Banos Irish Veterinary Journal 2023, 76(Suppl 1):19 Irish Veterinary Journal

https://doi.org/10.1186/s13620-023-00250-z

REVIEW Open Access

Selective breeding can contribute to bovine

tuberculosis control and eradication
Georgios Banos1*   

From Seventh International Conference on Mycobacterium bovis

Galway, Ireland. 7-10 June 2022. https://www.mbovis2022.com

Abstract
Bovine tuberculosis (bTB) persists in many countries having a significant impact on public health and livestock
industry finances. The incidence and prevalence of new cases in parts of the UK and elsewhere over the past dec-
ades warrant intensified efforts towards achieving Officially Tuberculosis Free (OTF) status in the respective regions.
Genetic selection aiming to identify and remove inherently susceptible animals from breeding has been proposed
as an additional measure in ongoing programmes towards controlling the disease. The presence of genetic varia-
tion among individual animals in their capacity to respond to Mycobacterium bovis exposure has been documented
and heritability estimates of 0.06-0.18 have been reported. Despite their moderate magnitude, these estimates
suggest that host resistance to bTB is amenable to improvement with selective breeding. Although relatively slow,
genetic progress can be constant, cumulative and permanent, thereby complementing ongoing disease con-
trol measures. Importantly, mostly no antagonistic genetic correlations have been found between bTB resistance
and other animal traits suggesting that carefully incorporating the former in breeding decisions should not adversely
affect bovine productivity. Simulation studies have demonstrated the potential impact of genetic selection on reduc-
ing the probability of a breakdown to occur or the duration and severity of a breakdown that has already been
declared. Furthermore, research on the bovine genome has identified multiple genomic markers and genes asso-
ciated with bTB resistance. Nevertheless, the combined outcomes of these studies suggest that host resistance
to bTB is a complex, polygenic trait, with no single gene alone explaining the inherent differences between resistant
and susceptible animals. Such results support the development of accurate genomic breeding values that duly cap-
ture the collective effect of multiple genes to underpin selective breeding programmes. In addition to improving host
resistance to bTB, scientists and practitioners have considered the possibility of reducing host infectivity. Ongoing
studies have suggested the presence of genetic variation for infectivity and confirmed that bTB eradication would be
accelerated if selective breeding considered both host resistance and infectivity traits. In conclusion, research activ-
ity on bTB genetics has generated knowledge and insights to support selective breeding as an additional measure
towards controlling and eradicating the disease.
Keywords Bovine Tuberculosis, Cattle, Genetics, Genomics, Selective breeding

*Correspondence: Introduction
Georgios Banos Tuberculosis is a key disease with multiple pathogen and
georgios.banos@sruc.ac.uk host species involved in transmission and consistently
1
Scotland’s Rural College (SRUC), Department of Animal and Veterinary
Sciences, Easter Bush, Midlothian EH25 9RG, UK ranks in the top five most significant diseases worldwide
[1]. According to the World Health Organisation’s “End

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Banos I rish Veterinary Journal 2023, 76(Suppl 1):19 Page 2 of 12

