64
Targets for nutrigenomics in production animals: a
numbers game
G.S. Harper1 and P.L. Greenwood2
1
Strategic Science, Meat and Livestock Australia, 23 Kyabra Street, Newstead QLD 4006, Australia, gharper@
mla.com.au; 2Beef Industry Centre of Excellence, NSW Department of Primary Industries, University of New
England, Armidale NSW 2351, Australia
Summary
Nutrigenomics for production animals is likely to
deliver fundamental and novel information about the
responses of animals of specific genotypes to dietary
nutrients. Although the demand for individualised
nutrition is unlikely to match that in the field of human
health, diets specific for elite classes of animals and
optimised for critical developmental windows are
likely outcomes of current research. As was the case
for structural and functional genomics, nutrigenomics
for production animals will capitalise on large global
investments in human and model-animal nutrigenomics
by the private and public sectors. The Australian animal
science community cannot afford to rely on spill-
over of information from these larger studies because
intellectual property is rapidly secured and knowledge
is accumulating at an accelerating pace.
Keywords: nutrigenomics, nutrition, genomics, nutrient
effects
Introduction
Nutrigenomics is the study of nutrition using genomics.
Genomics refers to molecular characterisation of all
of the genetic material of an organism (the genome),
for which high-throughput technologies are used.
Nutrigenomics encompasses aspects of nutrigenetics
(effects of an individual’s genotype on its response
to nutrition), nutritional epigenetics (effects of
nutritional phenomena that change genome function
without changing nucleotide sequence) and nutritional
transcriptomics (effects of nutrients on the expression
of genes and regulatory elements). Unlike genetics,
which can be reductionist in its approach, the nutritional
sciences are more integrative and encompass the
entire animal, probably because all of an animal’s
physiological systems can be affected by nutrition. Why
coin the term, nutrigenomics (Peregrin, 2001)? Why
not continue to use terms such as nutrition, nutritional
biochemistry or physiology? In nutrigenomics, the
emphasis is on genomic aspects of nutrition and on
the use of techniques that enable gene expression to be
studied at a deeper level than was previously possible.
Nutrigenomics represents an opportunity to understand
nutrition at the level of the individual animal.
Animal nutritionists seek to understand sufficient
about gene regulation and expression to enable them
Recent Advances in Animal Nutrition in Australia 16 (2007)
65
to understand and ultimately influence the growth,
development, performance and health of animals. There
are many potential applications for nutrigenomics.
In companion and working animals, this might be
optimisation of diets for animals with specific breed
or genotypic propensities to express an interesting
or useful trait (colour and singing in birds; guiding
ability in dogs). Diets that minimise the expression
of deleterious traits such as laminitis in race horses
could be developed. In food production animals, one
priority would be optimisation of diets for energetically
efficient deposition of muscle and eating-quality traits
such as marbling or tenderness in beef. In species in
need of conservation, diets that optimise reproductive
performance and survival may be of most interest.
Clearly, animal nutrition science and the potential
applications of nutrigenomics are very broad.
In this article, we focus our discussion on
production animals, particularly cattle and sheep, and
on the measurable phenotype of liveweight gain after
weaning. This provides a convenient yardstick for
making comparisons across nutritional environments
and across the mammalian species where appropriate.
Transcriptional profiling and
biostatistics
Current work in nutrigenomics is focused on
transcriptional profiling or transcriptomics. This is the
measurement of the expression of individual genes or
DNA sequences using RNA products. Oligonucleotide
and cDNA microarrays enable rapid and global
quantification of mRNA concentrations in animal tissues
at particular moments in time. Given that thousands of
genes in the bovine genome are expressed at low levels
throughout postnatal life, the relative concentration
of any particular mRNA compared to the average
concentration of most mRNAs directly reflects the level
of expression of the particular gene. The concentration
of mRNA is measured indirectly in extracts of a tissue
by creation of a complimentary labelled strand of DNA
in a test tube. This labelled strand of DNA can then
be hybridised with complimentary DNA in an array
containing a known set of gene sequences that are
attached to a solid substrate, often glass or nylon. The
intensity of colour that results from this hybridisation
66
process is directly related to the amount of specific
mRNA present in the original tissue extract, and hence
the level of gene expression. In principle, the analyst can
determine which genes are highly expressed in response
to a specific treatment, and which are expressed at a
low level. However, in practice there is almost always
a problem with false positives: genes that appear to
be differentially expressed but are not (Reverter et
al., 2003; Reverter et al., 2004). The bioinformatics
and biostatistics that underpin expression analyses are
not trivial and at the research group level, this results
in structures and collaborative arrangements that are
markedly different to those that existed previously
within animal nutrition science.
