Small Ruminant Research 70 (2007) 48–59

Genetics of disease resistance in sheep and goats夽

S.C. Bishop a,∗ , C.A. Morris b
a Roslin Institute, Midlothian EH26 9HH, United Kingdom
b AgResearch Ruakura Research Centre, PB 3123 Hamilton, New Zealand
Available online 12 February 2007

Abstract
This review summarises the current state of knowledge of the genetic control of resistance to infectious and metabolic dis-
eases in small ruminants. Diseases covered include gastrointestinal nematode infections, diseases due to mycotoxins, bacterial
diseases including footrot and mastitis, ectoparasites such as flies and lice, and scrapie, the small ruminant transmissible spongiform
encephalopathy. In all cases there is well-documented evidence for between-animal genetic variation in resistance to the disease
and, in the case of some of the infectious diseases, resistance to infection. These heritable differences between animals lead to
opportunities to breed animals for enhanced resistance to the disease. For some diseases, including nematode parasite infections,
resistance to various forms of mycotoxin poisoning and fly-strike, the feasibility of breeding for resistance has been demonstrated
in experimental flocks. Importantly, in other cases, including (again) nematode parasite infections and some forms of mycotoxin
poisoning, but also mastitis, footrot and scrapie, there are now breeding programmes selecting commercial animals for enhanced
resistance. In almost all cases, the evidence for genetic variation and the documented success of breeding for resistance occurs in
sheep rather than goats. For nearly all the diseases discussed, there are now concerted efforts to find genetic markers associated
with resistance to infection, potentially allowing selection for increased resistance in the absence of infection. Such selection is
now implemented for scrapie, as a part of national scrapie eradication programmes, and selection using genetic markers is currently
being explored for nematode parasite resistance, footrot resistance and resistance to facial eczema, a mycotoxin poisoning example.
Functional genomics, combining gene mapping and gene expression studies, is now being applied to a number of diseases, an
example being the identification of genes whose expression underlies genetic differences in resistance to nematode parasites. It is
likely that integrated studies combining quantitative and functional genomics, large-scale data collection (both within and between
breeds) and epidemiological prediction will lead to new opportunities for breeders to select sheep and goats for enhanced resistance
to a variety of diseases.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Infection; Epidemiology; Genomics; Mycotoxin; Breeding

1. Introduction

In recent years there has been a huge increase in the

research and application of disease genetics in sheep and
goats. This has been due to a number of factors: a growing
夽 This paper is part of the special issue entitled “The Outlook of appreciation of the role that host genetics can play in dis-
Quantitative and Molecular Genetics Applications in Improving Sheep ease control, an increase in the tools available to dissect
and Goats” guest edited by David Notter, R. Leyden Baker and Noelle host genetic variation in disease resistance, and growing
Cockett.
∗ Corresponding author. Tel.: +44 131 527 4200; pressures on breeders to select animals that are healthier
fax: +44 141 440 0434. and more resistant both to infectious and metabolic dis-
E-mail address: [email protected] (S.C. Bishop). eases. Evidence for host genetic variation in aspects of

0921-4488/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.smallrumres.2007.01.006
 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59 49

