Summary auto-generated
This study examined sequence divergence of the measles virus (MV) haemagglutinin (H) gene in 75 strains, including wild-type isolates, vaccine strains, and laboratory-adapted variants. Phylogenetic analysis confirmed that MV genotypes identified using the H gene matched those previously established using the nucleocapsid (N) gene, validating both genetic markers for genotype classification. In Madrid, Spain, researchers documented multiple abrupt genotype switches over 25 years, including a complete replacement of genotype C2 with D3 between July and October 1993. Notably, MV showed extremely low mutation rates during epidemics (approximately 4-6×10⁻⁴ nucleotide substitutions per site annually in the H gene), which is an order of magnitude lower than influenza virus mutation rates. The low ratio of non-synonymous to synonymous mutations suggested that adaptive immune selection did not drive H gene divergence during circulation in populations. Adaptation of MV to different primate cell cultures resulted in minimal H gene changes, whereas adaptation to rodent brain tissue produced substantial sequence alterations. No evidence of recombination between MV genotypes was found.
Key findings
- Phylogenetic analysis of H gene sequences produced genotype groupings identical to those based on N gene sequences, confirming both genes are valid genotyping markers
- MV mutation rate in the H gene during epidemics (~4-6×10⁻⁴ per nucleotide per year) is approximately 10-fold lower than human influenza A virus, indicating MV is an extremely stable virus
- Madrid experienced four distinct genotype switches since the late 1960s, with complete replacement of genotype C2 by D3 between July-October 1993, suggesting importation of new virus strains rather than local evolution
- Adaptation to primate cell cultures produced minimal H gene changes, whereas rodent brain adaptation caused substantial mutations with strong selective pressure for amino acid sequence changes
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Abstract
Phylogenetic analysis of the sequence of the H gene of 75 measles virus (MV) strains (32 published and 43 new sequences) was carried out. The lineage groups described from comparison of the nucleotide sequences encoding the C-terminal regions of the N protein of MV were the same as those derived from the H gene sequences in almost all cases. The databases document a number of distinct genotype switches that have occurred in Madrid (Spain). Well-documented is the complete replacement of lineage group C2, the common European genotype at that time, with that of group D3 around the autumn of 1993. No further isolations of group C2 took place in Madrid after this time. The rate of mutation of the H gene sequences of MV genotype D3 circulating in Madrid from 1993 to 1996 was very low (5 x 10(-4) per annum for a given nucleotide position). This is an order of magnitude lower than the rates of mutation observed in the HN genes of human influenza A viruses. The ratio of expressed over silent mutations indicated that the divergence was not driven by immune selection in this gene. Variations in amino acid 117 of the H protein (F or L) may be related to the ability of some strains to haemagglutinate only in the presence of salt. Adaptation of MV to different primate cell types was associated with very small numbers of mutations in the H gene. The changes could not be predicted when virus previously grown in human B cell lines was adapted to monkey Vero cells. In contrast, rodent brain-adapted viruses displayed a lot of amino acid sequence variation from normal MV strains. There was no convincing evidence for recombination between MV genotypes.