In functional genomic laboratories it is common
to use the same microarray slide platform across many
nutritional studies, but slides from different studies
are analysed separately because of computational
limitations or because of the impracticality of analysing
samples from different studies within a slide. However,
exploitation of covariance structures amongst gene
expression data across studies can allow estimation of
significant effects. In 2004, an approach for combining
multiple studies was proposed. I used multivariate mixed
models and the assumption of a non-zero correlation
among genes across experiments, while constraining the
analysis to a null-residual covariance. The method was
applied to the analysis of three experiments in nutrition
and genetics of cattle: a nutritional restriction study,
a breed-comparison study and an in vitro cell-culture
study (Reverter et al., 2004). The three experiments
were analysed jointly using 54 arrays of the same form,
each with 19,200 spots and 7638 “elements” or genes.
The resulting seven-variate model contained 752,476
equations and 56 covariances. To identify differentially
expressed genes, model-based clustering to a linear
combination of random gene × variety interactions was
applied. Biological interpretation of the findings was then
enhanced using bioinformatics. An iterative algorithm
to distinguish between gene ontological classes that
were significantly changed in each experiment and
those that were common amongst experiments was
then applied. This approach identified 118 genes with
coordinate expression that associated loosely around
biological functions such as adipogenesis, protein
turnover and energy metabolism when applied across
nine expression experiments (Reverter et al., 2006).
This example shows how nutrigenomic approaches
enable work to be conducted at levels well above
those at which previous work has been conducted.
Previously, many workers relied on a gene-by-gene
approach to nutritional research. Researchers identified
a gene or small family of genes for a particular purpose
using a mixture of candidate gene analysis, historical
precedent, or other factors. They then used tools such
as DNA probes, antibodies, knockout mice, cells
culture or molecular effectors of the gene to analyse its
properties and the properties of genes closely associated
with it. However, the gene-by-gene approach, although
effective in uncovering molecular detail, is too slow
for studying the multitude of interactions involved in
regulation of mammalian growth and development. If all
25,000 genes of the genome interacted randomly with
three other genes to notionally determine a phenotypic
trait, the number of combinations would be in the order
of 1013. With the current methodology, at least a year of
study would be required to understand each interacting
group of genes; therefore, it would take centuries to
investigate all interactions. A more efficient approach
such as the nutrigenomic approach is required.
Nutrient diversity
Mammals are exposed to a diverse range of nutrients,
non-nutrients and anti-nutrients through their diets.
Foraging ruminant species face particular challenges,
as the diversity of the plant kingdom could potentially
be presented to the rumen microflora and the gut wall
(Dunshea et al., 2006). At one level, this diversity can
be reduced by assessing each new compound as part
of a whole diet and in terms of the amount of energy
liberated through its metabolism and the chemical form
of the metabolites. The next level of complexity involves
the bioactive effects of compounds, i.e., physiological
effects over and above those associated with nutritional
value. In human nutrigenomics, essential nutrients such
as Ca, Zn, Se and folate, and non-essential nutrients
such as phytochemicals (carotenoids, flavonoids,
indoles), zoochemicals (conjugated linoleic acid,
n-3 fatty acids), fungochemicals (e.g., mushroom
products) and bacteriochemicals (e.g., compounds
formed during food fermentation) are of interest. It has
been found for example, that groups of people with
specific genotypes have requirements for essential
nutrients that are significantly different from those of
the broader population, which challenges concepts such
as recommended daily allowances. Likewise, there
is mounting evidence for the existence of genotype-
specific responses of human populations to particular
carcinogens and for the existence of interactions
between nutrients such as Se and the development of
cancer in response to standardized doses of carcinogens
(Ratnasinghe et al., 2000).
As the extent of phenotyped populations and
financial resources available for production animal
studies is less than that available for human medical
research, animal scientists should focus on large
nutrient × gene effects rather than effects that are of
mechanistic interest. Populations of animals for which
phenotypes have been recorded are available and a
degree of phenotype–genotype association has been
achieved. These phenotype–genotype associations
have been established using animals categorized using
SGA (sheep) or BREEDPLAN (cattle) and constant
or controlled levels of nutrition (Allingham et al.,
2006). Standardised exogenous treatments such as
hormonal growth-promoting compounds are also of
interest (Hunter et al., 2001). The next phase of this
work should include the control of nutrient intake in
experimental populations for which genotype is either
controlled experimentally or at least defined accurately.
Examples include cattle genotypes associated with
increased meat tenderness (Van Eenenaam et al., 2007)
and sheep genotypes associated with increased meat
yield (Cockett et al., 2005).