disease resistance has now been documented for many for a variety of parasite species including Haemonchus
diseases, in all major domestic livestock species (Bishop, contortus, Trichostrongylus colubriformis, Teladorsagia
2005), and small ruminants are notable for the large num- circumcincta and various Nematodirus species. In most
ber of diseases where host genetic variation has been cases, it is the impact of nematode parasites on the
documented. growing lamb or kid that is of interest. However, nema-
The term ‘disease resistance’ is often loosely used, tode infections are also problematic for reproductive
and may mean different things according to the con- females undergoing the stress of late gestation and early
text in which it is being used. The first distinction is lactation and some attention has been given to host
between infectious and non-infectious, or metabolic, dis- genetic variation in resistance during the peri-parturient
eases. For infectious diseases, infection may be defined period. Benefits from genetically improving nema-
as the colonisation of a host by organisms such as viruses, tode resistance should include decreased anthelmintic
bacteria, protozoa, helminths and ectoparasites, whereas requirements and/or reduced pasture contamination
disease describes the pathogenic consequence of infec- leading to decreased larval challenge and hence indi-
tion. Disease resistance is used generically to cover rect benefits on health and performance (Bishop and
resistance to infection, i.e. a host’s ability to moderate Stear, 2003). Direct effects on performance traits are
the pathogen or parasite lifecycle, and also resistance less clear-cut and appear to vary according to produc-
to the disease consequence of infection. Sometimes tol- tion environment, the level and species of challenge and
erance is used to describe a host’s ability to withstand the trait of interest. The wide variety of observed rela-
pathogenic effects of infection. Resilience is related to tionships between performance traits and resistance is
tolerance, and describes an animal’s ability to maintain summarised by Bishop and Stear (2003).
performance in the face of a disease challenge. Breed differences in resistance to nematode infections
This paper aims to review the current state of evi- have been well documented, particularly for tropical
dence for genetic variation in disease resistance in small or sub-tropical sheep facing H. contortus challenge. A
ruminants for a variety of diseases. It does not aim to thorough summary of breed differences along with a
be exhaustive; rather, it describes the current state of consideration of how these breed differences might be
knowledge for key diseases and likely future trends. exploited in practical breeding programmes is given
The emphasis will be on infectious diseases, however by Baker and Gray (2004). Although many of the
the impact of mycotoxins on small ruminants and the individual breed comparison studies lack power, a con-
evidence for between-animal variation in resistance to sensus between studies has emerged. For example, Baker
this category of disease will also be discussed in detail. and Gray (2004) conclude that for breeds seen in the
Factors influencing the likely occurrence of host genetic Caribbean or in southern states of the US, there is
variation and the application of this knowledge to practi- ample evidence for the Barbados Blackbelly, the St.
cal breeding situations are considered in the Discussion Croix and the Florida Native and Gulf Coast Native
section. breeds being relatively resistant, when compared to
non-adapted breeds. When assessed under South–East
2. Parasitic diseases Asian conditions (Indonesia and the Philippines), the
relative resistance of the Barbados Blackbelly and the
On a global scale, ruminant diseases caused by St. Croix is still observed, with the Indonesian Thin
gastrointestinal nematode parasite infections are the dis- Tail sheep being intermediate between the resistant St.
eases with the greatest impact upon animal health and Croix and the susceptible Merino (e.g. Subandriyo,
productivity (Perry et al., 2002). The quantification of 2002). In Indian studies, the Garole breed appears to
genetic variation between animals in their resistance, confer enhanced resistance compared to other breeds
and the search for genes or QTL contributing to such (Nimbkar et al., 2003). It is, however, in African studies
differences, has been a major undertaking in nearly all that the greatest body of work and most convinc-
major sheep producing countries in recent years, with the ing results on breed differences have been produced.
primary justification for this research being the need to Repeated evidence, summarised by Baker and Gray
find alternative and sustainable control strategies in the (2004), has demonstrated the favourable resistance and
face of growing anthelmintic resistance (Waller, 1997; tolerance characteristics of the Red Maasai breed, and
Jackson and Coop, 2000). demonstration of how this resistance translates into
As described below, genetic differences between improved performance characteristics under different
host animals in nematode parasite resistance have been environmental conditions is given by Baker et al. (2004).
observed in all major production environments, and Additionally, the Sabi is another sheep breed with
50 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59

