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Current Bioinformatics


ISSN (Print): 1574-8936
ISSN (Online): 2212-392X

Research Article

Analysis of Codon Usage Patterns in the Human Papillomavirus Oncogenes

Author(s): Myeongji Cho, Hayeon Kim, Mikyeong Je and Hyeon S. Son*

Volume 16, Issue 1, 2021

Published on: 14 June, 2020

Page: [13 - 23] Pages: 11

DOI: 10.2174/1574893615999200614173136

Price: $65


Background: Persistent high-risk genital human papillomavirus (HPV) infection is a major cause of cervical cancer in women. The products of the viral transforming genes E6 and E7 in the high-risk HPVs are known to be similar in their amino acid composition and structure. We performed a comparative analysis of codon usage patterns in the E6 and E7 genes of HPVs.

Methods: The E6 and E7 gene sequences of eight HPV subtypes were analyzed to determine their nucleotide composition, relative synonymous codon usage (RSCU), effective number of codons (ENC), neutrality, genetic variability, selection pressure, and codon adaptation index (CAI). Additionally, a correspondence analysis (CoA) was performed.

Results: The analysis to determine the effects of differences in composition on the codon usage patterns revealed that there might be usage bias for ‘A’ nucleotides. This was consistent with the results of the RSCU analysis, which demonstrated that the selection of A/T-rich patterns and the preference for A/T-ended codons in HPVs are influenced by compositional constraints. Moreover, the results reveal that selection pressure plays an important role in the CoA results for the RSCU values, Tajima’s D tests, and neutrality tests.

Conclusion: The results of this study are consistent with previous findings that most papillomavirus genes are under purifying selection pressure, which limits changes to the encoded proteins. Natural selection and mutation pressures resulting in changes in the nucleotide composition and codon usage bias in the two tumor genes of HPV act differently during the evolution of the HPV subtype; thus, throughout the viral life cycle, HPV can constantly evolve to adapt to a new environment.

Keywords: Human papillomavirus, E6, E7, codon usage pattern, RSCU, natural selection.

