Rabies and Rabies Virus in Wildlife in Mainland China, 1990–2013

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International Journal of Infectious Diseases 25 (2014) 122–129

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International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Review

Rabies and rabies virus in wildlife in mainland China, 1990–2013

a,b, a,b a,b

Lihua Wang *, Qing Tang , Guodong Liang

State Key Laboratory for Infectious Disease Prevention and Control, Key Laboratory for Medical Virology, National Institute for Viral Disease Control and

Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai St., Changping Dist., Beijing 102206, China

Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China

A R T I C L E I N F O S U M M A R Y

Article history: The number of wildlife rabies and wildlife-associated human and livestock rabies cases has increased in

Received 6 March 2014

recent years, particularly in the southeast and northeast regions of mainland China. To better understand

Received in revised form 17 April 2014

wildlife rabies and its role in human and livestock rabies, we reviewed what is known about wildlife

Accepted 17 April 2014

rabies from the 1990s to 2013 in mainland China. In addition, the genetic diversity and phylogeny of

Corresponding Editor: Eskild Petersen,

available wildlife-originated rabies viruses (RABVs) were analyzed. Several wildlife species carry rabies

Aarhus, Denmark

including the bat, Chinese ferret badger, raccoon dog, rat, fox, and wolf. RABVs have been isolated or

detected in the bat, Chinese ferret badger, raccoon dog, Apodemus, deer, and vole. Among them, the bat,

Keywords: Chinese ferret badger, and raccoon dog may play a role in the ecology of lyssaviruses in mainland China.

Wildlife rabies

All wildlife-originated RABVs were found to belong to genotype 1 RABV except for a bat-originated Irkut

Genetic diversity

virus isolated in 2012. Several substitutions were found between the glycoprotein of wildlife-originated

Phylogeny

RABVs and vaccine strains. Whether these substitutions could affect the efﬁcacy of currently used

Mainland China

vaccines against infections caused by these wildlife-originated RABVs needs to be investigated further.

Phylogenetic analysis showed that RABVs in the bat, Chinese ferret badger, and raccoon dog were distinct

from local dog-originated RABVs, and almost all collected wildlife-originated isolates were associated

with older China clades II to V, suggesting the possibility of wildlife reservoirs in mainland China through

the ages.

ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-

nc-nd/3.0/).

The role of the domestic dog in the spread of RABVs has been

1. Introduction

established in China, and almost 95% of human cases have been

5–9

associated with dog transmission. However, the number of

Rabies is one of the oldest diseases in recorded human history,

wildlife rabies and wildlife-associated human and livestock rabies

dating back more than 4000 years. It occurs in over 150 countries

cases has increased in recent years, particularly in the southeast

and territories. More than 70 000 human rabies deaths occur

and northeast regions of China (Figure 1 and Table 1). The majority

annually, and Asia accounts for approximately 80% of the

have occurred in the most recent 10 years. Viruses have also been

worldwide total. Rabies was ﬁrst reported in about 556 BC and

isolated or detected in wildlife, including the bat, Chinese ferret

has persisted in China for more than 2500 years. Rabies has been 10–20

badger, raccoon dog, Apodemus, deer, vole, and wolf. To better

one of the most important infectious diseases in China since the

understand wildlife rabies and its role in human and livestock

4,5

1950s. Although comprehensive preventive measures have been

rabies, we reviewed what is known about wildlife rabies from the

taken in past decades (including dog vaccination and post-

1990s to 2013 in mainland China. Additionally, the genetic

exposure prophylaxis following human exposure), rabies remains

diversity and phylogeny of available wildlife-originated RABVs

4–7

a signiﬁcant public health problem in mainland China.

were analyzed.

Currently, China is second only to India in the number of people

killed by rabies worldwide, and the epidemic area has expanded to

2. Species of wildlife carrying rabies in mainland China

almost the entire country. Many provinces are beginning to report

5–8

their ﬁrst cases in more than 10 years.

Any warm-blooded animal can catch rabies and pass rabies to

human beings. Dogs are the main vectors of rabies and have

5–9

played a pivotal role in human rabies in mainland China.

* Corresponding author. Tel.: +86 10 58900896; fax: +86 10 58900840.