favourable resistance characteristics, when compared studies have looked directly at traits describing the prop-
to the Dorper (Matika et al., 2002). Goats have been erties of the infection: Stear et al. (1997) demonstrated
less thoroughly studied than sheep. The strongest evi- that in growing lambs the average worm size and num-
dence for breed differences in goats comes from studies ber of eggs in utero in adult female worms were strongly
involving the Small East African breed, which gener- heritable traits but the numbers of larvae or adult worms
ally emerges as being resistant when compared with present in the gut were only weakly inherited, whereas
other breeds (e.g. Baker et al., 2001). Additionally, Baker in a small study Gauly et al. (2002) found the converse.
and Gray (2004) discuss evidence for greater relative Antibody responses have been investigated on a number
resistance of indigenous goats in Thailand and the Philip- of occasions. For example, Douch et al. (1995) reported
pines, compared to Anglo-Nubian derived breeds and moderate heritabilities for IgG specific to Trichostrongy-
crosses. To summarise, it is generally breeds of sheep lus colubriformis, and Davies et al. (2005) reported
or goats that have evolved in the face of continued strong and consistent heritabilities for IgA specific to
strong challenges that are the more resistant or resilient, T. circumcincta. Davies et al. (2005) also investigated
when compared with exotic or less well adapted breeds. the heritabilities of several other indicators of immune
Additionally, such breed differences are not restricted response or pathogenesis, including pepsinogen and
to resistance to nematode parasites, as similar differ- fructosamine concentrations and eosinophil numbers. In
ences have been seen for liver fluke (Fasciola hepatica nearly all cases these indicator traits were moderately to
and F. gigantica). For example, the Indonesian Thin Tail strongly heritable, and favourably genetically correlated
breed has been shown to be more resistant than the St. with both FEC and worm size and fecundity. How-
Croix which, with the Florida Native sheep, is appar- ever, further investigation is probably required before
ently more resistant that the Barbados Blackbelly (results such measures could be advocated as replacements for
summarised by Baker and Gray, 2004). Many fewer FEC.
breed comparisons for parasite resistance have been per- Studies in sheep to detect QTL for nematode resis-
formed in temperate regions, mainly because the focus tance or detect associations with candidates are now
for genetic improvement in these regions has been pre- well advanced in New Zealand, Australia, Kenya, US
dominantly on within-breed improvement of production and Europe, including UK, France, Italy and Spain,
traits. although results are not always readily available in
Many studies have quantified within-breed heritabili- the public domain. Full or partial genome scans have
ties, usually using faecal egg count (FEC) as the indicator revealed QTL for FEC on chromosome 1 (for T. colu-
of relative nematode resistance. In almost all cases (e.g. briformis (Beh et al., 2002; Diez-Tascon et al., 2002)
Woolaston and Piper, 1996; Woolaston and Windon, and H. contortus (Cockett et al., 2005)), chromosome
2001; Morris et al., 1997a, 2000; Bishop et al., 1996; 2 (for Nematodirus (Davies et al., 2006)), chromo-
Bishop et al., 2004; Gruner et al., 2004; Eady et al., some 3 (for T. colubriformis (Beh et al., 2002), general
1996; McEwan et al., 1992, 1995) FEC, once appro- Strongyles challenge (Paterson et al., 2001; Davies et
priately transformed, is a moderately heritable trait in al., 2006) and Nematodirus (Davies et al., 2006)), chro-
lambs, and one which responds to selection. FEC tends mosome 6 (for T. colubriformis (Beh et al., 2002)) and
to be less heritable in kids and does (Vagenas et al., 2002; H. contortus (Cockett et al., 2005)), chromosome 14
Woolaston et al., 1992; Morris et al., 1997b; Mandonnet (Nematodirus (Davies et al., 2006)), chromosome 19
et al., 2001), however Vagenas et al. (2002) showed that (H. contortus (Cockett et al., 2005)) and chromosome
responses to selection for decreased FEC can be achieved 20 (general Strongyles challenge (Davies et al., 2006)).
over a short time period. In the periparturient ewe, FEC Further, Marshall et al. (2005) report several significant
is also a moderately heritable trait (Bishop and Stear, QTL for H. contortus FEC, in sheep from the Golden
2001; Morris et al., 1998; Watson et al., 1995; Woolaston, Ram flock within which a major gene for resistance is
1992) as well as being genetically correlated with resis- believed to be segregating. The most consistently sig-
tance in the lamb (Morris et al., 1998). Resistance to nificant region is that containing the interferon gamma
different species of nematodes tends to be related, with locus on chromosome 3. Additionally, QTL for IgA pro-
genetic correlations between the FEC values arising from duced in response to Strongyle challenge have been
different species or genera of parasites generally being reported by Davies et al. (2006) on chromosomes 3,
close to 0.5 (e.g. Bishop et al., 2004) or higher in some in the interferon gamma region, and 20, in the MHC
cases (e.g. Gruner et al., 2004). (Major Histocompatibility Complex) region. The study
Traits other than FEC may also be used to assess resis- by Cockett et al. (2005) also found a QTL for packed
tance to nematodes or host response to infection. Two red blood cell volume (PCV) after H. contortus chal-
 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59 51