Graphical Abstract
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[] [PMID: 30207593]
Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003; 16(1): 1-17.
[] [PMID: 12525422]
Okunade KS. Human papillomavirus and cervical cancer. J Obstet Gynaecol 2020; 40:(5): 602-8.
Unger ER, Barr E. Human papillomavirus and cervical cancer. Emerg Infect Dis 2004; 10(11): 2031-2.
[] [PMID: 16010736]
Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189(1): 12-9.
[<12::AID-PATH431>3.0.CO;2-F] [PMID: 10451482]
Crook T, Tidy JA, Vousden KH. Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell 1991; 67(3): 547-56.
[] [PMID: 1657399]
Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989; 243(4893): 934-7.
[] [PMID: 2537532]
Münger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002; 89(2): 213-28.
[] [PMID: 12445661]
Wu Y, Chen Y, Li L, Yu G, He Y, Zhang Y. Analysis of mutations in the E6/E7 oncogenes and L1 gene of human papillomavirus 16 cervical cancer isolates from China. J Gen Virol 2006; 87(Pt 5): 1181-8.
[] [PMID: 16603519]
Heck DV, Yee CL, Howley PM, Münger K. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci USA 1992; 89(10): 4442-6.
[] [PMID: 1316608]
Sharp PM, Li WH. Codon usage in regulatory genes in Escherichia coli does not reflect selection for ‘rare’ codons. Nucleic Acids Res 1986; 14(19): 7737-49.
[] [PMID: 3534792]
Sharp PM, Li WH. An evolutionary perspective on synonymous codon usage in unicellular organisms. J Mol Evol 1986; 24(1-2): 28-38.
[] [PMID: 3104616]
Wong EH, Smith DK, Rabadan R, Peiris M, Poon LL. Codon usage bias and the evolution of influenza A viruses. codon usage biases of influenza virus. BMC Evol Biol 2010; 10: 253.
[] [PMID: 20723216]
Wright F. The ‘effective number of codons’ used in a gene. Gene 1990; 87(1): 23-9.
[] [PMID: 2110097]
Comeron JM, Aguadé M. An evaluation of measures of synonymous codon usage bias. J Mol Evol 1998; 47(3): 268-74.
[] [PMID: 9732453]
Librado P, Rozas J. DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 2009; 25(11): 1451-2.
[] [PMID: 19346325]
Kumar S, Stecher G, Tamura K. MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol 2016; 33(7): 1870-4.
[] [PMID: 27004904]
Madeira F, Park YM, Lee J, et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 2019; 47(W1): W636-41.
[] [PMID: 30976793]
Katoh K, Rozewicki J, Yamada KD. MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization. Brief Bioinform 2019; 20(4): 1160-6.
[] [PMID: 28968734]
Sharp PM, Li WH. The codon Adaptation Index--a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res 1987; 15(3): 1281-95.
[] [PMID: 3547335]
Nakamura Y, Gojobori T, Ikemura T. Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res 2000; 28(1): 292.
[] [PMID: 10592250]
Puigbò P, Bravo IG, Garcia-Vallve S. CAIcal: a combined set of tools to assess codon usage adaptation. Biol Direct 2008; 3: 38.
[] [PMID: 18796141]
Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 1989; 123(3): 585-95.
[PMID: 2513255]
Biswas S, Akey JM. Genomic insights into positive selection. Trends Genet 2006; 22(8): 437-46.
[] [PMID: 16808986]
Tsompana M, Abad J, Purugganan M, Moyer JW. The molecular population genetics of the Tomato spotted wilt virus (TSWV) genome. Mol Ecol 2005; 14(1): 53-66.
[] [PMID: 15643950]
Moradi Z, Nazifi E, Mehrvar M. Occurrence and evolutionary analysis of coat protein gene sequences of Iranian isolates of Sugarcane mosaic virus. Plant Pathol J 2017; 33(3): 296-306.
[] [PMID: 28592948]
Cladel NM, Bertotto A, Christensen ND. Human alpha and beta papillomaviruses use different synonymous codon profiles. Virus Genes 2010; 40(3): 329-40.
[] [PMID: 20157772]
Zhao KN, Chen J. Codon usage roles in human papillomavirus. Rev Med Virol 2011; 21(6): 397-411.
[] [PMID: 22025363]
Pepin KM, Domsic J, McKenna R. Genomic evolution in a virus under specific selection for host recognition. Infect Genet Evol 2008; 8(6): 825-34.
[] [PMID: 18804189]
Zhao KN, Liu WJ, Frazer IH. Codon usage bias and A+T content variation in human papillomavirus genomes. Virus Res 2003; 98(2): 95-104.
[] [PMID: 14659556]
Ikemura T. Codon usage and tRNA content in unicellular and multicellular organisms. Mol Biol Evol 1985; 2(1): 13-34.
[PMID: 3916708]
Van Doorslaer K. Evolution of the papillomaviridae. Virology 2013; 445(1-2): 11-20.
[] [PMID: 23769415]
Rozenblatt-Rosen O, Deo RC, Padi M, et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 2012; 487(7408): 491-5.
[] [PMID: 22810586]
White EA, Howley PM. Proteomic approaches to the study of papillomavirus-host interactions. Virology 2013; 435(1): 57-69.
[] [PMID: 23217616]
White EA, Kramer RE, Tan MJ, Hayes SD, Harper JW, Howley PM. Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J Virol 2012; 86(24): 13174-86.
[] [PMID: 23015706]
White EA, Sowa ME, Tan MJ, et al. Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proc Natl Acad Sci USA 2012; 109(5): E260-7.
[] [PMID: 22232672]
Zanier K, Charbonnier S, Sidi AO, et al. Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science 2013; 339(6120): 694-8.
[] [PMID: 23393263]
Carvajal-Rodríguez A. Detecting recombination and diversifying selection in human alpha-papillomavirus. Infect Genet Evol 2008; 8(5): 689-92.
[] [PMID: 18675939]
Chen Z, Terai M, Fu L, Herrero R, DeSalle R, Burk RD. Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses. J Virol 2005; 79(11): 7014-23.
[] [PMID: 15890941]
DeFilippis VR, Ayala FJ, Villarreal LP. Evidence of diversifying selection in human papillomavirus type 16 E6 but not E7 oncogenes. J Mol Evol 2002; 55(4): 491-9.
[] [PMID: 12355268]
Ghittoni R, Accardi R, Hasan U, Gheit T, Sylla B, Tommasino M. The biological properties of E6 and E7 oncoproteins from human papillomaviruses. Virus Genes 2010; 40(1): 1-13.
[] [PMID: 19838783]
Sharp PM, Emery LR, Zeng K. Forces that influence the evolution of codon bias. Philos Trans R Soc Lond B Biol Sci 2010; 365(1544): 1203-12.
[] [PMID: 20308095]
Seo SH, Jin HT, Park SH, Youn JI, Sung YC. Optimal induction of HPV DNA vaccine-induced CD8+ T cell responses and therapeutic antitumor effect by antigen engineering and electroporation. Vaccine 2009; 27(42): 5906-12.
[] [PMID: 19651174]
Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer 2002; 2(1): 59-65.
[] [PMID: 11902586]

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