**2. Marbling**

Marbling is the term used to describe the presence of macroscopically visible fat within muscle (**Figures 1** and **2**). Coarse marbling refers to white areas of fat through and around muscle bundles, generally as continuous bands arising from the subcutaneous adipose tissue. By contrast, fine or "snowflake" marbling is characterized by more even white flecks resulting in pink rather than red muscle.

#### *Muscular Dystrophies*

#### **Figure 1.**

*Loin at the eleventh intercostal level of carcass of Melaleuka Stud steer M508 (wy63 ak25 dx13), MSA MB 1100, DOF 471. There are extensive areas of fine marbling as indicated by pink muscle with fine flecks. Note 88% Wagyu (63% black, 25% red). See also Figure 5 for microscopic features.*

#### **Figure 2.**

*Loin at the eleventh intercostal level of carcass of Melaleuka Stud heifer M621 (wy75 dx25), MSA MB 920, DOF 443. There is a predominance of fat arborizing from the subcutaneous tissue and creating coarse marbling. The muscle areas are dark red in comparison to Figure 1. Note lower MSA MB of 920 but similar days on feed (DOF).*

These two forms may coexist but can be distinguished and quantified by skilled observers. Fine marbling is associated with improved taste and tenderness [1]. Further, it has been shown to relate to a preferred fatty acid profile. Accordingly, there is copious funding and now a substantial understanding of the environmental and genetic factors which favor fine rather than coarse.

## **3. Interspecies translation**

Interspecies translation from cattle to man has unrecognized potential. Firstly, cattle are close to humans in evolutionary time and fall within that window of 50–100 million years of separation (or last common ancestor) which is characterized by very similar proteins but vastly different regulations of expression. The same window may explain the fact that the two species have synergized over some 40,000 years of contact and at least 7000 years of domestication. As one example, infections can be similar and, in some cases, are transmissible from one to the other, but close exposure to cattle is generally innocuous implying some form of immunity. As for example in the case of pox and tuberculosis. We argue that cattle are both relevant and relatively safe for translational studies.

**105**

[5, 12–14].

*Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy*

study and treat genetically determined diseases prospectively [2].

Secondly, domestic cattle are well maintained, closely observed, and very well understood. There are huge databases and DNA banks which have been in existence for 50 years. Innumerable breeds can be compared often under different environmental conditions. Many of these breeds have been closed for hundreds of years and then intentionally crossed with each other. There is great potential for meaningful studies of population genetics and family and haplotype associations and, even more so, for structure-function genomics. Metabolic and inflammatory pathways are relatively well understood and are supported by inestimable funding available to ensure future supplies of meat, milk, cheese, butter, leather,

Thirdly, cattle are plentiful and even more so than humans. Because the generation time and life expectancy are much shorter, there are excellent opportunities to

White muscle disease or selenium/vitamin E deficiency occurs quite commonly in livestock raised on leached soils. The pathology resembles dystrophy in some respects. A mutation in the selenoprotein N gene (SEPN1) is responsible for some types of congenital muscular dystrophies and myopathies [3]. Kakulas [4] demonstrated that dystrophy-like changes explained the weakness observed in quokkas on Rottnest Island. Importantly, the condition could be corrected by treating the deficiency raising the possibility that human dystrophies could be reversible if the

The term genome is used here to refer to the architecture of DNA sequences, whereas others have come to use the term in the context of single-nucleotide polymorphisms wherever they occur. The difference is fundamental to the discovery of gene clusters with coherent cis and trans interactions between conserved sequences known as ancestral haplotypes [5–9]. Many studies have shown that the SNP approach in livestock and humans fails to identify these critical sequences and can be misleading at best [10]. SNPs are neutral markers of parentage rather than

One major benefit of ancestral haplotypes as opposed to SNPs is that it is possible to use interspecies translation. During mammalian evolution, polymorphic frozen blocks have diverged to some extent although the functionally important

As shown in **Figure 3** and **Table 1**, there are similarities between genomic regions on Hosa 17 and Bota 19. Although there have been architectural changes such as insertions and transversions, the gene content has been preserved.