lenge in the same location on chromosome 1 as the FEC 3.1. Facial eczema
QTL.
Several studies have also looked at associations Facial eczema (FE) is a costly animal health problem
between specific genes or markers and FEC. In particu- in low-lying areas of northern New Zealand (Smith et
lar, Coltman et al. (2001) found significant associations al., 1997). The disease is also found in other countries
with a microsatellite within the interferon gamma gene including Australia, South Africa and Spain, but gen-
in feral sheep, and various associations with microsatel- erally only in isolated areas. The disease is caused by
lites in or near the MHC have been observed (Schwaiger sporidesmin, a toxin produced by spores from the sapro-
et al., 1995; Janssen et al., 2002). phytic fungus Pithomyces chartarum, which grows on
In summary, genetic variation in many aspects of the dead litter at the base of most pastures. In the warm,
host resistance to nematodes is well documented. There humid conditions common in autumn, fungal growth and
has been some success in QTL detection, but gener- spore formation can be rapid, resulting in large num-
ally the number of significant QTL reported is probably bers of toxic spores in the pasture. Sporidesmin is a
less than expected given the input into this area. The toxin that causes injury to many body tissues includ-
current trends are to attempt to fine map QTL, for ing the liver, where there is hepatocyte damage and
example using dense single nucleotide polymorphism blockage of the bile duct. As a result of liver dys-
(SNP) markers, and to study the functional signifi- function, the chlorophyll pigment absorbed from the
cance of genes that may underlie host responses to gut is not completely metabolised and excreted, leav-
infection. Early results suggest that microarray stud- ing a partial breakdown product (phylloerythrin) to enter
ies do have the ability to detect genes differentially the bloodstream instead. Light-activated phylloerythrin
expressed between ‘resistant’ and ‘susceptible’ sheep, causes blistering of the skin where skin capillaries are
with pathways implicated in these differences including exposed to the sun, most critically on white areas such
the development of acquired resistance and the struc- as on the face and udder (hence the name of the dis-
ture of the intestinal smooth muscle (Diez-Tascón et al., ease). FE reduces growth and fleece production; it has
2005). major effects on reproduction and, in severe cases, FE
may cause death. The heritability of FE-induced liver
injury in sporidesmin-dosed sheep was estimated as
3. Metabolic diseases: resistance to mycotoxins 0.42 ± 0.09 (Campbell et al., 1981), using analyses of
liver injury scores assessed at slaughter. The activity of a
Mycotoxins, or toxins produced by fungi, are com- liver enzyme in serum (gamma-glutamyltransferase, fol-
mon in the diet of grazing ruminants in temperate lowing sporidesmin dosing: Towers and Stratton, 1978)
countries. These toxins include sporidesmin, lolitrem, may be used as a phenotypic measure of susceptibil-
ergovaline and zearalenone, and their distribution and ity in the live animal, and this phenotype has a similar
prevalence within the environment depend largely on heritability (0.45 ± 0.05) to liver injury score in sheep
the interplay of pasture conditions and climate. Some (Morris et al., 1995a). Selection lines of lambs, bred for
mycotoxins, for example zearalenone, are also found resistance or susceptibility to FE have been developed
commonly in grain stored under poorly controlled con- in New Zealand since 1975 (Morris, 1998), and they are
ditions (e.g., barley, wheat or maize, stored above the maintained for biochemical and now genomic studies of
recommended moisture contents), so that these myco- resistance.
toxins may become part of the diet of concentrate-fed Currently, testing of animals for resistance to FE
animals and poultry under some circumstances (D’Mello is being carried out in ram breeding flocks (Morris et
et al., 1999). Mycotoxins become economically impor- al., 1994), and resistant rams are being sold to indus-
tant if they occur at sufficiently high concentrations try flocks. Using phenotypic measurement and selection
and in the diets of large numbers of animals. Examples procedures is feasible for this trait because it has a
are sporidesmin (facial eczema) and lolitrem (ryegrass moderate-to-high heritability, but the selection process
staggers) in New Zealand sheep, cattle, goats and deer, could be aided by the use of genetic markers, especially
ergovaline (tall fescue toxicosis) in American beef cat- because of the welfare issues associated with a direct
tle, and zearalenone (reproductive abnormalities) in New challenge in order to rank rams for disease resistance.
Zealand sheep and United States pigs. Genetic variation Studies are underway for FE, to determine the under-
in the host has been recorded following experimental lying genes associated with resistance/susceptibility of
dosing with the above mycotoxins, and examples are the host to this mycotoxin (Phua et al., 1999). Some
given below. commonality of resistance mechanisms across toxins, as
52 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59

described below, may assist in the search for candidate Zealand. It may interfere with reproductive functions in
genes or the elucidation of relevant enzyme pathways. sheep because its chemical structure is similar to that of
oestrogen. Examples of the potential reproductive cost
3.2. Ryegrass staggers of zearalenone in the diet of New Zealand sheep have
been reported (Jagusch et al., 1986; Smith et al., 1988,
Ryegrass staggers (RGS) is caused by the toxin, 1990; Towers and Sprosen, 1993). Zearalenone is broken
lolitrem, produced by the endophytic association of down in the liver, and breakdown products are excreted
perennial ryegrass (Lolium perenne L.) and the fungus via urine and faeces. The partitioning between urine and
Neotyphodium lolii. The toxin causes neuromuscular faeces has yet to be genetically evaluated, but the con-
incoordination in sheep when put under stresses such centrations of zearalenone breakdown products in urine
as mustering with dogs, with susceptible animals being have been shown to be heritable. Following oral dosing
unable to run or walk. The condition also affects suscep- of sheep with zearalenone at physiological levels, animal
tible dairy cows, impeding machine-milking operations. response (i.e. the concentrations of breakdown products
The disease occurs in New Zealand in summer and in urine, adjusted for urine volume) has an estimated
autumn, but it also occurs in Southern Australia and heritability of 0.32 ± 0.10 (Morris et al., 2005a). Fol-
California (Glenn, 2005). A scoring system for RGS lowing experimental dosing with zearalenone during the
susceptibility has been developed to combine records period around ovulation, lower concentrations of zear-
of severity and time of clinical incidence, and the heri- alenone breakdown products are genetically associated
tability of this RGS score in sheep has been estimated at with higher ovulation rates in ewes (rg = −0.55; Morris
0.43 ± 0.05 (C.A. Morris, unpublished). Selection lines et al., 2005b). The correlation may be negative because
of sheep bred for resistance or susceptibility to RGS have one of the breakdown products (α-zearalenol) is more
been developed and maintained in New Zealand since toxic than zearalenone itself, so that fast breakdown of
1993 (Amyes et al., 2002). Some of the detoxification the zearalenone toxin (at least if excreted via urine) may
pathways by which sheep can cope with RGS and FE be counterproductive.
may be in common, because there is a moderate positive
genetic correlation (0.31) between resistance to the two 4. Bacterial diseases
diseases (Morris et al., 1995b).
4.1. Mastitis
3.3. Heat stress
Mastitis is an inflammation of the mammary gland
Ergovaline, alone or in combination with other toxins resulting from bacterial infections, particularly staphy-
such as lolitrem, may lead to heat stress in sheep and cat- lococci, whose reservoir is generally in the udder or teat.
tle. Ergovaline causes vasoconstriction, so that animals This disease is primarily of importance in dairy sheep
are less able to dispose of surplus heat through the pelt and goats, hence it is covered in greater detail in the
or hide. It has been shown to be a contributing factor to dairy sheep review in this volume (Barillet, 2007). This
perennial ryegrass toxicosis in sheep and cattle in south- section will only summarise major points.
ern Australia (Reed et al., 2005) and as the cause of tall Subclinical mastitis is generally diagnosed by an
fescue toxicosis in cattle in southern USA (Paterson et increase in somatic cell counts (SCC) in the milk of
al., 1995). According to Reed et al. (2005), mass deaths ewes, although in goats the predictive value of SCC is
can occur from grazing infected pastures, and there have less established (Bergonier et al., 2003). SCC may also
been three such occurrences in Southern Australia in be used to help select for increased resistance to mastitis,
the last 20 years (over 29,000 sheep deaths in 2002). A and recent estimates of the heritability for SCC are gener-
mouse model of ergovaline susceptibility has been devel- ally in the range 0.10–0.20 (El-Saied et al., 1999; Barillet
oped, showing that differences in animal susceptibility et al., 2001; Rupp et al., 2003; Serrano et al., 2003;
are heritable (Hohenboken and Blodgett, 1997), and it is Gonzalo et al., 2003; Legarra and Ugarte, 2005). Unlike
of note that some of the variation is common with that for bovine mastitis, where SCC is unfavourably genetically
resistance to facial eczema (Hohenboken et al., 2000). correlated with milk yield, relationships between milk
production and mastitis traits are not consistent in sheep,
3.4. Zearalenone with published genetic correlations between SCC and
milk yield ranging from positive, i.e. antagonistic, to
Zearalenone is a fungal toxin produced by Fusarium negative. Consensus values are yet to emerge. Atten-
species commonly found on pastures in autumn in New tion is now turning to the mapping of QTL for SCC in
 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59 53