E-mail address: [email protected] (L. Wang). However rabies has also been reported in wildlife and livestock

http://dx.doi.org/10.1016/j.ijid.2014.04.016

1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129 123

Figure 1. Distribution of wildlife and livestock rabies reported in mainland China from the 1990s to 2013. Species of wildlife and livestock reported to carry rabies are

indicated next to the name of each province. Provinces: AH, Anhui; BJ, Beijing; CQ, Chongqing; FJ, Fujian; HA, Henan; HB, Hebei; HI, Hainan; HLJ, Heilongjiang; HuB, Hubei;

HuN, Hunan; GD, Guangdong; GS, Gansu; GX, Guangxi; GZ, Guizhou; JL, Jilin; JS, Jiangsu; JX, Jiangxi; LN, Liaoning; NM, Inner Mongolia; NX, Ningxia; QH, Qinghai; SC, Sichuan;

SD, Shandong; SH, Shanghai; SN, Shaanxi; SX, Shanxi; TJ, Tianjin; XJ, Xingjiang; XZ, Tibet; YN, Yunnan; ZJ, Zhejiang. CFB, Chinese ferret badger; RD, raccoon dog.

including the Chinese ferret badger, raccoon dog, bat, Apodemus, 2.2. Raccoon dog

deer, vole, fox, wolf, cat, pig, yellow bull, goat, sheep, cattle, buffalo,

and donkey. Cases of wildlife rabies have occurred in both rabies In mainland China, raccoon dogs are distributed widely in the

endemic areas (southeast) and sporadic areas (northeast) of northeastern and southwestern regions of rabies-endemic

14,21

mainland China (Figure 1, Table 1). areas. Two outbreaks of raccoon dog rabies have been recorded

in mainland China. One occurred in the county of Qingyuan of

2.1. Chinese ferret badger Liaoning Province in 1982, causing more than 30 raccoon dog

13 14

deaths. The other occurred in Inner Mongolia in 2007. The

As one of the most popular wildlife animals, Chinese ferret latter outbreak was caused by one wild raccoon dog, and 15

badgers (Melogale moschata) are distributed mostly in the domestic raccoon dogs died. The rabid animals had typical clinical

5,11

southeast region of China. Since 1995, Chinese ferret badger signs of rabies, and samples tested positive by direct ﬂuorescence

rabies outbreaks have occurred periodically in the southeast of assay (DFA), reverse transcription polymerase chain reaction

mainland China, including the provinces of Anhui, Jiangxi, and (RT-PCR), and mouse inoculation test (MIT). Genetic analysis of

Zhejiang. RABVs were ﬁrst detected in Chinese ferret badgers the isolated virus showed that the outbreak was caused by an

collected in Zhejiang Province in 2008, and have since been arctic-like RABV. This was the ﬁrst report of arctic-like RABV in

detected continuously in Chinese ferret badgers (alive and China.

dead) collected in Anhui, Jiangxi, and Zhejiang provinces

12,19,20

(Figure 1, Table 1). Nucleotide sequencing revealed 2.3. Bat

99.4–99.8% homology within the Chinese ferret badger isolates,

and 83–89% homology to the dog RABV isolates in the Other than carnivores, the bat is the most important natural

nucleoprotein and glycoprotein genes in the same rabies- reservoir host of RABVs known today. In recent years, several

12,19,20

endemic regions. In addition, one study showed appar- research groups have conducted long-term studies to investigate

ently healthy Chinese ferret badgers with a high percentage of whether bats carry rabies in mainland China; RABV antibodies

rabies seroconversion (69.6%). Although the titration of virus were detected in the serum of collected bats. Of the bat serum

neutralizing antibodies (VNA) was very low, ranging from 0 to samples collected from four southern provinces (Yunnan, Guangxi,

2.6 IU/ml, the high percentage of rabies seroconversion in Guangdong, and Hainan) of China in 2010, 2.2% (15/685) were

Chinese ferret badgers is an interesting discovery, and could be positive for RABV antibodies. However, no bat-originated

due to abortive rabies infections in the Chinese ferret badger lyssavirus was isolated until 2012: the ﬁrst bat-originated

population. lyssavirus (Irkut virus, IRKV-THChina12; in Murina leucogaster)