Nutritional restriction and
compensatory growth
Nutritional restriction in production animals is of
particular interest because of the significance of meat
yield to production systems in the developing world and
in extensive grazing systems in the developed world.
It is pertinent at this time because much of Australia
is currently experiencing severe drought. Nutritional
restriction is also of interest because it is a definable
animal treatment with known biological consequences,
certainly more definable than replete nutritional
treatments. Restriction-based treatments provide an
opportunity to elucidate physiological responses of
various genotypes at the level of the individual gene
and the gene network.
Relatively little is known about the molecular
response of skeletal muscle to nutritional restriction in
production animal species. Recent microarray studies
by our colleagues (Lehnert et al., 2006; Reverter et
al., 2006) examined molecular changes induced by
long-term severe dietary restriction in young steers
and Byrne et al., (2005) described responses to short-
term dietary restriction. This body of work provides a
detailed insight into the molecular changes in bovine
skeletal muscle that accompany prolonged atrophy in
response to body weight loss and to hypertrophy during
re-alimentation and recovery. The histochemical and
gene expression changes observed after 114 d of body
weight loss were consistent and indicate that atrophy
is characterized by the preferential sacrifice of fast-
twitch glycolytic fibres. The downregulation of genes
associated with structural muscle proteins such as alpha
actin (ACTA1) and tropomyosin (TPM2) and with
muscle enzymes such as ATPase (ATP1A2) and creatine
kinase (CKM) all indicate that some indiscriminate loss
of muscle fibre mass occurs. However, whereas genes
for both myosin binding proteins 1 and 2 (MYBPC1
and 2) were downregulated after 114 d, MYBPC2
(fast isoform binding protein) transcription was more
profoundly affected than MYBPC1 (slow isoform
binding protein) transcription, suggesting that some
specificity in turnover occurs. Expression of muscle
enzymes of the glycolytic pathway (e.g., ALDOA,
ENO, GAPDH, PGK1, PKM2 and TPI1) appears to be
profoundly affected by nutritional restriction. Overall,
the observation that body weight-loss treatments
induced more profound downregulation of transcription
in fast-twitch glycolytic myofibres than in slow-twitch
oxidative fibres indicates that sparing of slow-twitch
fibres occurs.
The response of mammalian muscle to starvation
has been thoroughly studied at the gross myofibre level
67
in humans, pigs, hamsters and mice (see Lehnert et
al., 2006) and shows that preferential atrophy of the
fast, glycolytic fibres does indeed occur. It is unclear
whether the preferential atrophy of glycolytic muscle
fibres in mammals is an adaptation to cope with cycles
of nutritional plenty and deprivation. Interestingly,
proponents of this hypothesis argue that preferential
atrophy of glycolytic fibres provides an evolutionary
advantage because reduction of the number of these
fibres conserves glucose (Hocquette et al., 1995).
Restriction of dietary energy or protein has often
been associated with changes in protein synthesis,
particularly that of extracellular matrix proteins such
as collagen. An important observation of Lehnert et al.
(2006) and others in our group (Reverter et al., 2003) is
the coordinated downregulation of transcripts coding for
extracellular matrix proteins which are associated with
supramolecular complexes with collagen in the matrix.
Interestingly, coordinated upregulation of expression
of these genes was not observed during compensatory
growth.
Lehnert et al. (2006) also studied gene expression in
cattle with a view to identifying the molecular processes
that drive compensatory growth in muscle. Data from
this study were compared to those obtained during
muscle regeneration and murine expression profiling
studies in which significantly increased expression of
extracellular matrix-related and myogenic factors genes
occurred (Goetsch et al., 2003). In the comparison, only
one differentially expressed extracellular matrix-related
gene (MRCL3) was identified during compensatory
growth of cattle. The timing of sampling (84 d after the
start of realimentation) is likely to have influenced this
finding. By this time, a normal growth trajectory was
evident, although others indicated that some effects of
nutrient restriction on the connective tissue extracellular
matrix in meat persist for an extended period of time
(Allingham et al., 1998). To understand the compensatory
growth response, future gene expression studies should
coincide with the commencement of realimentation to
characterize acute adaptations to severe, chronic body
weight loss.