dairy ewes, in both experimental crosses and commer- Escayg et al., 1997). A specific association with the
cial breeding programmes, as described by Barillet et al. DQA2 gene has been used in New Zealand as a marker
(2005). A summary of the results is presented by Barillet for footrot resistance (Hickford et al., 2004). This test is
(2007). now commercially available (Hickford, 2000) as a tool
to select more tolerant or resistant animals, without hav-
4.2. Footrot ing to expose the animals to infection. As with other
diseases discussed in this paper, breeding for footrot
Footrot, a bacterial disease caused by Dichelobac- resistance would be aided by integrated strategies that
ter (Bacteroides) nodosus (D. nodosus), is a common combined phenotypic assessment with genetic markers.
cause of lameness in both lambs and mature sheep, and Moreover, a clear need exists to search for additional
it is considered to be one of the major welfare prob- markers outside of the MHC region.
lems in sheep. Footrot is highly contagious, being easily
transmitted from sheep to sheep via pasture, bedding or 5. Flies, ticks and vector-borne diseases
handling pens, and it can be spread by sheep that do not
show clinical signs of disease. In addition to the wel- 5.1. Flystrike and lice
fare concerns, it is also a major cause of economic loss
and currently it is estimated to have economic costs to the In Australia, susceptibility to fly-strike in Merino
UK industry of £31M per annum (Nieuwhof and Bishop, sheep has an intermediate heritability (0.26; Raadsma,
2005). 1991), and there is a positive genetic correlation (>0.9)
Assessing the genetic control of footrot and sub- between fly-strike and fleece-rot. It has been shown that a
sequently breeding for resistance is aided by the fact major gene for fly-strike severity is segregating in lines of
that footrot severity is relatively easily scored under experimental Merinos genetically selected for or against
field conditions. For example, using Australian Merino fleece rot and fly-strike (Mortimer et al., 2001). Less
sheep, a footrot lesion scoring method was developed research has been carried out on the genetics of host
by Egerton and Roberts (1971) and refined by Raadsma susceptibility to fly-strike in New Zealand than with
(2000a) into a system that separated clinical signs into fly-borne pests in Australia, but with the arrival of the
8 categories. Using this system, Raadsma et al. (1994) Australian blow-fly (Lucilia cuprina) into New Zealand
demonstrated substantial genetic variation in resistance (Heath and Bishop, 1995), probably by wind disper-
both to challenge with virulent isolates of D. nodosus, sal, there is a need for intensive study. In environments
and also to natural challenge. Although heritabilities of where fly-strike is a threat, the lack of an effective con-
individual assessments of severity of the disease were trol is a major barrier and welfare issue to establishing
low to moderate, genetic correlations between indicators low input enterprises. According to Raadsma (2000b),
were high, approaching unity, and heritability estimates the Merino host in Australia does not produce an anti-
from repeated measurements approached 0.30. A prac- body response to flies, but it generates wool and skin
tical application of this approach has been described by substances in response to moisture and bacterial agents
Patterson and Patterson (1989) who successfully bred in the fleece rot; these may deter flies from landing or
for enhanced footrot resistance in Merinos. Additional from laying eggs. The mechanism may, thus, be different
evidence of the feasibility of selecting sheep for footrot in principle from the major-gene resistance of Bos tau-
resistance using phenotypic observations is given by rus cattle (Frisch, 1994) to ticks (Boophilus microplus),
Skerman and Moorhouse (1987), who report an eval- in which at least one of the resistance pathways is for
uation of lines of New Zealand Corriedale ewes selected host eosinophils to secrete histamine in response to ticks
for enhanced footrot resistance. Therefore, breeding for (Schleger et al., 1981). However, investigations on tem-
enhanced footrot resistance using phenotypic assess- perate cattle suggest that volatile chemicals produced by
ment alone is possible and feasible, provided that footrot the host animal play a major role in determining the num-
is present in the flock. If breeders maintain a footrot ber of flies carried by individual animals (Birkett et al.,
free status, then phenotypic selection is not feasible and 2004).
genetic markers may be required. Sheep have also been found to show individual vari-
Less work has been done on QTL or genetic marker ation in their response to infestation by lice (Bovicola
tests for footrot resistance than on phenotypic assessment ovis), and to the related allergic skin condition, ‘cockle’
of resistance, however associations between resistance (Pfeffer et al., 2003). Research in New Zealand Rom-
and MHC markers, particularly within the MHC class ney sheep has shown that the heritability of lice count
II region, have been published (Litchfield et al., 1993; increases from weaning (3 months) to 11 months of
54 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59