124 L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129

Table 1

Summary of reported wildlife rabies and wildlife-associated human rabies in mainland China, 1990–2013

a b

Provinces Counties Period Rabies cases Number Conﬁrmation method Ref.

tested

Chinese ferret ZJ Lishui 2008 1 23 DFA/RT-PCR 19

badger rabies

JX Fuzhou 2009 1 23 DFA/MIT/RT-PCR 12

ZJ, AH, JX / 2010 9 265 FAT/MIT 20

Bat rabies GX Nanning, Bobai 2000 3 320 RT-PCR/MIT 25

GX Nanning, Ningming 2005–2006 6 268 IFAT/FAVN 23

HI Boao 2005–2006 2 183 IFAT/FAVN 23

GD Yangchun 2005–2006 7 207 IFAT/FAVN 23

JL Tonghua 2012 1 261 DFA/RT-PCR/MIT 10

Rat rabies HA Nanyang 1987 3 97 ELISA/MIT/RT-PCR 17, 24

GX Nanning 2000 2 65 RT-PCR/MIT 25

ZJ Lishui 2008 1 57 DFA/RT-PCR 15

Wolf rabies NM Jalaite 1991 2 Clinical diagnosis and epidemiological 26

investigation

Fox rabies NM ALaShan ZuoQi 1999 1 Clinical diagnosis and epidemiological 27

investigation

Raccoon dog rabies LN Qingyuan 1982 1 1 MIT/clinical diagnosis 13

NM Zhengxiangbaiqi 2007 15 5 DFA/MIT/RT-PCR/ clinical diagnosis 14

Chinese ferret ZJ Huzhou 1994 7 Clinical diagnosis and epidemiological 37 badger-originated investigation

human rabies

ZJ Changxing 1994–1995 6 Clinical diagnosis and epidemiological 20

investigation

ZJ Lin’an, Chun’an, 1996–2004 29 Clinical diagnosis and epidemiological 38

Tonglu, Jiande, investigation

Quzhou, Huzhou,

Changxing

ZJ Coteau 2002–2004 7 Clinical diagnosis and epidemiological 39

investigation

ZJ Hangzhou 2006–2007 2 Clinical diagnosis and epidemiological 20

investigation

ZJ Qing Tian, Lishui 2008 2 Clinical diagnosis and epidemiological 20,26

investigation

AH Xuancheng, Shexian, 2002–2005 29 Clinical diagnosis and epidemiological 20

Huangshan, Jingxian investigation

JX Wuyuan 2007–2008 4 Clinical diagnosis and epidemiological 20

investigation

SC Yaan 2004 1 Clinical diagnosis and epidemiological 41

investigation

Bat-originated JL Tonghua 2002 1 Clinical diagnosis and epidemiological 9

human rabies investigation

JL Longjing 2010 1 Clinical diagnosis and epidemiological 10

investigation

Rat-originated SC Santai 1989 2 Clinical diagnosis and epidemiological 45

human rabies investigation

ZJ Taizhou 1981–2003 1 Clinical diagnosis and epidemiological 47

investigation

JS Binhai 1991 1 Clinical diagnosis and epidemiological 46

investigation

Wolf-originated NM Jalaite 1991 6 Clinical diagnosis and epidemiological 26

human rabies investigation

XJ Tacheng 1996 1 Clinical diagnosis and epidemiological 18 investigation

AH, Anhui; GD, Guangdong; GX, Guangxi; HA, Henan; HI, Hainan; JL, Jilin; JS, Jiangsu; JX, Jiangxi; LN, Liaoning; NM, Inner Mongolia; SC, Sichuan; XJ, Xingjiang; ZJ, Zhejiang.

DFA, direct ﬂuorescence assay; RT-PCR, reverse transcription polymerase chain reaction; MIT, mouse inoculation test; FAT, ﬂuorescent antibody test; IFAT, indirect

ﬂuorescent antibody test; FAVN, ﬂuorescent antibody virus neutralization test; ELISA, enzyme-linked immunosorbent assay.

