Genetic diversity and evolution of Hantaan virus in China and its neighbors

Abstract

Background: Hantaan virus (HTNV; family Hantaviridae, order Bunyavirales) causes hemorrhagic fever with renal syndrome (HFRS), which has raised serious concerns in Eurasia, especially in China, Russia, and South Korea. Previous studies reported genetic diversity and phylogenetic features of HTNV in different parts of China, but the analyses from the holistic perspective are rare.

Methodology and principal findings: To better understand HTNV genetic diversity and gene evolution, we analyzed all available complete sequences derived from the small (S) and medium (M) segments with bioinformatic tools. Eleven phylogenetic groups were defined and showed geographic clustering; 42 significant amino acid variant sites were found, and 19 of them were located in immune epitopes; nine recombinant events and eight reassortments with highly divergent sequences were found and analyzed. We found that sequences from Guizhou showed high genetic divergence, contributing to multiple lineages of the phylogenetic tree and also to the recombination and reassortment events. Bayesian stochastic search variable selection analysis revealed that Heilongjiang, Shaanxi, and Guizhou played important roles in HTNV evolution and migration; the virus may originate from Zhejiang Province in the eastern part of China; and the virus population size expanded from the 1980s to 1990s.

Conclusions/significance: These findings revealed the original and evolutionary features of HTNV, which will help to illustrate hantavirus epidemic trends, thus aiding in disease control and prevention.

Fig 1. Map showing the sampling dates and geographic distribution of HTNV isolates included in this study.

The geographic distribution of the HTNV isolates analyzed in this study. The size of a pie represents the number of isolates in the corresponding region. The pie slices are colored according to the sampling years. AH, Anhui; GD, Guangdong; GZ, Guizhou; HB, Hubei; HLJ, Heilongjiang; HN, Hunan; HTNV, Hantaan virus; JL, Jilin; JS, Jiangsu; JX, Jiangxi; LN, Liaoning; RUS, Russia; SC, Sichuan; SD, Shandong; SK, South Korea; SX, Shaanxi; TJ, Tianjin; YN, Yunnan; ZJ, Zhejiang. Map source: Natural Earth (https://www.naturalearthdata.com/).

Fig 2. Phylogenetic trees of S and M genes reconstructed by MrBayes.

Posterior node probabilities/SH-like approximate likelihood values/ultrafast bootstrap values for major nodes (black circles) are shown. Split network analysis of HTNV was also shown. The region and host features for each sample were labeled after the strains’ names. The brackets below the group name indicated the regions associated to each group. AH, Anhui; GD, Guangdong; GZ, Guizhou; HB, Hubei; HLJ, Heilongjiang; HN, Hunan; HTNV, Hantaan virus; JL, Jilin; JS, Jiangsu; JX, Jiangxi; LN, Liaoning; M, medium; RUS, Russia; S, small; SC, Sichuan; SD, Shandong; SK, South Korea; SX, Shaanxi; TJ, Tianjin; YN, Yunnan; ZJ, Zhejiang.

Fig 3. The “significant amino acid marker” of each group.

The specific amino acid sites of each group are marked by different colors. NP, nucleocapsid protein.

Fig 4. The MCC tree, root state posterior probabilities, and effective population sizes of HTNV.

(A) MCC tree showing the evolutionary relationships and timescale of HTNV. Branch colors denote inferred location states, as shown in the legend. The most recent common ancestor and 95% credibility intervals are shown near the node. The root state posterior probabilities for the different regions were shown in the histogram. (B) A map with each region colored by the root state posterior probability. (C) Bayesian skyline plot showing population size through time for HTNV. Highlighted areas correspond to 95% HPD intervals. HPD, highest posterior density; HTNV, Hantaan virus; MCC, maximum clade credibility. Map source: Natural Earth (https://www.naturalearthdata.com/).

Fig 5. Reconstructed phylogeographic linkage and the total number of location state transitions of HTNV.

(A) The phylogeographic linkage constructed reconstruction of the HTNV using BEAST. Color of lines represents the Bayes factor of migration between two regions. The map was created by SpreadD3 software, and the geographic data were provided by Natural Earth (https://www.naturalearthdata.com/). (B) Histogram of the total number of location state transitions inferred from the HTNV data set. BEAST, Bayesian evolutionary analysis sampling trees; HTNV, Hantaan virus.