age, with the 11-month heritability being estimated at BSE, thus leading to the possibility that BSE could trans-
0.39 ± 0.15. mit unnoticed in sheep populations. In particular, the
ARQ/ARQ genotype is susceptible to some forms of
6. Transmissible spongiform encephalopathies scrapie and is also susceptible to experimentally infected
BSE (Foster et al., 2001; Jeffrey et al., 2001), indicating
Transmissible spongiform encephalopathies (TSEs) the need to reduce the frequency of not only the VRQ
are fatal degenerative diseases of the central nervous sys- allele, but also the ARQ allele, whilst increasing the ARR
tem that affect many mammalian species. Well-known frequency. The importance of TSEs has led to the devel-
examples include BSE in cattle, scrapie in sheep and opment of breeding programmes throughout Europe
Creutzfeld–Jakob disease (CJD) in humans. Scrapie is aimed at reducing and eventually eliminating TSEs from
known to have been endemic in some European sheep respective national sheep flocks. For example, descrip-
populations for more than 250 years. Features of TSEs tions of the UK breeding programme, the National
are long asymptomatic incubation periods, with death Scrapie Plan (NSP), including rules on animal usage,
typically occurring several months or years after infec- may be found at: http://www.defra.gov.uk/animalh/bse/
tion (Detwiler and Baylis, 2003). othertses/scrapie/nsp/index.html.
The infectious causal agent for TSEs is not as yet Several questions arise from the focussed selection
defined and is still the topic of controversy. However, the on PrP genotype. Firstly, it is not clear precisely what
prion protein (PrP) has been implicated and TSE pathol- the mechanism of resistance is, i.e. whether PrP geno-
ogy is characterised by accumulation of wrongly folded types code for relative resistance to infection (or risks
PrP, PrPsc , in lymphoid tissues and the nervous system, of clinical signs of disease), or whether or not they
especially the brain. Thus, presence of PrPsc defines the simply influence incubation period, as seen in mouse
presence of the disease. In sheep, the presence of the models (Moore et al., 1998) with possible transmission
disease depends jointly upon exposure to infection and from asymptomatic carriers. In this latter case, the likely
the genotype of the animal, as determined by the PrP reduction in scrapie incidence resulting from the breed-
gene located on chromosome 13. Natural exposure to ing programme would be slightly reduced. Secondly, it is
infection will only lead to disease in genetically suscep- known that genetic variation for scrapie exists outside of
tible animals. In sheep, the PrP gene shows variability the standard PrP alleles. For example, further variabil-
at several codons, and variability at codons 136, 154 and ity within the PrP gene associated with scrapie has been
171 jointly determine much of the variation in relative described, particularly at codon 141 (Moum et al., 2005),
susceptibility to clinical scrapie (Goldmann et al., 1991; and genetic variability in scrapie survival time for sheep
Hunter et al., 1991, 1996). Thus scrapie susceptibility of fixed PrP genotype has been described and mapped to
alleles may be defined by the combination of variants regions unlinked to the PrP gene (Moreno et al., 2002).
at these three codons. Using standard abbreviations for Furthermore, Diaz et al. (2005) demonstrated substantial
the amino acids coded at these codons, the five common non-PrP genetic variation in survival time of sheep in a
alleles in sheep are: ARR, AHQ, ARH, ARQ and VRQ flock undergoing a scrapie epidemic. Therefore, there
(Detwiler and Baylis, 2003). Pair-wise combinations of is additional unexploited variation in scrapie resistance.
these alleles are referred to as the PrP genotype; thus the Thirdly, the effect of genotypes in terms of scrapie resis-
five alleles lead to 15 genotypes. Characterisation of the tance may not be consistent across breeds. Apart from
15 PrP genotypes, in terms of their relative resistance experimental imprecision, the reason for this observation
to scrapie, is given at http://www.defra.gov.uk/animalh/ is not known, however it has been hypothesised as pos-
bse/othertses/scrapie/nsp/pdf/genotypes.pdf. In general sibly being due to different scrapie strains circulating in
terms, genotypes containing the ARR allele are relatively different breeds, or the interacting effects of other genes
resistant and genotypes containing the VRQ allele are (Baylis and Goldmann, 2004). Lastly, possible relation-
susceptible. It is a reasonable assumption that the ARQ ships between PrP genotype and performance traits are
allele is the wildtype, based on allele frequencies and the often raised as a barrier to widespread uptake of PrP
fact that all other alleles can be derived from this allele selection by breeders. However, despite a growing num-
by a single mutation. ber of studies investigating this possibility, convincing
The apparently simple genetic control of scrapie leads and consistent relationships have yet to be demonstrated.
to the opportunity to breed sheep for increased scrapie Goats are also considered to be very susceptible to
resistance (Dawson et al., 1998). The need to do this scrapie, however information is still largely anecdotal.
is enhanced by the difficulty in distinguishing between Although the caprine PrP gene is highly polymorphic,
the clinical signs of scrapie and experimentally infected linkages to scrapie resistance have yet to be convincingly
 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59 55