Bota 19 was chosen as the reference because of its critical role in determining the degree of marbling between individuals of a breed, F1 crosses and between breeds

Hosa 17 was chosen for comparison because it contains some of the same genes such as TCAP. Further analysis revealed an extraordinary degree of preservation or synteny in spite of an evolutionary separation time of at least 50 million years and therefore millions of generations. Implicit is that there are functional reasons for

*DOI: http://dx.doi.org/10.5772/intechopen.82685*

**4. Other instances of translation**

basic defect could be corrected.

**5. Genomic approach**

functionally important [11].

sequences tend to be conserved.

similarities in genomic architecture.

and fertilizer.

*Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy DOI: http://dx.doi.org/10.5772/intechopen.82685*

Secondly, domestic cattle are well maintained, closely observed, and very well understood. There are huge databases and DNA banks which have been in existence for 50 years. Innumerable breeds can be compared often under different environmental conditions. Many of these breeds have been closed for hundreds of years and then intentionally crossed with each other. There is great potential for meaningful studies of population genetics and family and haplotype associations and, even more so, for structure-function genomics. Metabolic and inflammatory pathways are relatively well understood and are supported by inestimable funding available to ensure future supplies of meat, milk, cheese, butter, leather, and fertilizer.

Thirdly, cattle are plentiful and even more so than humans. Because the generation time and life expectancy are much shorter, there are excellent opportunities to study and treat genetically determined diseases prospectively [2].

### **4. Other instances of translation**

*Muscular Dystrophies*

**Figure 1.**

**Figure 2.**

**104**

These two forms may coexist but can be distinguished and quantified by skilled

*Loin at the eleventh intercostal level of carcass of Melaleuka Stud heifer M621 (wy75 dx25), MSA MB 920, DOF 443. There is a predominance of fat arborizing from the subcutaneous tissue and creating coarse marbling. The muscle areas are dark red in comparison to Figure 1. Note lower MSA MB of 920 but similar days on feed (DOF).*

Interspecies translation from cattle to man has unrecognized potential. Firstly, cattle are close to humans in evolutionary time and fall within that window of 50–100 million years of separation (or last common ancestor) which is characterized by very similar proteins but vastly different regulations of expression. The same window may explain the fact that the two species have synergized over some 40,000 years of contact and at least 7000 years of domestication. As one example, infections can be similar and, in some cases, are transmissible from one to the other, but close exposure to cattle is generally innocuous implying some form of immunity. As for example in the case of pox and tuberculosis. We argue that cattle are both relevant and relatively

observers. Fine marbling is associated with improved taste and tenderness [1]. Further, it has been shown to relate to a preferred fatty acid profile. Accordingly, there is copious funding and now a substantial understanding of the environmental

*Loin at the eleventh intercostal level of carcass of Melaleuka Stud steer M508 (wy63 ak25 dx13), MSA MB 1100, DOF 471. There are extensive areas of fine marbling as indicated by pink muscle with fine flecks. Note* 

*88% Wagyu (63% black, 25% red). See also Figure 5 for microscopic features.*

and genetic factors which favor fine rather than coarse.

**3. Interspecies translation**

safe for translational studies.

White muscle disease or selenium/vitamin E deficiency occurs quite commonly in livestock raised on leached soils. The pathology resembles dystrophy in some respects. A mutation in the selenoprotein N gene (SEPN1) is responsible for some types of congenital muscular dystrophies and myopathies [3]. Kakulas [4] demonstrated that dystrophy-like changes explained the weakness observed in quokkas on Rottnest Island. Importantly, the condition could be corrected by treating the deficiency raising the possibility that human dystrophies could be reversible if the basic defect could be corrected.

### **5. Genomic approach**

The term genome is used here to refer to the architecture of DNA sequences, whereas others have come to use the term in the context of single-nucleotide polymorphisms wherever they occur. The difference is fundamental to the discovery of gene clusters with coherent cis and trans interactions between conserved sequences known as ancestral haplotypes [5–9]. Many studies have shown that the SNP approach in livestock and humans fails to identify these critical sequences and can be misleading at best [10]. SNPs are neutral markers of parentage rather than functionally important [11].

One major benefit of ancestral haplotypes as opposed to SNPs is that it is possible to use interspecies translation. During mammalian evolution, polymorphic frozen blocks have diverged to some extent although the functionally important sequences tend to be conserved.

As shown in **Figure 3** and **Table 1**, there are similarities between genomic regions on Hosa 17 and Bota 19. Although there have been architectural changes such as insertions and transversions, the gene content has been preserved.