TB strategy” new tuberculosis cases and deaths world- some actually die. This variation is partly attributed to
wide must be reduced by 90% and 95%, respectively, by genetic factors manifested in protein-coding genes and/
the end of the 2016-2035 period [2]. The ambitiousness or regulatory sequence elements that render certain
of these goals combined with the fact that about one animals inherently more resistant or susceptible to the
third of the time has already elapsed set the stage for a disease than others. In the case of bTB, identifying ani-
considerable amount of intensified activity and atten- mals that carry genetic variants contributing to infection
tion, at multiple levels, to all Mycobacterium infections, resistance and selecting them for breeding can promote
including Mycobacterium bovis (M. bovis), the key patho- the overall population resistance and contribute to bTB
gen agent responsible for bovine tuberculosis. control. In a similar but more conservative scenario, indi-
Bovine tuberculosis (bTB) presents a global prob- vidual animals bearing genetic variants that render them
lem to the industry. As a zoonotic disease, bTB receives susceptible to the disease are identified and removed
due attention as a public health, financial, and politi- from the breeding process, thereby removing said vari-
cal issue. As such, monitoring, control, and eradication ants from the subsequent generations. The potential of
programmes have been established in multiple afflicted selective breeding in bTB control is reflected in a rela-
countries and regions. tively recent strategy review commissioned by the UK
In the United Kingdom (UK), bTB is endemic and government, led by Sir Charles Godfray of the University
costly to the tune of £175-200 million annually [3, 4]. of Oxford [8] where a relevant excerpt reads as follows:
The disease has returned and consolidated its presence ”There is evidence that cattle vary genetically in their sus-
in parts of Great Britain and Northern Ireland over the ceptibility to bovine TB and, once infected, there may be
past 30-40 years. The key policy in place at the moment genetic variation in their propensity to spread the infec-
is national surveillance based mostly on animal reaction tion to other animals. It is thus possible to select for bet-
to the single intradermal comparative cervical tuber- ter disease susceptibility and transmission traits as part of
culin (SICCT) test, commonly known as the “skin test”, cattle breeding programmes.” [8].
culling of positive animals, post-mortem examination The present review discusses the genetic component
and confirmation, and declaration of a bTB breakdown of variation in host response to bTB infection and dem-
in the herd where the positive animal(s) was found com- onstrates how this variation may be applied in selective
bined with movement restrictions. Scotland has been breeding programmes towards enhancing cattle resist-
the only Officially Tuberculosis Free (OTF) nation in the ance to bTB. Results from relevant studies are summa-
UK since 2009, while the goal is for England to achieve rised showing and quantifying the potential impact on
this status by 2038 followed by the other regions. To disease control and eradication. Further to disease resist-
achieve OTF status, the percentage of new breakdowns ance, the role of genetics in reducing animal infectivity
must not exceed 0.1% per year for six consecutive years regarding bTB is briefly discussed.
[5]. According to 2009 data, 5-6% of herds in the non-
OTF parts of the UK were affected [6] and the figure did Genetic variation among animals for resistance to bTB
not improve until recently [7]. However, the number of The genetic basis of host resistance and susceptibility to
new breakdowns in England in the 12-month period to bTB infection was addressed in a 2010 review [9] and
March 2022 was 2,892, down 8.80% from the previous potential future benefits were already acknowledged at
12-month period ending in March 2021 [7]. A similar the time. Multiple studies were subsequently conducted
reduction was observed in the number of cattle slaugh- and quantified the genetic variation for bTB in different
tered due to a bTB incident in the corresponding time cattle populations and countries, using a variety of sta-
period. An average annual decreasing trend of about 8% tistical models and trait definitions, and reported her-
in new herd incidents was also observed in the previous itability estimates that range mostly between 0.06 and
four 12-month periods. The challenge now is not only 0.18 [10–15]. The majority of studies were based on large
to maintain but, importantly, accelerate this downwards amounts of field data combined with extensive animal
trend over the next decades to ensure the OTF target is pedigree information. Although different datasets and
met. trait definitions were considered in these studies, all
Selective breeding has been proposed as an additional phenotypes related to animal response to bTB infection
possible means to control bTB, thereby contributing to and reflected their susceptibility or resistance to the dis-
the ongoing monitoring and eradication programmes. ease. The range of reported heritability estimates means
The main premise is that individual animals exposed to that 6-18% of the differences observed among individual
the same pathogenic conditions responsible for a dis- animals in their response to the pathogen are attributed
ease react and respond differently: some animals remain to heritable genetic factors. In two studies based on the
healthy, others become a little sick, others more so, and UK national bTB surveillance data, heritability of bTB
Banos Irish Veterinary Journal 2023, 76(Suppl 1):19 Page 3 of 12

