Comprehensive Evolutionary Analysis of Complete Epstein–Barr Virus Genomes from Argentina and Other Geographies

Blazquez, A. C.; Berenstein, Ariel; Torres, Carolina; Izquierdo, Agustín; Lezama, Carol; Moscatelli, Guillermo; Matteo, Elena Noemí de; Lorenzetti, Mario Alejandro; Preciado, María Victoria

doi:10.3390/v13061172

Cited by 12 publications

(13 citation statements)

References 42 publications

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“…We present a detailed phylogenetic analysis of EBV genomic sequences of samples obtained from Africa (primarily from BL patients) analyzed together with non-African EBV clades from elsewhere ( 26 ). Our EBV genomic and LMP-1 findings confirm impressions from earlier studies ( 23 , 24 , 38 , 40 , 41 , 48 , 49 ) that EBV from Africa is genetically separate from EBV in Asia. Our results also confirm that there is extensive genetic diversity in LMP-1 , as previously suspected ( 25 – 27 ).…”

Section: Discussionsupporting

confidence: 90%

“…The scale bar of phylogenetic distance (0.006) indicates high similarity of the sequences of EBV genomes. The tree shows, as has been reported in several previous reports ( 24 , 38 , 40 , 41 , 48 ), that the sequences of EBV from Africa are genetically separate from those in Asia. The phylogenetic tree shows four major genetic branches in EBV from Africa and two genetic branches in EBV from Asia, of which one branch splits into two sub-branches.…”

Section: Resultssupporting

confidence: 80%

“…LMP-1 has been linked to biological changes that influence transmission, transformation, and tumor microenvironment ( 65 ). Phylogenetic studies have revealed distinct phylogroups of EBV ( 23 , 24 , 38 , 40 , 41 , 48 , 49 ), and principle components analysis of WGS data has identified SNVs that are correlated with ancestry ( 48 ). However, access to HTS is still limited, especially for large epidemiological studies conducted in Africa, where eBL is a public health problem.…”

Section: Discussionmentioning

confidence: 99%

“…The 219 complete genomes were aligned by MAFFT v7 (36), installed on the NIH high-performance computing (HPC) Biowulf cluster, and the MSA file (https://github.com/smbulaiteye/ EBVBL_Africa_focus.git) was used to construct unrooted phylogenetic trees using the Neighbor-Joining (NJ) and the Jukes-Cantor method to measure the genetic distance of the aligned sequences. Although the NJ method may not be optimal for calculating the phylogenetic distance or accurately characterizing consequences of evolutionary diversification (37), this was not the focus of our paper because EBV evolution has been addressed in several recent excellent reports (24,(38)(39)(40)(41). We utilized the NJ method because it has reasonable performance and accuracy for studies of genotype clades and geographic and/or phenotype patterns (42).…”

Section: Methods Ebv Samples Compiled To Study Genomic Variationsmentioning

confidence: 99%

“…The successful whole genome sequencing (WGS) of EBV samples ( 13 , 20 , 21 ) and increasing access to high-throughput sequencing (HTS) data of EBV from tumor and non-tumor samples present new opportunities to investigate genomic variations of EBV that may be associated with EBV-associated cancers. HTS studies have been utilized to discover genomic variations in EBV associated with NPC ( 22 , 23 ) and to investigate EBV genomic variations in samples from regions that were previously underrepresented, such as South America ( 24 ), and genomic variations in EBV from Africa or from BL ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

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Epstein-Barr Virus in Burkitt Lymphoma in Africa Reveals a Limited Set of Whole Genome and LMP-1 Sequence Patterns: Analysis of Archival Datasets and Field Samples From Uganda, Tanzania, and Kenya

et al. 2022

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Epstein-Barr virus (EBV) is associated with endemic Burkitt lymphoma (eBL), but the contribution of EBV variants is ill-defined. Studies of EBV whole genome sequences (WGS) have identified phylogroups that appear to be distinct for Asian versus non-Asian EBV, but samples from BL or Africa, where EBV was first discovered, are under-represented. We conducted a phylogenetic analysis of EBV WGS and LMP-1 sequences obtained primarily from BL patients in Africa and representative non-African EBV from other conditions or regions using data from GenBank, Sequence Read Archive, or Genomic Data Commons for the Burkitt Lymphoma Genome Sequencing Project (BLGSP) to generate data to support the use of a simpler biomarker of geographic or phenotypic associations. We also investigated LMP-1 patterns in 414 eBL cases and 414 geographically matched controls in the Epidemiology of Burkitt Lymphoma in East African children and minors (EMBLEM) study using LMP-1 PCR and Sanger sequencing. Phylogenetic analysis revealed distinct genetic patterns of African versus Asian EBV sequences. We identified 281 single nucleotide variations (SNVs) in LMP-1 promoter and coding region, which formed 12 unique patterns (A to L). Nine patterns (A, AB, C, D, F, I, J, K and L) predominated in African EBV, of which four were found in 92% of BL samples (A, AB, D, and H). Predominant patterns were B and G in Asia and H in Europe. EBV positivity in peripheral blood was detected in 95.6% of EMBLEM eBL cases versus 79.2% of the healthy controls (odds ratio [OR] =3.83; 95% confidence interval 2.06-7.14). LMP-1 was successfully sequenced in 66.7% of the EBV DNA positive cases but in 29.6% of the controls (ORs ranging 5-11 for different patterns). Four LMP-1 patterns (A, AB, D, and K) were detected in 63.1% of the cases versus 27.1% controls (ORs ranges: 5.58-11.4). Dual strain EBV infections were identified in WGS and PCR-Sanger data. In conclusion, EBV from Africa is phylogenetically separate from EBV in Asia. Genetic diversity in LMP-1 formed 12 patterns, which showed promising geographic and phenotypic associations. Presence of multiple strain infection should be considered in efforts to refine or improve EBV markers of ancestry or phenotype.Lay SummaryEpstein-Barr virus (EBV) infection, a ubiquitous infection, contributes to the etiology of both Burkitt Lymphoma (BL) and nasopharyngeal carcinoma, yet their global distributions vary geographically with no overlap. Genomic variation in EBV is suspected to play a role in the geographical patterns of these EBV-associated cancers, but relatively few EBV samples from BL have been comprehensively studied. We sought to compare phylogenetic patterns of EBV genomes obtained from BL samples in Africa and from tumor and non-tumor samples from elsewhere. We concluded that EBV obtained from BL in Africa is genetically separate from EBV in Asia. Through comprehensive analysis of nucleotide variations in EBV’s LMP-1 gene, we describe 12 LMP-1 patterns, two of which (B and G) were found mostly in Asia. Four LMP-1 patterns (A, AB, D, and F) accounted for 92% of EBVs sequenced from BL in Africa. Our results identified extensive diversity of EBV, but BL in Africa was associated with a limited number of variants identified, which were different from those identified in Asia. Further research is needed to optimize the use of PCR and sequencing to study LMP-1 diversity for classification of EBV variants and for use in epidemiologic studies to characterize geographic and/or phenotypic associations of EBV variants with EBV-associated malignancies, including eBL.

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