No information available.

was isolated and identiﬁed in Jilin Province (northeast region of 2.4. Rat

China). The nucleoprotein gene of IRKV-THChina12 shared

92.4%/98.9% (nucleotide) and 92.2%/98.8% (amino acid) identity Rabies-carrying rats have been identiﬁed in China since the

with the two known Irkut virus isolates from Russia. The 1990s. The ﬁrst rat-originated lyssavirus, MRV (Mouse Rabies

identiﬁcation of IRKV-THChina12 represents the ﬁrst isolation of virus), was isolated from a vole collected in Henan Province in

10 24

a bat RABV in mainland China. The latter ﬁnding conﬁrmed the 1992. Phylogenetic analysis based on the whole genome showed

existence of bat RABVs in common Chinese bat species, and we MRV to be distinct from local dog-originated RABVs. In addition,

believe that additional bat RABV species will be identiﬁed in 65 rats captured in Guangxi Province in 2000 showed 3.1% (2/65)

mainland China with more extensive surveillance. positivity for RABV by RT-PCR. RABVs were also identiﬁed in

L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129 125

Apodemus agrarius in Zhejiang Province in 2009. Although these 3.3. Bat

viruses were distinct from local dog-originated RABVs based on

phylogenetic analysis, they belonged to the genotype 1 RABVs. Bats have played an important role in the transmission of rabies

Rabies in rats is rather unusual, globally. However in mainland to other animals and human beings throughout the Americas and

42,43

China, particularly in the rabies endemic areas, rats are widely in Europe. The ﬁrst bat-associated human rabies case in

distributed, which increases the chance of contact with rabid mainland China, reported in 2002, was that of a staff member at a

animals. These cases of reported rat rabies would come from television broadcasting station in Tonghua County in northeast

contact with rabid animals. Jilin Province. The victim suffered bat bites to the ear and died 10

days after the ﬁrst manifestation of disease symptoms. In 2010,

2.5. Rabies in other wildlife and livestock another bat-associated human rabies case was reported in

Longjing City in Jinlin Province. The victim suffered bat bites to

Rabid foxes and wolves attacking livestock or humans and the hand and died 10 days following the ﬁrst manifestation of

causing rabies outbreaks have been reported in Inner Mongolia and disease symptoms. Both cases developed acute progressive

18,26,27

Xinjiang Province, indicating that the fox and wolf carry encephalomyelitis consistent with rabies infection, 30 and 20 days,

rabies in mainland China. Cats, pigs, yellow bulls, goats, sheep, respectively, after the bites. These results indicate that bats pose a

cattle, buffalo, and donkeys have also been reported to carry rabies threat to human health in mainland China.

5,26–34

in mainland China. Based on analysis of the epidemiology

and viruses isolated or detected in these livestock, these cases were 3.4. Rat rabies

related to local dog rabies.

Several human rabies cases were reported to have been caused

by rats in the high-epidemic rabies areas of mainland China in the

45–47

3. Role of wildlife in human and domestic animal rabies in 1990s. Thereafter, rat-originated human rabies cases were

mainland China rare. Considering that RABVs have been detected in rats and that

human rabies cases caused by rats have been reported, and taking

3.1. Chinese ferret badger into account the frequency of human contact with rats due to their

wide distribution and high density in mainland China, we

Although rabies in Chinese ferret badgers has been reported in recommend that the role of rats in transmitting RABVs to humans

other countries, Chinese ferret badger-associated human rabies and animals be evaluated, particularly in rabies-endemic areas,

20,35,36

has been reported only in China. Human cases caused by even though some experts have reported that rats do not have any

rabid Chinese ferret badgers were ﬁrst recorded in Huzhou, epidemiological role in the transmission of rabies to humans.

Zhejiang Province in 1994. Since then, Chinese ferret badger-

associated human rabies has increased and is a public health 3.5. Other wildlife

concern in mainland China. From 1996 to 2004, more than 30

human cases were caused by Chinese ferret badger bites in Wolf-associated human or animal rabies has been reported in

38,39

Zhejiang Province. From 2004 to 2007, no human rabies cases China since the 1990s. In 1991, two wolves attacked 31 people and

caused by Chinese ferret badger bites were reported in these areas. 127 domestic animals in Jalaite in Inner Mongolia, causing six

In 2008, Chinese ferret badger-related human cases reemerged in human rabies cases and 19 domestic animal rabies cases.