Bota 19 was chosen as the reference because of its critical role in determining the degree of marbling between individuals of a breed, F1 crosses and between breeds [5, 12–14].

Hosa 17 was chosen for comparison because it contains some of the same genes such as TCAP. Further analysis revealed an extraordinary degree of preservation or synteny in spite of an evolutionary separation time of at least 50 million years and therefore millions of generations. Implicit is that there are functional reasons for similarities in genomic architecture.

#### **Figure 3.**

*Marbling and muscular dystrophy are syntenic on bovine chromosome 19 (Bota 19) and human chromosome 17 (Hosa 17). Colored boxes represent segments with the same gene content. Crossed joining lines indicate inverted translocations. Numbers represent Mb. Synteny was determined by the positions of homologous genes in the human assembly Hg 38 and bovine assembly BosTau8 located using the UCSC genome browser. Inverted sections and the exact location of boundaries between blocks were determined by dotplots comparing the two sequences. Adapted from: [13] Locations of Muscular Dystrophy Genes: (a) MYH2, (b) PMP22, (c) TRPV2, (d) SREBF1, (e) TCAP, (f) CAVIN1, (g) BECN1, (h) SGCA and Meat Quality Genes (A)SREBF1, (B) MPRIP, (C) TCAP, (D) GH, (E) UTS2R, (F) FASN shown here. See Table 1 for more information about these genes.*


**107**

MSTN Hosa 2q32.2 Bota chr2: 6.21Mb

CAPN3 Hosa 15q15.1 Bota chr10: 37.8Mb

*Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy*

**Gene location Description Human muscular dystrophy Meat quality trait**

Congenital generalized lipodystrophy, type 4; (CGL4) is caused by mutations in CAVIN1 that result in CAV 3 deficiency [29]

Growth Hormone A polymorphism of

Expression of BECN1 was reduced in patients with muscular dystrophies BTHLM1 and UMCD1 which were caused by COL6A1 mutations [30]

Involved in proteolysis and beef aging [31]

growth hormone is associated with fatty acid composition of Wagyu beef [32]

Fatty Acid Synthase is highlighted in GWAS for fatty acid content and composition of Wagyu and Hanwoo beef [33, 34]

A polymorphism of UTS2R is associated with IMF content of Wagyu x Holstein beef

**trait**

Mutations in myostatin cause double muscling in several cattle breeds [36]

SNPs within CAPN3 are associated with tenderness in *Bos Indicus* cattle [37]

[39]

Yet further analysis suggests some explanations for the co-location of similar genes. Irrespective of cis and trans interactions between the protein products, there is evidence of co-regulation (see, e.g., SREBP). In this context, we conclude that, although products and their regulating transcription factors are preserved, separation has permitted the insertion of species-specific elements, which control the

Importantly, as shown in **Figure 3** and **Table 1**, Hosa 17 contains multiple candidates for involvement in human muscular dystrophy. There is even more complexity

Thus, syntenic analysis has suggested a novel approach to identification of

**Gene location Description Human muscular dystrophy Meat quality** 

Myostatin Muscle hypertrophy was caused

by a homozygous mutation in

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by homozygous or compound heterozygous mutation in

myostatin [35]

CAPN3

quantitative differences between humans and cattle.

in explaining the multiple candidates as shown in **Tables 2** and **3**.

operative elements in marbling and in some forms of dystrophy.

Calpains are nonlysosomal intracellular cysteine proteases. CAPN3 is a muscle-

specific large subunit

*DOI: http://dx.doi.org/10.5772/intechopen.82685*

Cavin is an essential factor in the biogenesis of caveolae

Beclin-1 participates in the regulation of autophagy

Fatty Acid Synthase the key enzyme of de novo lipogenesis to produce saturated fatty acids

A receptor abundant in heart and pancreas and responsive to Urotensin II which has potent vasoactive properties

*Details of relevant genes in Bota 19 and Hosa 17.*

CAVIN1 Hosa 17q21.2 Bota chr19: 43.14Mb

BECN1 Hosa 17q21.31 Bota chr19: 43.47Mb

GH1 Hosa 17q23.3 Bota Chr19: 48.77Mb

FASN Hosa 17q25.3 Bota Chr19: 51.38 Mb

UTS2R Hosa17q25.3 Bota Chr19: 50.81 Mb

**Table 1.**


*Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy DOI: http://dx.doi.org/10.5772/intechopen.82685*