documented (Detwiler and Baylis, 2003). However, it is able animals do not cope with the disease challenges. It
expected that as scrapie surveillance increases and more may also be used to help address public pressures or
scrapie cases are detected, then PrP effects on resistance government directives on issues such as antibiotic usage
will become better established. or potential zoonoses, with PrP selection programmes
In summary, genetic control of scrapie is well estab- being an example. A successful breeding strategy should
lished in sheep, and this forms the basis of many national cost-effectively reduce the impact of the disease, i.e. alter
breeding programmes for scrapie resistance. The situa- disease epidemiology, in a reasonable time period (e.g.
tion in goats is less clear, and more data are needed here. less than 20 years which for sheep and goats is about
However, even in the case of sheep, there are still a num- 5–6 generations of selection). As with all disease con-
ber of issues to be addressed. Experimentation in this trol strategies, pathogen or parasite evolution in response
field is costly and time-consuming. Therefore, it is rec- to the changes in the host population genotypes is a
ommended that the importance of different issues are risk. This risk will generally be minimised by combining
explored by means of epidemiological modelling and complementary control strategies, e.g. by using genet-
interrogation of surveillance data, in addition to struc- ics along with appropriate interventions or bio-security
tured experiments. measures. Additionally, where genetic approaches are
used, risks will be reduced if selection can be based on
7. Discussion and conclusions the combined effect of several or many genes, rather than
relying on a single gene. In all cases, the principle is to
As has been demonstrated in this review, there are present the pathogen or parasite with as many barriers as
many diseases in sheep and goats for which host genetic possible.
variation exists, with a growing number of QTL or genes Encouragingly, there are a number of examples where
identified that contribute to these differences. A fea- breeding programmes have been successful in selecting
ture of future studies will be the interrogation of the commercial animals for enhanced resistance. As out-
genetic architecture underlying resistance, including the lined above, these include nematode parasite infections,
use of high-density SNP maps to enable genome-wide some forms of mycotoxin poisoning, mastitis, footrot
association tests to be performed. A further feature will and scrapie in sheep. In most cases selection has been
be functional genomic studies, particularly those using on phenotypic measures of resistance, but as previously
microarrays, to determine gene expression following outlined, marker-based selection is now implemented
infection and gene expression differences between hosts at the whole population level in several countries for
that differ in their relative resistance. The combination of scrapie resistance. Furthermore, selection using genetic
such studies should markedly improve our understand- markers is currently being explored for nematode para-
ing of how hosts differ in their disease resistance, as has site resistance, footrot resistance and resistance to facial
already been demonstrated by Diez-Tascón et al. (2005). eczema. Apart from the study described by Vagenas et
However, in all cases the rate-limiting step in such stud- al. (2002), there have been few selection experiments
ies is likely to be the acquisition of phenotypes and the or breeding programmes for disease resistance in goats,
identification of populations with particular resistance however there is evidence for both within and between
attributes. For this reason, it is essential that collabora- breed variation which can be utilised in breeding pro-
tive studies be integrated from the molecular through to grammes.
the population level. It is often asked why genetic variation in resistance or
An important question is which of the case studies tolerance exists at all: why hasn’t natural selection elim-
described above actually represent tractable cases where inated genetic variation for disease resistance? These
selection for increased resistance is feasible. Issues to be issues are covered in more detail by Gibson and Bishop
considered here include (i) the importance of the disease (2005). In summary, complex host–parasite interactions
relative to other diseases or production traits; (ii) the tools guide the evolution of both hosts and parasites, and are
available with which to perform the selection—for exam- one of the major reasons for the maintenance of genetic
ple does one use indicator traits measured on the animal variation in natural populations. Combining genetic the-
or genetic markers that may explain some of the variation ory and epidemiology gives insight into why genetic
in resistance; and (iii) in the case of infectious diseases, variation in resistance persists. Firstly, selection pres-
what are the epidemiological or flock level implications sures, especially those for disease resistance, will differ
of improving resistance. In general, breeding for resis- across time and environments. Secondly, natural selec-
tance will be considered when current control strategies tion will not make populations completely resistant to
are not adequate, sustainable or cost-effective, and avail- infection: as natural selection moves a host population
56 S.C. Bishop, C.A. Morris / Small Ruminant Research 70 (2007) 48–59