resistance was 0.09-0.12 in dairy cattle [14] and 0.09-0.11 animal location and movement data, production history,
in beef cattle (author’s unpublished results, 2020). and extensive animal pedigree information.
More recent studies included animal genomic data The study first combined SICCT test and post-mortem
based on genotyping with genome-wide DNA arrays in data, namely records on bTB lesions and M. Bovis culture
the calculations and reported higher heritability esti- results, to define the health status of each animal, which
mates of 0.21-0.27 [16–19]. The advantage of using such would constitute their individual phenotype for bTB
data is that they more accurately capture finer details of infection. Furthermore, probabilities of animal infection
the genetic background dictating animal resistance to the at different stages of a breakdown were assigned to each
disease. The caveat is that the amount of genomic data is animal that eventually tested positive to the SICCT test
usually smaller compared to the size of pedigree data on [14]. These probabilities were based on the sensitivity
which conventional genetic studies are based; heritability estimates of the test as reported in the literature. Animals
estimates also tend to be sometimes inflated. Fortunately, that remained healthy throughout the epidemic were
animal genotyping costs are decreasing rapidly, and the included in the data as controls.
number of individual animals genotyped has been nota- A genetic model was developed to analyse these bTB
bly increasing in many breeding programmes worldwide, phenotypes [14]. The model was subsequently expanded
leading to improved accuracy of the genomic estimates. and, in its final form, accounts for multiple non-genetic
More discussion on genome-wide data in bTB studies is factors that are known to affect the trait, such as the
provided in a later section of this review. location and duration of the breakdown, the calendar
The overall magnitude of heritability reported so far year and month the breakdown started, the herd size,
may seem moderately low but for most animal traits of the age and lactation number of the cow, and factors
interest estimates normally do not exceed 0.50. Herit- such as heterosis and recombination, since the genetic
ability of health-related traits is known to be generally evaluation combines data from multiple dairy breeds
modest to low, usually less than 0.15. Nevertheless, the and must account for breed composition and potential
genetic variation manifested in the above heritability esti- crossbreeding.
mates for bTB resistance is enough to achieve progress Further to non-genetic effects, the model includes
with selective breeding. The latter has been decisively an animal additive genetic effect that, after data analy-
demonstrated for other cattle health traits with similar sis, provides an estimate of the genetic merit of each
or even lower heritability values such as clinical masti- individual animal for resistance to bTB that accounts
tis, lameness, and metabolic diseases, which now feature for all other sources of systematic variation fitted in the
prominently in selective breeding programmes world- model. Here, although the phenotypic data pertain only
wide [20]. to milking cows, breeding values are also estimated for
In conclusion, there is confidence that genetic variation their sires, through the pedigree connections that are
in cattle for bTB resistance is indeed sufficient to identify included in the data analysis. Actually, the sire breeding
animals that are inherently more resistant than others to values are more accurate than those of individual cows
M. Bovis infection. Selective breeding programmes would on the account of the former being associated with mul-
then need appropriate genetic evaluation systems and tiple progeny with records in the system. In a validation
tools in place to properly identify the inherently resistant exercise, the correlation of the sire estimated breeding
and susceptible animals in order to inform breeding deci- values with the proportion of infected milking daughters
sions that will underpin enhanced resistance in the sub- was -0.68, suggesting that sires with highly positive val-
sequent generations. ues of genetic merit are associated with reduced infection
rate in their progeny [14]. Similarly, the daughters of the
20 genetically most resistant sires are 21% less likely to
Genetic evaluations for bTB resistance become infected that those of the 20 most susceptible
Research conducted on bTB surveillance data in the UK sires [14].
led to the development of a national genetic evaluation Importantly, the correlation between genetic evalua-
of dairy cattle for bTB resistance [14]. This system esti- tions for bTB resistance and other animal traits is mostly
mates the genetic merit or breeding value of each indi- zero, suggesting that selective breeding to enhance ani-
vidual dairy bovine reared in the country for resistance mal resistance to the disease would not compromise
to the infection. Supported by the Agriculture and Horti- improvement in the other traits [14]. In fact, moderate
culture Development Board, the national farm levy body, positive desirable correlations have been reported of bTB
the genetic evaluation project collated relevant data with lifespan and the Profitable Lifetime Index (£PLI),
from different national databases, including: bTB records the overall dairy selection index in the UK that combines
from surveillance in Great Britain and Northern Ireland, the economically important animal traits in one single
Banos I rish Veterinary Journal 2023, 76(Suppl 1):19 Page 4 of 12

