Mutational pressure and natural selection in epidermal growth factor receptor gene during germline and somatic mutagenesis in cancer cells

Khrustalev, Vladislav Victorovich; Khrustaleva, Tatyana Aleksandrovna; Poboinev, Victor Vitoldovich; Yurchenko, Konstantin Vyachislavovich

doi:10.1016/j.mrfmmm.2019.03.001

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…To find out the preferable direction of those nucleotide mutations, the numbers of sites with each type of nucleotide substitution were calculated and divided by the usage of a corresponding nucleotide in a reference sequence ( Khrustalev et al, 2019 ). Calculated frequencies of nucleotide mutations were compared with each other.…”

Section: Resultsmentioning

confidence: 99%

Translation-Associated Mutational U-Pressure in the First ORF of SARS-CoV-2 and Other Coronaviruses

et al. 2020

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Within 4 months of the ongoing COVID-19 pandemic caused by SARS-CoV-2, more than 250 nucleotide mutations have been detected in ORF1ab of the virus isolated from infected persons from different parts of the globe. These observations open up an obvious question about the rate and direction of mutational pressure for further vaccine and therapeutics designing. In this study, we did a comparative analysis of ORF1a and ORF1b by using the first isolate (Wuhan strain) as the parent sequence. We observed that most of the nucleotide mutations are C to U transitions. The rate of synonymous C to U transitions is significantly higher than the rate of non-synonymous ones, indicating negative selection on amino acid substitutions. Further, trends in nucleotide usage bias have been investigated in 49 coronaviruses species. A strong bias in nucleotide usage in fourfold degenerate sites toward uracil residues is seen in ORF1ab of all the studied coronaviruses: both in the ORF1a and in the ORF1b translated thanks to the programmed ribosomal frameshifting that has an efficiency of 14 – 45% in different species. A more substantial mutational U-pressure is observed in ORF1a than in ORF1b perhaps because ORF1a is translated more frequently than ORF1b. Mutational U-pressure is there even in ORFs that are not translated from genomic RNA plus strands, but the bias is weaker than in ORF1ab. Unlike other nucleotide mutations, mutational U-pressure caused by cytosine deamination, mostly occurring during the RNA plus strand replication and also translation, cannot be corrected by the proof-reading machinery of coronaviruses. The knowledge generated on the mutational U-pressure that becomes stronger during translation of viral RNA plus strands has implications for vaccine and nucleoside analog development for treating COVID-19 and other coronavirus infections.

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Section: Resultsmentioning

confidence: 99%

Translation-Associated Mutational U-Pressure in the First ORF of SARS-CoV-2 and Other Coronaviruses

et al. 2020

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“…Actually, to test this hypothesis one needs to check mutations in APP gene of the offspring and/or parents of a sequenced individual. Interestingly, the direction of nucleotide usage bias (C4f-bias) is opposite to the preferable direction of germline nucleotide mutations (GC to AT) not only in the APP gene, but in a gene coding for human epidermal growth factor receptor (EGFR) as well (Khrustalev et al, 2019). However, in the last one the rates of germline missense mutations are not signi cantly higher than the rates of synonymous mutations (Khrustalev et al, 2019).…”

Section: Fundamental Questions Raised By the Current Studymentioning

confidence: 99%

Germline mutations directions are different between introns of the same gene: case study of the gene coding for amyloid-beta precursor protein

2022

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Amyloid-beta precursor protein (APP) is highly conserved in mammals. This feature allowed us to compare nucleotide usage biases in 4-fold degenerated sites along the length of its coding region for 146 species of mammals and birds in search of fragments with signi cant deviations. Even though cytosine usage has the highest value in 4-fold degenerated sites in APP coding region from all tested placental mammals, in contrast to marsupial mammals with the bias toward thymine usage, the most frequent germline and somatic mutations in Human APP coding region are C to T and G to A transitions. The same mutational AT-pressure is characteristic for germline mutations in introns of Human APP gene. However, surprisingly, there are several exceptional introns with deviations in germline mutations rates.The most of those introns surround exons with exceptional biases in nucleotide usage in 4-fold degenerated sites. Existence of such fragments in exons 4 and 5, as well as in exon 14, can be connected with the presence of lncRNA genes in complementary strand of DNA. Exceptional nucleotide usage bias in exons 16 and 17 that contain a sequence encoding amyloid-beta peptides can be explained either by the presence of yet unmapped lncRNA(s), or by the autonomous expression of a short mRNA that encodes just C-terminal part of the APP providing an alternative source of amyloid-beta peptides. This hypothesis is supported by the increased rate of T to C transitions in introns 16-17 and 17-18 of Human APP gene relatively to other introns. HighlightsNucleotide usage bias in APP gene coding region is not uniform Some fragments demonstrate higher species-to-species variations Certain introns of Human APP gene accumulate mutations in speci c manner Some anomalies in mutational pressure can be explained by lncRNA expression Autonomous transcription from the 3'-terminal part of the gene is possible

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“…To find out the preferable direction of those nucleotide mutations, the numbers of sites with each type of nucleotide substitution were calculated and divided by the usage of a corresponding nucleotide in a reference sequence 15 . Calculated frequencies of nucleotide mutations were compared with each other.…”

Section: Mutational Pressure In Sars-cov-2 Orf1mentioning

confidence: 99%

Translation-associated mutational U-pressure in the first ORF of SARS-CoV-2 and other coronaviruses

Khrustalev

Giri

Khrustaleva

et al. 2020

Preprint

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Within four months of the ongoing COVID-19 pandemic caused by SARS-CoV-2, more than 250 nucleotide mutations have been detected in the ORF1 of the virus isolated from different parts of the globe. These observations open up an obvious question about the rate and direction of mutational pressure for further vaccine and therapeutics designing. In this study, we did a comparative analysis of ORF1a and ORF1b by using the first isolate (Wuhan strain) as the parent sequence. We observed that most of the nucleotide mutations are C to U transitions. The rate of synonymous C to U transitions is significantly higher than the rate of nonsynonymous ones, indicating negative selection on amino acid substitutions. Further, trends in nucleotide usage bias have been investigated in 49 coronaviruses species. A strong bias in nucleotide usage in fourfold degenerated sites towards uracil residues is seen in ORF1 of all the studied coronaviruses. A more substantial mutational U pressure is observed in ORF1a than in ORF1b owing to the translation of ORF1ab via programmed ribosomal frameshifting. Unlike other nucleotide mutations, mutational U pressure caused by cytosine deamination, mostly occurring in the RNAplus strand, cannot be corrected by the proof-reading machinery of coronaviruses. The knowledge generated on the direction of mutational pressure during translation of viral RNAplus strands has implications for vaccine and nucleoside analogue development for treating covid-19 and other coronavirus infections.

show abstract

Mutational pressure and natural selection in epidermal growth factor receptor gene during germline and somatic mutagenesis in cancer cells

Cited by 6 publications

References 27 publications

Translation-Associated Mutational U-Pressure in the First ORF of SARS-CoV-2 and Other Coronaviruses

Translation-Associated Mutational U-Pressure in the First ORF of SARS-CoV-2 and Other Coronaviruses

Germline mutations directions are different between introns of the same gene: case study of the gene coding for amyloid-beta precursor protein

Translation-associated mutational U-pressure in the first ORF of SARS-CoV-2 and other coronaviruses

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