towards resistance, the selection pressure for resistance a selection index, so that the resistance and performance
decreases. Depending upon the type of disease, a certain traits get appropriate relative weightings, and any rela-
proportion of susceptible animals can be carried without tionship that may exist is correctly accounted for. The
exposing the population as a whole to risks of epidemics selection index approach will require relative economic
(Bishop and MacKenzie, 2003). Once the number of weightings for disease resistance which, in principle, are
genetically susceptible animals falls below this level, estimated in the same way as for any other trait, i.e. the
selection pressure for resistance ceases as the disease marginal benefit of improving the resistance goal trait
will no longer be present, i.e. cannot be maintained, when all other traits are held constant. In the disease trait
in the population. Thirdly, modern domestic livestock context, this may include epidemiological benefits aris-
populations have been selected for other characteris- ing from selection, as illustrated by Bishop et al. (2004)
tics, with disease impacts masked by non-genetic control and implemented in the New Zealand sheep breeding
measures. Lastly, consideration of indigenous breeds of programmes for nematode resistance (J.C. McEwan,
livestock subject to endemic disease challenge for hun- pers. comm.).
dreds or thousands of years leads to the conclusion that Finally, it is our prediction that studies into the elu-
in such cases there has been host–parasite co-evolution, cidation and utilisation of genes underlying genetic
leading to tolerance of infection as an evolutionary strat- variation in resistance will continue to increase. Pres-
egy in which the host can survive the impact of infection sures due to many factors, e.g. economics, legislation,
without unduly impacting on the ability of the parasite decreasing effectiveness of current intervention strate-
to complete its lifecycle. gies, food safety and zoonotic concerns, will force
In terms of practical implementation, an issue is breeders to consider genetic solutions to a wider range
possible trade-offs between disease resistance and per- of diseases. At the same time, through a combination of
formance. Relationships between resistance, tolerance genome mapping and functional genomics, researchers
and animal performance are often poorly quantified and will elucidate genes underlying differences in resistance.
misunderstood. For example, the conclusion is often A parallel need is the development of recording proto-
drawn that resistant animals are necessarily less produc- cols, electronic data capture and large-scale databases
tive animals, particularly when comparing productive to provide the phenotypic data necessary to underpin
characteristics of (e.g.) hardy locally adapted animals the genomic technologies. If achieved, these technolo-
vs. high performing but susceptible exotic animals. Most gies, along with an understanding of the epidemiological
likely, all that is being observed in this case are differ- impact of increasing resistance, should provide breeders
ent selection histories for the two populations. Moreover, with the required tools to increase genetic resistance to
relative breed rankings for performance, and hence breed a variety of diseases.
choice or optimal crossbreeding strategy, will depend
upon the environment. For example, for nematode resis- Acknowledgements
tance, Baker et al. (2004) demonstrated that productivity
advantages observed for the relatively resistant Red Maa- S.C.B. wishes to thank the BBSRC for funding,
sai breed over the more susceptible Dorper breed in the and C.A.M. wishes to acknowledge the New Zealand
face of strong nematode challenge in a sub-humid trop- Foundation for Research, Science and Technology. Both
ical environment disappeared in a moderate challenge authors wish to thank many colleagues for fruitful dis-
semi-arid environment. Strategies to combine within- cussions that have led to the development of many
and between-breed variation in resistance are discussed concepts outlined in this paper, including Mike Stear,
by Baker and Gray (2004). Frank Jackson, Jo Conington, Leyden Baker, Neale Tow-
The nature of relationships between performance and ers, Alec Begg and Ross Alexander.
disease resistance is considered by Bishop and Stear
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