#### **Table 1.**

*Muscular Dystrophies*

MYH2 Hosa 17p13.1 Bota chr19: 30.13Mb

**Figure 3.**

PMP22 Hosa 17p12 Bota chr19: 33.35Mb

TRPV2 Hosa 17p11.2 Bota chr19: 33.816Mb

SREBF1 Hosa 17p11.2 Bota chr19: 35.23Mb

MPRIP Hosa 17p11.2 Bota chr19: 35.557Mb

SGCA Hosa 17q21.33 Bota chr19: 37.11Mb

TCAP Hosa 17q12 Bota chr19: 40.69Mb

**Gene location Description Human muscular dystrophy Meat quality trait**

*Marbling and muscular dystrophy are syntenic on bovine chromosome 19 (Bota 19) and human chromosome 17 (Hosa 17). Colored boxes represent segments with the same gene content. Crossed joining lines indicate inverted translocations. Numbers represent Mb. Synteny was determined by the positions of homologous genes in the human assembly Hg 38 and bovine assembly BosTau8 located using the UCSC genome browser. Inverted sections and the exact location of boundaries between blocks were determined by dotplots comparing the two sequences. Adapted from: [13] Locations of Muscular Dystrophy Genes: (a) MYH2, (b) PMP22, (c) TRPV2, (d) SREBF1, (e) TCAP, (f) CAVIN1, (g) BECN1, (h) SGCA and Meat Quality Genes (A)SREBF1, (B) MPRIP, (C) TCAP, (D) GH, (E) UTS2R, (F) FASN shown here. See Table 1 for more information about these genes.*

Peripheral myelin protein-22 Duplication of peripheral myelin

Proximal myopathy and ophthalmoplegia is caused by heterozygous, compound heterozygous, or homozygous mutation in MYH2 leading to a lack In pork, IMF, water holding capacity, and meat color [19]

SREBF1 is involved in adipogenesis and polymorphisms are associated with fatty acid composition of Japanese Black Cattle

Haplotypes diffentiated by polymorphsims in MRIP are associated with differences in intramuscular fat development in Wagyu

A polymorphism of TCAP is associated with IMF content and fatty acid composition of beef [13, 28]

[23]

[25]

of type 2a fibres [18]

TRPV2 [21]

protein 22 causes Charcot-Marie-Tooth disease type 1A [20]

Muscular dystrophy is ameliorated in dystrophin-deficient mdx mice by dominant-negative inhibition of

Mutations of LMNA that cause Emery-Dreifuss muscular dystrophy (EDMD2-AD) and familial partial lipodystrophy (FPLD2) result in less binding of lamin A to SREBP1 [22]

Mutations in SGCA cause limbgirdle muscular dystrophy type 2D. SGCB, SGCD, and SGCG are associated with LGMD types 2E, 2F,

Limb-girdle muscular dystrophy type 2G (LGMD2G) is caused by mutations in the TCAP gene [27]

and 2C, respectively [26]

MYH2 encodes the myosin heavy chain isoform that is expressed in fast type 2A

Transient receptor potential cation channel, V2: responds to

Sterol regulatory elementbinding protein-1 controls cholesterol homeostasis by stimulating transcription of sterol-regulated genes

Myosin phosphatase rhointeracting protein targets myosin phosphatase to regulate the phosphorylation of myosin

light chain [24]

Sarcoglycan, alpha Sarcoglycans form part of the dystrophin-glycoprotein

Titin-cap (telethonin) is a sarcomeric protein localized to the periphery of Z discs that define the border of the sarcomere as a structural anchor and signaling center

complex

heat and cations

muscle fibers

**106**

*Details of relevant genes in Bota 19 and Hosa 17.*

Yet further analysis suggests some explanations for the co-location of similar genes. Irrespective of cis and trans interactions between the protein products, there is evidence of co-regulation (see, e.g., SREBP). In this context, we conclude that, although products and their regulating transcription factors are preserved, separation has permitted the insertion of species-specific elements, which control the quantitative differences between humans and cattle.