value [14]. This result consolidates the expectation that Genetic evaluations for bTB resistance are also avail-
enhancing the inherent cattle resistance to bTB would able in the Republic of Ireland [25] and are offered as
have favourable effects on animal longevity, with the tools for genetic selection to complement the on-going
associated benefits of enriched animal welfare, reduced national bTB control programme towards accelerating
waste, and improved environmental footprint. the disease eradication process. These evaluations are
A subsequent study expanded the bTB genetic evalua- based on relevant population genetic research conducted
tions to include genome-wide marker data from animal on Irish bTB surveillance data [13, 15] that demonstrated
genotyping using DNA arrays [21]. Different models of the presence of sufficient genetic variation and the fea-
genomic analysis were investigated and the single-step sibility of accurate genetic evaluations for the trait. The
Best Linear Unbiased Prediction (BLUP) method [22, 23], actual evaluations are run since 2019 by the Irish Cattle
which allows the simultaneous combination of all phe- Breeding Federation for both dairy and beef breeds in the
notypic, genomic and pedigree data available, resulted in country [25]. Estimated breeding values are expressed as
the most accurate estimates of animal genetic merit for the predicted proportion of infected progeny of a sire. In
bTB resistance [21]. Results from this type of analysis this regard, contrary to the UK genetic evaluation, lower
would facilitate the identification and selection of young values are desirable. For example, when two sires with
breeding animals early in life, thereby delivering faster estimated breeding values of 5% and 10% are assessed,
benefits of selective breeding in bTB control and eradica- 5% fewer progeny of the first sire are expected to be diag-
tion programmes. nosed as infected compared to the second.
Research on the genetics of bTB resistance in dairy Despite being expressed on distinctly different scales
cattle has led to the development of the official UK in Ireland and the UK, estimated breeding values for
national genetic evaluation, run since 2016 at the Edin- resistance to bTB offer essentially the same information,
burgh Genetic Evaluation Services on behalf of the namely, they identify and separate genetically resistant
Agriculture and Horticulture Development Board. The and susceptible individuals. Thus, they have the same
genetic evaluation outcome, the actual selection index, potential utility in supporting selective breeding pro-
has been termed “TB Advantage” [24] and is now avail- grammes in the respective countries. The key is in the
able for dairy sires of all breeds with progeny (milking interpretation and proper use.
daughters) in the national bTB surveillance programme. These genetic evaluations are now well tested and vali-
TB Advantage is expressed on a scale normally ranging dated nationally, so that combination and a joint analysis
from -4 to +4, where, for every +1 point in the index, 1% of data from the two countries to produce across-coun-
fewer daughters are expected to become infected during try estimated breeding values for bTB become a real-
a bTB breakdown. This information allows dairy farmers istic option. Experience with the international genetic
to focus on the most positive or remove the most nega- evaluations provided by the International Bull Evaluation
tive TB Advantage bulls from the list of potential sires Service (Interbull) [26] since 1994 for an array of other
selected to artificially inseminate their cows. bovine traits has been very positive. It is clearly possible
Another research project investigated the feasibility of to combine data from different countries and populations
a genetic evaluation for bTB resistance in UK beef cat- with good genetic links, account for differences in the
tle. Data analyses were conducted on 437,235 animals, national definitions and systems, analyse jointly, and then
progeny of 36,790 sires from 53 beef breeds. These data express the estimated breeding values of all selection
pertained to 8,648 bTB breakdowns where 7.3% of the candidates available internationally on the national scale
animals were infected (author’s unpublished results, used in each country. In addition to enhancing the accu-
2020). Significant genetic variation was detected for bTB racy of the genetic evaluation and broadening the selec-
resistance and was manifested in variation in the result- tion pool for the farmers, outcomes facilitate trade across
ing estimated breeding values of the sires, thereby dem- the border, streamline the use of bovine genetics available
onstrating the feasibility to distinguish breeding animals globally, and promote collaboration and harmonisation
expected to produce bTB resistant from susceptible of practices in the participating countries.
progeny. As was the case with dairy breeds, correlations
of these breeding values with beef traits such as animal Genomic architecture of cattle resistance to bTB
growth, carcass characteristics and lifespan were either The advent and broad implementation of bovine
negligible or moderately favourable, suggesting that genome-wide DNA arrays (chips) based on tens or hun-
genetic selection to enhance bTB resistance in beef cattle dreds of thousands of Single Nucleotide Polymorphism
would not compromise the current breeding goal. Incor- (SNP) markers have enabled research that cast closer
poration of bTB in the official national genetic evaluation insights on genomic regions and genes associated with
process of beef cattle is imminent. animal traits of interest. The key principle is that these
Banos Irish Veterinary Journal 2023, 76(Suppl 1):19 Page 5 of 12

