by a mutation in another gene. The phenotype of the double mutant is much stronger... (Review)
Review
A genetic enhancer is a mutation in one gene that intensifies the phenotype caused by a mutation in another gene. The phenotype of the double mutant is much stronger than the summation of the single mutant phenotypes. The isolation of enhancers can lead to the identification of interacting genes, including genes that act redundantly with respect to each other. Examples in Caenorhabditis elegans of dominant enhancers are presented first, followed by a review of recessive enhancers of null mutations. In some of these cases, the interacting genes are related in structure and function, but in other cases, the interacting genes are nonhomologous. Recessive enhancers of non-null mutations can also be useful. A powerful advance for the identification of recessive enhancers is genome-wide screening based on RNA interference.
Topics: Animals; Caenorhabditis elegans; Enhancer Elements, Genetic; Genes, Helminth; Genes, Recessive; Mutation
PubMed: 18023119
DOI: 10.1895/wormbook.1.27.1 -
Cold Spring Harbor Perspectives in... Feb 2015Changes in gene copy number are among the most frequent mutational events in all genomes and were among the mutations for which a physical basis was first known. Yet... (Review)
Review
Changes in gene copy number are among the most frequent mutational events in all genomes and were among the mutations for which a physical basis was first known. Yet mechanisms of gene duplication remain uncertain because formation rates are difficult to measure and mechanisms may vary with position in a genome. Duplications are compared here to deletions, which seem formally similar but can arise at very different rates by distinct mechanisms. Methods of assessing duplication rates and dependencies are described with several proposed formation mechanisms. Emphasis is placed on duplications formed in extensively studied experimental situations. Duplications studied in microbes are compared with those observed in metazoan cells, specifically those in genomes of cancer cells. Duplications, and especially their derived amplifications, are suggested to form by multistep processes often under positive selection for increased copy number.
Topics: DNA; DNA Transposable Elements; Gene Amplification; Gene Deletion; Gene Dosage; Gene Duplication; Genes, Bacterial; Inverted Repeat Sequences; Models, Genetic; Mutation Rate; Plasmids
PubMed: 25646380
DOI: 10.1101/cshperspect.a016592 -
Cell May 2019Recent studies of the tumor genome seek to identify cancer pathways as groups of genes in which mutations are epistatic with one another or, specifically, "mutually... (Review)
Review
Recent studies of the tumor genome seek to identify cancer pathways as groups of genes in which mutations are epistatic with one another or, specifically, "mutually exclusive." Here, we show that most mutations are mutually exclusive not due to pathway structure but to interactions with disease subtype and tumor mutation load. In particular, many cancer driver genes are mutated preferentially in tumors with few mutations overall, causing mutations in these cancer genes to appear mutually exclusive with numerous others. Researchers should view current epistasis maps with caution until we better understand the multiple cause-and-effect relationships among factors such as tumor subtype, positive selection for mutations, and gross tumor characteristics including mutational signatures and load.
Topics: Algorithms; Computational Biology; Epistasis, Genetic; Genes, Neoplasm; Humans; Models, Genetic; Mutation; Neoplasms; Oncogenes
PubMed: 31150618
DOI: 10.1016/j.cell.2019.05.005 -
Gerontology 2012There is mounting evidence for an age-dependent accumulation of somatic mutations as a result of the inherent imperfection of DNA replication and repair. A possible... (Review)
Review
BACKGROUND
There is mounting evidence for an age-dependent accumulation of somatic mutations as a result of the inherent imperfection of DNA replication and repair. A possible age-related decline in genome maintenance systems may exacerbate this age-related loss of genome integrity. A review of the current methods of mutation detection is timely in view of the lack of insight as to the magnitude of somatic mutation accumulation, the types of mutations that accumulate, and their functional consequences.
OBJECTIVE
In this paper we review the current methods for measuring genome instability in organisms during aging or in relation to life span.
METHODS
The review is based on established and novel concepts from the existing literature, with some examples from our own laboratory.
RESULTS
Studies using cytogenetic assays and endogenous or transgenic mutation reporter assays provide strong evidence for age-related increases of different types of mutations in animals and humans during aging. This increase in DNA mutations is tissue-specific and also differs between species.
CONCLUSION
Today, our knowledge of somatic mutation profiles in aging is mainly derived from cytogenetics and the use of endogenous and transgenic mutation reporter assays. The emergence of new approaches, most notably massively parallel sequencing, will give us deeper insight into the nature of spontaneous genome instability and its possible causal relationship to aging and age-related disease.