Zhejiang Province: one human case was caused by infection after Thereafter, wolf-associated human and animal rabies were

capture and consumption of Chinese ferret badger meat. Chinese reported sporadically. From 1996 to 2006, several wolf-associated

ferret badger-associated human cases have also been reported in human and animal rabies cases were reported in Xinjiang

18,48

other provinces of China. From 2002 to 2005, seven Chinese ferret Province. To date, most wolf-associated rabies cases reported

badger-associated human cases were reported in Anhui Province; in northeast China have usually been a spillover of dog rabies

in addition, from 2007 to 2008, four Chinese ferret badger- rather than a true cycle of wolf rabies. According to those reports,

associated human cases were reported in Wuyuan, Jiangxi wolf rabies may not be a threat to humans in other areas, including

Province. In 2004, an independent report stated that a peasant high-epidemic rabies areas in the southeast and east regions of

had died of rabies after being bitten by a Chinese ferret badger in mainland China.

Yaan, Sichuan Province. The Chinese ferret badger-associated Foxes are a major vector of rabies and are a RABV reservoir for

rabies patients have included Chinese ferret badger hunters who sylvatic rabies in Eurasia and parts of the Americas. Wild foxes

capture and sell Chinese ferret badgers, farmers with occasional exist in the northwest, south, and northeast regions of China;

exposure to sick Chinese ferret badgers, and residents exposed to additionally, foxes are bred for fur production in China. Although

sick Chinese ferret badgers in their yard or house. Currently, rabid foxes attacking goats and causing rabies outbreaks has been

Chinese ferret badger trading and the consumption of its meat are reported in Inner Mongolia, fox rabies and fox-associated human

common in the southeast areas of China, resulting in a frequent and animal rabies are rare in China, probably due to the small

20 27

source of Chinese ferret badger bites or contact with humans. number of animals, resulting in minimal contact with humans.

Awareness that the Chinese ferret badger is a reservoir of RABVs According to the literature, the role of foxes in transmitting rabies

could help people to protect themselves, particularly those infection to humans and other animals is negligible in China.

resident in the southern part of China.

4. Genetic diversity and evolutionary characteristics of

3.2. Raccoon dog wildlife-originated RABVs and relationship to dog-originated

RABVs in mainland China

Although two raccoon dog rabies outbreaks have been recorded

in mainland China since 1982, no human rabies caused by a rabid 4.1. Genetic diversity of the glycoprotein gene in wildlife

raccoon dog has been reported. However, because raccoon dogs

have been conﬁrmed to carry arctic-like RABV in mainland China, Open reading frames (ORFs) of glycoprotein (G) genes of RABVs

raccoon dogs should not be allowed contact with domestic animals in wildlife, livestock, and domestic animals were 1575 nucleotides

13,14

or human beings. in length, encoding a 524-amino acid polyprotein, as reported

126 L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129

Figure 2. Multiple alignment of G protein amino acid residues 1–505 for wildlife-, livestock-, and dog-originated RABVs and vaccine strains used in Mainland China. Antigenic

site GI (amino acid 231), GII (amino acids 34–42 and 198–200), GIII (amino acids 330–338), and G5 (amino acids 244–281) are underlined. Triangles indicate the N-linked

glycosylation sites. Dotted lines indicate the T-cell epitopes.

L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129 127

50,51

previously for other RABVs in China. Comparison of RABV G 4.2. Wildlife-originated RABVs are almost exclusively isolated with

genes between wildlife and domestic animals (including dogs) older lineages

revealed putative amino acid sequence identities of 87.2% to 99.8%.