SNPs are within or in high linkage disequilibrium with Potential impact of selective breeding on the disease
genes and genomic regulatory regions that control dynamics
important animal traits. This approach has found wide- Genetic improvement with selective breeding is a long-
spread use in livestock breeding programmes [27]. term process and benefits become visible in future gen-
Multiple genomic association studies using data from erations. From the moment the genetically most resistant
the above mentioned DNA arrays have been conducted breeding animals are identified and mated, it would take
on bTB resistance in various bovine populations in at least one generation to see the effect in their progeny.
different countries [15, 16, 18, 19, 28–31]. The major- The process will continue in the subsequent generation
ity of the studies reported single markers with rela- and then in the following one and so on, and benefits
tively modest effects on the trait. Furthermore, mainly gradually accumulate. The process is slow, but the effects
different markers were found associated with cattle are permanent and cumulative. The benefits of selec-
resistance to bTB across these studies, partly reflecting tive breeding have been observed in multiple livestock
differences among populations, trait definitions, DNA traits not least those associated with animal production,
array specifications, and models of statistical analysis. health, fertility, and longevity over the past century and
Nevertheless, the overall picture is that of a trait that is have been duly documented [20].
not being controlled by only a single or a few genes. Presence of heritable genetic variation and the feasibil-
In addition, a few regional heritability mapping stud- ity of harnessing it in the estimation of accurate genetic
ies have been conducted using genome-wide SNP data evaluations of animals, as discussed above, may underpin
[16, 18, 32]. Some of these studies revealed genomic selective breeding practices aiming to enhance resistance
regions associated with bTB resistance that included to bTB and contribute to the overall control and even-
significant SNPs identified in the genomic association, tual eradication of the disease. In a generational context,
but others were not necessarily consistent with sin- these selection tools have become available relatively
gle marker results on the same data. In the latter case, recently and the full effects are expected to materialise in
these would be genomic regions that harbour multi- due course in the subsequent generations.
ple markers and genes, each with a small undetectable In the meantime, simulation studies have been con-
effect, but combined with a more substantial and dis- ducted to predict and quantify the long-term effect of
cernible effect on bTB resistance. selective breeding for enhanced animal resistance or
Using publicly available bovine genome assemblies, reduced susceptibility to bTB. In one such study, animal
several annotated genes were identified neighbouring data were simulated reflecting the current bTB dynam-
SNPs or being located within genomic regions associ- ics in the UK regarding disease prevalence, and size and
ated with bTB traits in the aforementioned studies. duration of bTB breakdowns [39]. A model of disease
Further studies more closely examined specific candi- transmission was implemented based on a sequence
date genes affecting the host’s resistance or susceptibil- of stages, where the animal: (i) is at first susceptible but
ity to the disease [33–38]. These studies offered novel not infected, (ii) is then exposed to the pathogen, (iii)
insights into the function and role of the individual becomes infectious and (iv) is finally detected as infected
genes in networks and pathways that are linked with with the SICCT test and, therefore, removed from the
the animal’s capacity to fight off infection. herd. This choice of model was based on empirical data
Table 1 summarises the genes that have been report- showing that infected cattle may become infectious
edly associated with cattle resistance to bTB in different before entering the detectable stage [40]. The same level
genomic association, regional heritability mapping, and of genetic variation among individual animals in bTB
candidate gene studies. The collective outcome of these resistance found in the real data analyses [14] was intro-
studies is that cattle resistance to bTB is a largely poly- duced in the simulations. Subsequently, various levels of
genic trait dictated by multiple genes across the bovine selection emphasis on bTB resistance were examined:
genome. Therefore, selective breeding based on genetic in the most intense selection scenario, the 10% geneti-
and genomic evaluations as previously discussed would cally most resistant sires were selected to breed the next
be the best approach towards genetic improvement of generation, whereas in the least intense case 70% were
the trait. Furthermore, identification of single mark- selected. The latter reflects a conservative approach
ers and genomic regions with noticeable effects may where the 30% genetically most susceptible animals are
inform the genetic evaluation process, with due empha- removed from breeding. A baseline scenario of no selec-
sis being placed on these markers and regions result- tion was also examined for comparison. Twenty genera-
ing in an increase in the accuracy of the estimate of the tions of selection were simulated, roughly corresponding
genetic merit of individual animals for resistance to to 80-100 years in a dairy cattle conventional breeding
bTB. programme.
Table 1 Genes associated with host resistance to bovine tuberculosis in different research studies in the past 10 years demonstrate the polygenic nature of the trait
Reference [28] [16] [29] [33] [30] [34] [35] [18] [32] [15] [31] [36] [19] [37] [38]
Year 2012 2014 2015 2015 2016 2016 2017 2017 2017 2019 2019 2020 2020 2020 2021