Topics: Aging; Aneuploidy; Animals; Animals, Genetically Modified; DNA Damage; DNA Mutational Analysis; DNA Repair; Genes, Reporter; Genomic Instability; Humans; Models, Genetic; Mutation
PubMed: 22156741
DOI: 10.1159/000334368 -
Journal of Clinical Laboratory Analysis 1997Cellular protooncogenes, tumor suppressor genes (antioncogenes), and DNA mismatch repair mutators are generally the key molecular genetic biomarkers undergoing... (Review)
Review
Cellular protooncogenes, tumor suppressor genes (antioncogenes), and DNA mismatch repair mutators are generally the key molecular genetic biomarkers undergoing alterations during carcinogenesis, i.e., activation of oncogenes, inactivation of tumor suppressors, and DNA mismatch repair gene defects are essential events in cancer causation. In pancreas cancer, high incidence of oncogene K-ras point mutations at the codon 12th is associated with premalignant and malignant transformation. Mutation in p53 tumor suppressor is also detected in pancreas adenocarcinoma. Concurrent loss of p53 and K-ras function may contribute to the clinical aggressiveness of pancreas cancer. Microsatellite instability and DNA mismatch repair defects may represent new mutator phenotype for pancreas carcinogenesis. Mutation of cell cycle regulators, such as inhibitor of CDK4 or p16 tumor suppressor gene, is a new molecular event in pancreas cancer. Mutation of cyclin-dependent kinases also may be involved in pancreas carcinogenesis. Loss or mutation of a new candidate tumor suppressor, DPC4 (deleted in pancreas carcinoma locus 4), is reported in pancreas cancer. The protein products of these gene mutations are potential tumor antigens, thus genotype expression can be detected by phenotype. Most of these emerging molecular genetic biomarkers are associated with regulation of cell growth and recognition, as well as gene expression, and may offer new insight into the cellular precursors to and genesis of pancreas cancer.
Topics: Biomarkers, Tumor; Carrier Proteins; Cell Division; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; DNA Repair; Enzyme Inhibitors; Gene Expression; Genes, Tumor Suppressor; Genes, p53; Genes, ras; Humans; Microsatellite Repeats; Mutation; Pancreatic Neoplasms
PubMed: 9219065
DOI: 10.1002/(sici)1098-2825(1997)11:4<225::aid-jcla9>3.0.co;2-7 -
Genetics Mar 2022Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this...
Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal gene MRP20. Initial results suggested that a single large effect locus influences the mutation's expressivity, with 1 allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutation's expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation.
Topics: Alleles; Genetic Background; Humans; Mutation; Phenotype
PubMed: 35078232
DOI: 10.1093/genetics/iyac013 -
GigaScience Dec 2022Cancer is widely regarded as a complex disease primarily driven by genetic mutations. A critical concern and significant obstacle lies in discerning driver genes amid an...
BACKGROUND
Cancer is widely regarded as a complex disease primarily driven by genetic mutations. A critical concern and significant obstacle lies in discerning driver genes amid an extensive array of passenger genes.
FINDINGS
We present a new method termed DriverMP for effectively prioritizing altered genes on a cancer-type level by considering mutated gene pairs. It is designed to first apply nonsilent somatic mutation data, protein‒protein interaction network data, and differential gene expression data to prioritize mutated gene pairs, and then individual mutated genes are prioritized based on prioritized mutated gene pairs. Application of this method in 10 cancer datasets from The Cancer Genome Atlas demonstrated its great improvements over all the compared state-of-the-art methods in identifying known driver genes. Then, a comprehensive analysis demonstrated the reliability of the novel driver genes that are strongly supported by clinical experiments, disease enrichment, or biological pathway analysis.
CONCLUSIONS
The new method, DriverMP, which is able to identify driver genes by effectively integrating the advantages of multiple kinds of cancer data, is available at https://github.com/LiuYangyangSDU/DriverMP. In addition, we have developed a novel driver gene database for 10 cancer types and an online service that can be freely accessed without registration for users. The DriverMP method, the database of novel drivers, and the user-friendly online server are expected to contribute to new diagnostic and therapeutic opportunities for cancers.
Topics: Humans; Genomics; Reproducibility of Results; Oncogenes; Mutation; Neoplasms
PubMed: 38091511
DOI: 10.1093/gigascience/giad106