The G gene of bat-originated IRKV-THChina12 was found to share The G and N gene sequences of all available lyssaviruses

66.9% to 71.6% amino acid identity with other wildlife- and carried by wildlife and domestic animals (including dogs) in

domestic animal-originated RABVs in China. Using the aG strain mainland China, together with corresponding sequences from

(GenBank accession number GQ412744) as the reference se- representative lyssaviruses, were aligned and subjected to

quence, we aligned the available G genes of wildlife-, domestic phylogenetic analysis. The G (Figure 3A) and N (Figure 3B) gene

livestock-, and dog-originated lyssaviruses with human vaccine phylogenetic trees showed similar topology structure. All of the

strains (CTN, Flury, and PV) and veterinary vaccine strains (SAD wildlife-originated lyssaviruses were grouped within the classic

and ERA) in China. The highly variable regions are located in the RABV, with the exception of the bat-originated IRKV-THChina12.

transmembrane region (amino acids 440–461) and cytoplasmic The wildlife-originated lyssaviruses were distributed across ﬁve

carboxy terminal domain (amino acids 462–505) (Figure 2). major sub-clades (designated clades I–V). As reported previous-

Several substitutions were found in the linear epitope G5 (amino ly, clade I is a relatively recent lineage that is gaining dominance

acids 253–275) of wildlife-originated lyssaviruses. Among the T- and is now responsible for most of the new rabies cases in

53 50,51,54–57

cell epitopes, amino acids 103–178, 244–291, and 336–452 were mainland China. The samples in clade I were isolated

more variable in wildlife and domestic livestock-originated almost exclusively from dogs, with almost all of the remaining

Chinese lyssaviruses. In addition, the bat-originated IRKV- samples collected from humans and domesticated animals. Only

THChina12 showed considerably lower conservation in all of two samples were isolated from wildlife (Chinese ferret badger-

these antigenic sites and epitopes. Whether these substitutions originated JX09-17 and wolf-originated hubei070308). Con-

would affect the antigenic properties of these wildlife-originated versely, for the older clades (clade II to clade V), a larger

RABVs, as well as the efﬁcacy of currently used vaccines against proportion of isolates were collected from wildlife, suggesting

these wildlife-originated RABV infections, should be investigated the existence of wildlife reservoirs in mainland China through

further. the ages.

Figure 3. Neighbor-joining phylogenetic tree (P-distance) for (A) the G gene, and (B) the N gene of RABVs isolated from wildlife, livestock, and dogs in mainland China. G and N

gene sequences of lyssaviruses isolated from wildlife, livestock, and dogs in mainland China were downloaded from GenBank and combined with representative strains of

lyssaviruses to form the dataset used in this study. Alignment of nucleotide sequences was performed using ClustalX software, version 2.1. Phylogenetic and evolutionary

analyses were conducted using MEGA, version 3.1. Bootstrap analysis was performed using 1000 replications, and values greater than 70% were regarded as strong evidence

for the particular phylogenetic groupings. Numbers indicate the bootstrap values from 1000 replicates. Clades I–V are indicated. Red dots indicate isolates from wildlife. Blue

triangles indicate isolates from livestock.

128 L. Wang et al. / International Journal of Infectious Diseases 25 (2014) 122–129

4.3. The relationship between dog- and wildlife-originated Acknowledgements

lyssaviruses in mainland China

This work was supported by grants from State Key Laboratory

In mainland China, the dog plays a pivotal role in rabies for Infectious Disease Prevention and Control (2014SKLID03), the

transmission, and approximately 95% of human rabies cases are National Natural Science Foundation of China (81290342), the

5–9

ascribed to dog bites. The phylogenetic analysis showed the Ministry of Science and Technology, China (2011CB504702), and

isolates from dogs and dog-associated human cases to be grouped the National Key Technology R&D Program of the Ministry of

mainly within the relatively recent lineage (clade I). Only one Science and Technology (2014BAI13B04). The funders had no role

Chinese ferret badger-originated strain and one wolf-originated in the study design, data collection and analysis, decision to

strain isolated recently have been identiﬁed within the China publish, or preparation of the manuscript.

clade I, which suggests that the incidence of wildlife rabies Ethical approval: Ethical approval was not required for this

spillover from domestic dogs has been emerging in China review.

recently. Other RABVs from Chinese ferret badgers, raccoon Conﬂict of interest: No conﬂict of interest to declare.

dogs, and bats were segregated into independent lineages

(Figure 3) and were distinct from dog- and other domestic

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