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Temporal landscape of mutational frequencies in SARS-CoV-2 genomes of Bangladesh: possible implications from the ongoing outbreak in Bangladesh.

ABSTRACT: Along with intrinsic evolution, adaptation to selective pressure in new environments might have resulted in the circulatory SARS-CoV-2 strains in response to the geoenvironmental conditions of a country and the demographic profile of its population. With this target, the current study traced the evolutionary route and mutational frequency of 198 Bangladesh-originated SARS-CoV-2 genomic sequences available in the GISAID platform over a period of 13 weeks as of 14 July 2020. The analyses were performed using MEGA X, Swiss Model Repository, Virus Pathogen Resource and Jalview visualization. Our analysis identified that majority of the circulating strains strikingly differ from both the reference genome and the first sequenced genome from Bangladesh. Mutations in nonspecific proteins (NSP2-3, NSP-12(RdRp), NSP-13(Helicase)), S-Spike, ORF3a, and N-Nucleocapsid protein were common in the circulating strains with varying degrees and the most unique mutations (UM) were found in NSP3 (UM-18). But no or limited changes were observed in NSP9, NSP11, Envelope protein (E) and accessory factors (NSP7a, ORF 6, ORF7b) suggesting the possible conserved functions of those proteins in SARS-CoV-2 propagation. However, along with D614G mutation, more than 20 different mutations in the Spike protein were detected basically in the S2 domain. Besides, mutations in SR-rich region of N protein and P323L in RDRP were also present. However, the mutation accumulation showed a significant association (p = 0.003) with sex and age of the COVID-19-positive cases. So, identification of these mutational accumulation patterns may greatly facilitate vaccine development deciphering the age and the sex-dependent differential susceptibility to COVID-19.

SUBMITTER: Saha O

PROVIDER: S-EPMC8274265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:During the long history of biological evolution, genome structures have undergone enormous changes. Nevertheless, some traits or vestiges of the primordial genome (defined as the most primitive nucleic acid genome for life on earth in this paper) may remain in modern genetic systems. It is of great importance to find these traits or vestiges for the study of the origin and evolution of genomes. As the shorter is a sequence, the less probable it would be modified during genome evolution. And if mutated, it would be easier to reappear at the same site or another site. Consequently, the genomic frequencies of very short nucleotide sequences, such as dinucleotides, would have considerable chances to be conserved during billions of years of evolution. Prokaryotic genomes are very diverse and with a wide range of GC content. Therefore, in order to find traits or vestiges of the primordial genome remained in modern genetic systems, we have studied the characteristics of dinucleotide frequencies across bacterial and archaeal genomes. We analyzed the dinucleotide frequency patterns of the whole-genome sequences from more than 1300 prokaryotic species (bacterial and archaeal genomes available as of December 2012). The results show that the frequencies of the dinucleotides AC, AG, CA, CT, GA, GT, TC, and TG are well-conserved across various genomes, while the frequencies of other dinucleotides vary considerably among species. The dinucleotide frequency conservation/variation pattern seems to correlate with the distributions of dinucleotides throughout a genome and across genomes. Further analysis indicates that the phenomenon would be determined by strand symmetry of genomic sequences (the second parity rule) and GC content variations among genomes. We discussed some possible origins of strand symmetry. And we propose that the phenomenon of frequency conservation of some dinucleotides may provide insights into the genomic composition of the primordial genetic system.

Project description:BackgroundHigh tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.MethodsIn this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.ResultsWe demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.ConclusionsThese results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.

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Temporal landscape of mutational frequencies in SARS-CoV-2 genomes of Bangladesh: possible implications from the ongoing outbreak in Bangladesh.

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