Countrya, IE, HO IE, HO ET, HAX TW, HO IE, HO TW, HO CN, HO UK, HO UK, HO IE. ML1 MX, HO IN, MLX CM, FX UK/PK, CN, HO
­Breedb ML2

No. animals 986 1,151 502 150 841 164 232 804 1,966 14,778 375 245 212 45 283
c
Approach GWAS GWAS, GWAS SCG GWAS SCG SCG GWAS, RHM GWAS GWAS SCG GWAS SCG SCG
RHM RHM

Chromosome
1 KALRN CD80, TIGIT,
NAALADL2
Banos I rish Veterinary Journal 2023, 76(Suppl 1):19

2 MYO3B SLC11A1 SLC11A1 PARD3B DNER SLC11A1

3 CTSS,
FCGR1A,
TRIM33
4 DPP6
5 CD163
6 TLR1, TLR6, ANTXR2 TLR1
TLR10,
RHOH
10 AP3B1 JMY
13 PTPRT MACROD2,
KIF16B
15 OR52E5,
ENSBTAG00000023125,
ENSBTAG00000047246,
ENSBTAG00000048223,
ENSBTAG00000023912
16 SRGAP2, RASSF5
17 CLGN
19 NOS2A
Page 6 of 12
Table 1 (continued)
Reference [28] [16] [29] [33] [30] [34] [35] [18] [32] [15] [31] [36] [19] [37] [38]
Year 2012 2014 2015 2015 2016 2016 2017 2017 2017 2019 2019 2020 2020 2020 2021

Countrya, IE, HO IE, HO ET, HAX TW, HO IE, HO TW, HO CN, HO UK, HO UK, HO IE. ML1 MX, HO IN, MLX CM, FX UK/PK, CN, HO
Banos Irish Veterinary Journal 2023, 76(Suppl 1):19

­Breedb ML2

No. animals 986 1,151 502 150 841 164 232 804 1,966 14,778 375 245 212 45 283
c
Approach GWAS GWAS, GWAS SCG GWAS SCG SCG GWAS, RHM GWAS GWAS SCG GWAS SCG SCG
RHM RHM
22 SLC6A6 RAF1, MKRN2,
MKRN2OS,
TSEN2, PPARG,
MIR2373
23 FKBP5 TNFα RNF144B LRRC1, RCAN2 HFE TNFα
LOC104975626,
KLHL31, GCLC,
DSB, BOLA-DYA,
BOLA-DYB,
BOLA-DOB,
LOC100140517,
MLIP,
LOC104975626
25 IL21R
29 ANO9, PICALM
SIGIRR
a
Country of study: IE Ireland, ET Ethiopia, TW Taiwan, CN China, UK United Kingdom, MX Mexico, IN India, CM Cameroon, PK Pakistan
b
Bovine breed of study: HO Holstein, HAX HO x Arsi Zebu cross, ML1 Multiple beef and dairy breeds, MLX Multiple indigenous breeds and crosses, FX Fulani and crosses, ML2 HO, Brown Swiss, Sahiwal
c
Data analysis method: GWAS Genome-Wide Association Study, RHM Regional Heritability Mapping, SCG Single Candidate Gene
Page 7 of 12
Banos I rish Veterinary Journal 2023, 76(Suppl 1):19 Page 8 of 12