Particularly interesting genes
Stearoyl-CoA desaturase (SCD) is considered a key
regulatory enzyme of the lipogenic pathway (Lehnert
et al., 2006). In rats, liver SCD activity decreased
during starvation and rapidly increased to high levels
upon re-feeding high carbohydrate diets (Oshino and
Sato, 1972). The reduction of SCD gene activity in the
liver of rats in response to leptin-mediated body weight
loss has recently been proposed as one of the main
mechanisms through which leptin exerts its effects
on body composition (Cohen et al., 2002). In contrast
to rodents, bovine SCD is expressed at high levels in
subcutaneous fat and muscle but not in liver. Microarray
analysis of lean skeletal muscle during body weight
loss shows that SCD gene transcripts are more highly
represented in the muscle of weight loss animals than
their rapid growth contemporaries. This result appears
68
to contradict existing data on SCD regulation in the
liver under conditions of body weight loss (Sprecher,
1981) and other findings on the response of skeletal
muscle lipid metabolism to diet (Cameron-Smith et
al., 2003). It is possible that SCD transcripts are more
highly represented in weight loss muscle because of
a reduction in the size or number of cells that do not
express SCD. SCD gene transcription in muscle may
be associated mainly with type-1 oxidative and type-
2A oxidative–glycolytic myofibre types. Recent data
on the effects of SCD1 deficiency on skeletal muscle
metabolism in the mouse showed that red muscles,
which have a greater proportion of oxidative fibres,
were much more profoundly affected than white
muscles (predominantly glycolytic) (Dobrzyn et al.,
2005). The lipid contents and profiles of bovine muscle
have important effects on meat quality (Pethick et al.,
2004). A novel way of modifying marbling, a phenotype
that has been resistant to manipulation, could involve
inducing accumulation of unsaturated fatty acids in
bovine muscle by moderate growth restriction. Detailed
studies of cellularity, lipid profiles and enzyme activities
of bovine growth-restricted muscle are required to
evaluate this possibility.
Elevated gene expression in response to
body weight loss
In addition to SCD, six other genes also exhibited
greater levels of expression in the muscle of animals
experiencing chronic weight loss (Lehnert et al., 2006).
The significance of these differential gene expression
signals warrants consideration because they may
be more highly represented because of proportional
changes in muscle fibre types rather than because of
a specific transcriptional response of skeletal muscle
tissue to nutrient deprivation. Studies with mice and
humans found that elevated expression of the ubiquitin-
protein ligases, atrogin-1 (MAFbx) and muscle RING
finger (MuRF1), is part of the molecular signature
of atrophic muscle (Jagoe et al., 2002; Glass, 2003).
Byrne et al. (2005) presented evidence of specific
regulation of the ubiquitin/proteasome pathway as
well as of ribosomal proteins after 27 d of body weight
loss. Although Lehnert et al. (2006) detected a large
number of differentially expressed genes, the ubiquitin-
associated sequestosome (SQSTM1) protein was the
only element of the ubiquitin/proteasome system that
appeared to be differentially regulated during sustained
muscle remodelling. This result may indicate that the
major reprogramming events in muscle in response to
nutritional deprivation were no longer evident by 84
d. Furthermore, their findings suggest that the muscle
of these animals exhibited a homeorhetic response
resulting in a coordinated shift in homeostasis (Bauman
and Currie, 1980), perhaps preparing the animal for
subsequent compensatory growth.
The cysteine and glycine-rich protein 3 (CSRP3),
also referred to as muscle LIM protein, is involved
in the regulation of myogenesis (Kong et al., 1997)
and was upregulated in the weight loss group after
120 d of restriction. This coincided with upregulation
of transcription of the myogenic regulatory factor,
MYOD1. The presence of elevated levels of both
CSRP3 and MYOD1 suggests a role in the maintenance
of satellite cells in atrophying muscle to enable rapid
recovery when nutrient supply is restored. Furthermore,
the cysteine-rich, angiogenic inducer, 61 (CYR61), has
recently been detected as a differentially expressed
transcript in denervated skeletal muscle (Magnusson
et al., 2005). A role for CYR61 in the maintenance of
mesenchymal stem cells may explain why its expression
in muscle is elevated during weight loss (Schutze et al.,
2005).
Muscle atrophy is partly mediated by oxidative
damage caused by pro-oxidants such as hydroxyl
radicals, which overwhelm antioxidant defences and
tissue repair mechanisms (Kondo et al., 1994). The
study of Lehnert et al. (2006) suggests that increased
expression of the antioxidant, sestrin-1 (SESN1;
Budanov et al., 2004), may be an adaptive response
for limiting oxidative damage caused by the release of
bound metals from fast glycolytic muscle fibres, which
atrophy at greater rates than other myofibre types during
prolonged undernutrition. This study appears to be the
first in which an upregulated antioxidant in atrophic
skeletal muscle has been documented.
In many cases, differentially expressed genes cannot
be fitted within a mechanistic framework that links
gene expression to phenotype (Lehnert et al., 2006).
