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Deep Sequencing of MHC-Adapted Viral Lines Reveals Complex Recombinational Exchanges With Endogenous Retroviruses Leading to High-Frequency Variants.
Middlebrook, Earl A; Stark, Derek L; Cornwall, Douglas H; Kubinak, Jason L; Potts, Wayne K.
Affiliation
  • Middlebrook EA; School of Biological Sciences, University of Utah, Salt Lake City, UT, United States.
  • Stark DL; Biosecurity and Public Health, Los Alamos National Laboratory, Los Alamos, NM, United States.
  • Cornwall DH; School of Biological Sciences, University of Utah, Salt Lake City, UT, United States.
  • Kubinak JL; School of Biological Sciences, University of Utah, Salt Lake City, UT, United States.
  • Potts WK; Department of Pathology, University of Utah, Salt Lake City, UT, United States.
Front Genet ; 12: 716623, 2021.
Article de En | MEDLINE | ID: mdl-34512727
ABSTRACT
Experimental evolution (serial passage) of Friend virus complex (FVC) in mice demonstrates phenotypic adaptation to specific host major histocompatibility complex (MHC) genotypes. These evolved viral lines show increased fitness and virulence in their host-genotype-of-passage, but display fitness and virulence tradeoffs when infecting unfamiliar host MHC genotypes. Here, we deep sequence these viral lines in an attempt to discover the genetic basis of FVC adaptation. The principal prediction for genotype-specific adaptation is that unique mutations would rise to high frequency in viral lines adapted to each host MHC genotype. This prediction was not supported by our sequencing data as most observed high-frequency variants were present in each of our independently evolved viral lines. However, using a multi-variate approach to measure divergence between viral populations, we show that populations of replicate evolved viral lines from the same MHC congenic mouse strain were more similar to one another than to lines derived from different MHC congenic mouse strains, suggesting that MHC genotype does predictably act on viral evolution in our model. Sequence analysis also revealed rampant recombination with endogenous murine leukemia virus sequences (EnMuLVs) that are encoded within the BALB/c mouse genome. The highest frequency variants in all six lines contained a 12 bp insertion from a recombinant EnMuLV source, suggesting such recombinants were either being favored by selection or were contained in a recombinational hotspot. Interestingly, they did not reach fixation, as if they are low fitness. The amount of background mutations linked to FVC/EnMuLV variable sites indicated that FVC/EnMuLV recombinants had not reached mutation selection equilibrium and thus, that EnMuLV sequences are likely continuously introgressing into the replicating viral population. These discoveries raise the question is the expression of EnMuLV sequences in mouse splenocytes that permit recombination with exogenous FVC a pathogen or host adaptation?
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Type d'étude: Prognostic_studies Langue: En Journal: Front Genet Année: 2021 Type de document: Article Pays d'affiliation: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Type d'étude: Prognostic_studies Langue: En Journal: Front Genet Année: 2021 Type de document: Article Pays d'affiliation: États-Unis d'Amérique