Results showed that any level of selective breed- them early and removing from the breeding process
ing would be associated with a faster ending of the epi- would yield additional benefits. Selective breeding prac-
demic compared to the scenario of no selection [39]. tices could then be expanded to harness this novel host
As expected, higher selection intensities had a stronger genetic variation and contribute to decreasing infection
impact on the epidemic profile. The probability of a rates.
breakdown to occur would half after about 5 generations Relevant genetic-epidemiological simulation studies
of intense selection of the top genetic merit sires. A more have suggested that selective breeding for reduced infec-
conservative approach based on avoiding the genetically tivity together with enhanced resistance to bTB would
most susceptible sires in breeding decisions would take lead to faster disease eradication than selecting only for
about 12 generations to reduce the probability of a break- enhanced resistance or, of course, not selecting at all [45,
down to one half. When a breakdown actually occurs, 46]. These simulation studies showed that the magnitude
selective breeding would decrease its duration and sever- of the benefit would vary depending on selection intensi-
ity manifested in the number of infected animals after the ties, the heritability of infectivity, and the genetic correla-
breakdown had been declared. After one generation of tion between infectivity and resistance. Several selective
selection, duration and severity could decrease by 5-10% breeding scenarios were assessed in these studies, and in
and 11-17%, respectively, dependent on the intensity of all cases the epidemic risk decreased dramatically, when
selection [39]. In practice, selection programmes may infectivity and resistance were considered together. For
be adapted to the geographical risk levels, with actively example, in one scenario assuming moderate selection
intense selection applied in high-risk areas and moderate intensity, trait heritability and prediction accuracy, the
conservative practices elsewhere. epidemic risk after five generations of selection decreased
The above research was based on a model reflect- by 50% when selective breeding decisions considered
ing the “worst-case” scenario where an animal becomes infectivity [45]. In another scenario with similar assumed
infectious and starts transmitting the disease before it parameters, it took seven generations for the bTB epi-
can be detected as infected and removed from the herd. demic to die out with selective breeding for reduced sus-
Although this assertion is consistent with the suggestion ceptibility and three generations when selective breeding
that cattle with bTB lesions in the respiratory tract should aimed at reducing both animal susceptibility and infec-
be considered potential transmitters of the pathogen and tivity [46].
sources of infection for other animals in the herd [41], However, the genetic basis of infectivity is still largely
previous non-genetic epidemiological studies on bTB unknown. Defining and characterising the proper ani-
typically assumed that infected animals usually react pos- mal phenotype is a serious challenge. Work is currently
itively to the SICCT test and are removed from the herd being conducted on this topic and a recent study on dairy
before they become infectious [42, 43]. The two models cattle data reported significant genetic variation among
are discussed in detail in [39]. Further genetic epidemi- index cases regarding the number of secondary cases
ological studies reversing the order of the two stages so attributed to them [47]. Here an index case would be the
that infected animals were detectable before they became first animal tested and confirmed bTB positive, thereby
infectious demonstrated that the benefits of selective instigating the breakdown, and secondary cases would
breeding were proportionally still the same compared to be the animals that tested positive in the first stages of
the no-selection option [39]. the breakdown and assumed to have been infected by the
Key conclusions drawn for this research were that index case. Thus, the trait may be considered as a proxy
genetic selection could accelerate bTB eradication, as a for animal infectiousness. Different models of analysis
complementary measure to already existing ones. Thus, were considered and preliminary heritability estimates of
selective breeding for enhanced animal resistance to bTB 0.09-0.21 derived were of similar magnitude as the herit-
can contribute to herds and regions achieving their OTF ability estimates for bTB resistance discussed previously.
goals faster. Continuing work addresses refinements in the defini-
tion of animal infectivity and modelling improvements.
Genetic background of bTB infectivity Although more research is definitely warranted to prop-
Further to improving animal resistance to bTB, a disease erly define and dissect the genetic basis of infectivity and
eradication programme would also benefit if the rate of understand the potential for genetic improvement, these
transmission from one animal to another decreased. first results are encouraging.
There is increasing evidence, albeit mostly empirical, that
individual animals differ in their capacity to infect their Novel bTB phenotypes
herd-mates. The presence of inherently super-spreader Availability of informative individual animal pheno-
individuals is now widely accepted [44] and identifying types for the traits of interest is the key and most crucial
Banos Irish Veterinary Journal 2023, 76(Suppl 1):19 Page 9 of 12