For example, the Kelch repeat and BTB (POZ) domain
containing 5 (KBTBD5) belong to a family of proteins
with unknown function. This gene was also identified
as a differentially expressed transcript when different
fat depots were compared in the bovine (Hishikawa et
al., 2005). The transmembrane 4 L 6 family member
(TM4SF2) also belongs to a family of membrane
proteins of unknown function (Maecker et al., 1997).
Recent work by our colleagues has attempted to
integrate metabolic networks controlling muscle growth
in production animals with existing knowledge of
networks in other mammalian species (Reverter et al.,
2006). A network for 822 genes was constructed using
a correlation-based method. Gene network modules for
muscle structural proteins and enzymes, extracellular
matrix, fat metabolism and protein synthesis were
identified, and proteins were grouped on the basis of
physical association. Three z-disk components, MYOZ1,
TCAP and PDLIM3, were significantly correlated,
but these molecules were poorly correlated with the
expression of various thick filament proteins (myosins)
and thin filament proteins (actin and tropomyosins).
They were also poorly correlated with the expression of
titin, the third major filament system, and expression of
titin was not significantly correlated with the cluster of
thick and thin filament proteins and enzymes. Expression
of many fast-twitch muscle structural proteins and
enzymes were correlated. However, expression of
slow-twitch and fast-twitch proteins was not correlated,
nor were there associations among slow-twitch protein
expression levels. Furthermore, significant associations
between various genes and transcription factors were
also identified by Reverter et al. (2006). These findings
have revealed various associations between and within
the structural components of skeletal muscle and have
recapitulated known muscle biology, while at the same
time indicating unexpected interactions between genes
and networks.
Restricted nutrition will remain a priority for animal
production researchers with interests in the developing
world and extensive systems of the developed world. As
the details of animal phenotype–genotype associations
are elucidated, a need to define specific nutrient
requirements of genetically elite animals will develop.
There will be a need to optimise the nutrition of animals
with specific genotypes so that the advantages of parasite
resistance, high yield or reproductive efficiency are not
lost because of inadequate or poorly-timed nutrition.
The next wave of technologies
Nutritional epigenetics
Epigenetics involves the alteration of gene expression
through DNA methylation and histone modification and
represents a potential source of unexplained phenotypic
variation for livestock productivity traits (Bell, 2006).
Much research in this field has been targeted at
understanding mechanisms that contribute to increased
susceptibility to adult diseases as a result of nutrition
during pregnancy and at specific stages of embryonic,
foetal and neonatal development (Waterland and Jirtle,
2004; Vickaryous and Whitelaw, 2005; Langley-Evans,
2006). Epigenetic research specific to development of
commercially important carcass tissues such as muscle
is progressing at a rapid pace (Brand-Saberi, 2005).
Epigenetic mechanisms may contribute to effects that
persist across generations (Drake and Walker, 2004).
These mechanisms may include transient nutritional
stimuli at key stages of development of organs and
tissues, which have persistent effects on expression
of genes. Nutritional epigenetics may enhance
understanding of the development of productivity
traits, which may in turn enable development of specific
nutritional management practices for improving
productivity.
Metabolomics
Metabolomics is the study of metabolism in an organism
and utilises high-throughput methodologies to define
phenotypes in terms of profiles and concentration
variances in key metabolites. High-throughput mass
spectrometry techniques coupled with biostatistical
packages has greatly facilitated the interpretation
of metabolic data relating to genetic variation,
treatment effects and nutrient effects. One example of
a metabolomic approach is a study by Noguchi et al.
(2006), who developed a diagnostic index for pathology
based on the concentrations of each of the amino acids
in particular body fluids.
69
Proteomics
Systematic analysis of the function of genes can take
place at the oligonucleotide level or at the protein level.
The latter approach has the advantage of being closest
to function, as proteins perform most of the reactions
necessary for the cell. The reader is directed to a recent
review by Bradshaw and Burlingame (2005) to learn
more about this technique.
Conclusion
When considering animal production practices of the
future, the scales of the genome, proteome and the
metabolome are daunting and future paths to product
delivery are obscure. The challenge is to harness the
power of the ‘omics’ technologies, bioinformatics and
biostatistics to discover novel pathways, genes and
single nucleotide polymorphisms. However, the targets
will not change; animal producers will always seek
animals that grow efficiently, reproduce effectively,
respond to selection pressure and produce high-quality
products that meet market demands. It is likely that
these new technologies will be the catalysts for rapid
advances rather than the harbingers of radical change.
Acknowledgements
Much of the research described in this article could
not have been performed without the support of our
colleagues at the Cattle and Beef Quality Cooperative
Research Centre and we are grateful for their
collaboration and support.
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