component of modern selective breeding programmes. predictions may constitute additional novel animal phe-
This entails data of high quality that reflect the true biol- notypes for bTB, warranting genetic studies to determine
ogy of the animal as closely as possible, available in suf- their suitability for genetic evaluations and improvement
ficient quantities to allow accurate calculations. Without with selective breeding.
said phenotypes, even the most advanced genomic tech-
nologies and the most elaborate statistical analysis mod- Closing remarks and outlook
els would have very little opportunity to demonstrate Bovine tuberculosis is a complex issue, and an array
their utility. of factors may determine whether an animal becomes
In the case of bTB, SICCT test records combined with infected, and a breakdown is declared. Complex prob-
post-mortem visible lesions and M. bovis culture results lems require complex strategies and solutions, and
constitute the phenotypes in current national genetic indeed this is the case with ongoing bTB control and
evaluations [24, 25]. Thanks to the ongoing national sur- eradication programmes in different countries. Genetic
veillance programmes, such data span multiple decades selection of inherently resistant individuals that will
and cover all affected geographic regions in a country. breed enhanced natural resistance into the subsequent
The depth and amount of data in combination with the generations is proposed as an additional component
high specificity of the SICCT test render these pheno- within these programmes.
types and resulting genetic evaluations valuable for selec- Further improvements in genomic evaluations are in
tive breeding purposes. scope with more targeted genotyping both in terms of
Other diagnostics that may provide new animal pheno- animals (bulls and cows) and DNA arrays, and incor-
types with improved sensitivity are worth consideration. poration of identified genomic regions with significant
Gamma-interferon assays have been long used for bTB effects on the trait in the calculation of breeding values.
diagnosis [48] often in combination with the SICCT test Decreasing DNA array genotyping costs, genotype impu-
[49], especially in high-risk geographic regions. Never- tation improvements, and new approaches such as geno-
theless, the development of individual animal phenotypes typing by low pass sequencing combined with imputation
for bTB based on gamma-interferon to complement the provide useful opportunities in this regard.
existing ones based on SICCT tests and post-mortem As previously mentioned, the polygenicity of host
examination results and use in bovine selective breeding resistance to M. bovis infection is now well accepted.
programmes has not been explored. Future genomic studies of DNA array and whole genome
Alternative phenotyping approaches have been pro- sequence data combined with post-genomic (tran-
posed in livestock improvement based on molecular scriptional and translational) research will cast fur-
traces in the milk of dairy cows that emanate from vari- ther insights into the complex architecture of the trait,
ous animal physiological processes [50]. Mid-infrared including focus on the location and function of both
(MIR) spectroscopy of milk samples may capture these protein-coding genes and regulatory elements [57].
traces in an effective, non-invasive, and non-interfer- Improvements in the functional annotation of the bovine
ing process. This has led to the accumulation of large genome [58] certainly facilitate such research activities,
amounts of MIR data in routine milk recording systems leading to enhanced precision and biological relevance of
in many countries. Analysis of MIR data already provides the genomic evaluation and selective breeding.
useful proxy phenotypes for different animal traits asso- Beyond host resistance to M. bovis infection, under-
ciated with milk composition [51], cow body energy [52], standing the genetics of infectivity at the individual ani-
pregnancy diagnosis [53], greenhouse gas emissions [54], mal level is only now starting and we have some way to
and feed intake [55]. go before being able to usefully inform genetic selec-
In a recent study, extensive cow milk MIR data were tion programmes aiming to decrease the rate of ani-
combined with bTB national surveillance records and mal-to-animal transmission. Nevertheless, this area of
machine learning was deployed to jointly analyse the scientific research and development is topical and war-
data and deliver a prediction pipeline of the bTB status of rants continuing attention and effort. Future bTB control
individual animals from their MIR spectral profiles [56]. programmes should be able to combine selective breed-
After optimisation of the training process, including data ing for increased host resistance with reduced animal
and network, the specificity, sensitivity and accuracy of infectivity.
predictions reached 0.94, 0.96 and 0.95, respectively [56]. Furthermore, as has been experienced with the
These results lend confidence in the method to predict genetics of just about any important animal trait,
future bTB status of individual animals, thereby offer- multi-actor collaboration is a prerequisite to the suc-
ing farmers a useful tool for early management decisions cessful development and implementation of selective
on cows likely to become infected. Furthermore, these breeding programmes. There is scope for continuing
Banos I rish Veterinary Journal 2023, 76(Suppl 1):19 Page 10 of 12

interdisciplinary research to understand why and how Consent for publication

Not applicable.
individual genes affect host traits and how host genet-
ics interact with pathogen variation. Moreover, there Competing interests
are opportunities for across-country cooperation to The author declares no competing interests.
facilitate international trade that is of key importance
to the bovine industry. There are national genetic Received: 26 October 2022 Accepted: 25 July 2023
evaluation systems for bTB in place in at least the UK Published: 24 August 2023
and Ireland and it is possible to pull data together and
produce international genetic evaluations, as is the
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