Importantly, as shown in **Figure 3** and **Table 1**, Hosa 17 contains multiple candidates for involvement in human muscular dystrophy. There is even more complexity in explaining the multiple candidates as shown in **Tables 2** and **3**.

Thus, syntenic analysis has suggested a novel approach to identification of operative elements in marbling and in some forms of dystrophy.



**109**

*Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy*

The alpha-7 integrin is a specific cellular receptor for the basement membrane proteins laminin-1, laminin-2, and laminin-4. The alpha-7 subunit is expressed mainly in skeletal and cardiac muscles and may be involved in differentiation and migration processes

Emerin is found along the nuclear rim of many cell types and is a member of the nuclear lamina-associated protein

Calcium-transporting ATPase lower cytoplasmic Ca(2+) concentration by pumping Ca(2+) to luminal or extracellular spaces. ATP2A1 is the ATPase type found in fast twitch muscles

Desmin is the muscle-specific member of the intermediate filament (IF) protein family. It is one of the earliest myogenic markers, both in the heart and somites, and is expressed in satellite stem cells and

Plectin-1 is one of the largest polypeptides known and is believed to provide mechanical strength to cells and tissues by acting as a cross-linking element of the

replicating myoblasts

cytoskeleton

*Details of relevant genes outside of Hosa 17/Bota 19.*

**Gene location Description Human muscular dystrophy Meat quality** 

**Absent protein Dystrophy type Gene location**

Dysferlin Limb-girdle muscular dystrophy 2B DYSF Hosa 2p13.2

Sarcoglycans Limb-girdle muscular dystrophies 2C-F SGCA Hosa 17q21.33 Bota 19

rippling muscle disease, hyperCKemia

Telethonin Limb-girdle muscular dystrophy 2G TCAP Hosa 17q12 Bota 19

congenital muscular dystrophy)

Collagen VI Ullrich congenital muscular dystrophy COL6A1&2 Hosa 21q22.3

Integrin alpha7 Mild congenital dystrophy/myopathy ITGA7 Hosa 12q13.2

DMD

Hosa Xp21.2-p21.1

SGCB Bota chr6 SGCD Hosa 5q33.2 Bota 7 SGCE Hosa 7q21.3 Bota 4 SGCG Bota chr12

CAV3 Hosa 3p25.3 Bota 22 CAVIN1 Hosa 17q21.2 Bota 19

LAMA2 Hosa 6q22.33, Bota 9

COL6A3 Hosa 2q37.3

Bota chrX: 115,342,323-117,606,340

**trait**

Congenital muscular dystrophy

Emery-dreifuss muscular dystrophy 1, X-LINKED;

Myopathy, myofibrillar, 1

Epidermolysis bullosa with muscular dystrophy Limb-girdle type 2Q

EDMD1

Brody myopathy

Dystrophin Xp21 muscular dystrophies (Duchenne, Becker)

Caveolin-3 Limb-girdle muscular dystrophy 1a,

Laminin a2 MDC1A ("merosin"-deficient

*DOI: http://dx.doi.org/10.5772/intechopen.82685*

during myogenesis

family

ITGA7 12q13.2

EMD Xq28

ATP2A1 (SERCA-1) 16p11.2

DES 2q35

PLEC 8q24.3

**Table 2.**


#### **Table 2.**

*Muscular Dystrophies*

CAPN1 Hosa 11q13.1 Bota chr29: 44.06Mb

DMD Hosa Xp21.2-.1 Bota chrX: 115.34Mb

LAMA2 Hosa 6q22.33 Bota chr9: 67.96Mb

MYOT Hosa 5q31.2 Bota chr7: 50.94Mb

CAV3 Hosa 3p25.3 Bota chr22: 17.83Mb

SGCD Hosa 5q33.2-.3 Bota chr7: 69.59Mb

SGCE Hosa 7q21.3 Bota chr4: 11.84Mb

SGCB Bota chr6: 69.53Mb

SGCG at Bota chr12: 34.92Mb COL6A1 COL6A2 21q22.3

COL6A3 2q37.3

**Gene location Description Human muscular dystrophy Meat quality** 

Dystrophin maintains the structural

LAMA2 gene encodes the alpha-2 chain of

Laminin-2 (merosin) is the main laminin

Sarcoglycan, delta is expressed in skeletal and heart muscles and to a lesser extent in smooth muscle. Delta-sarcoglycan is

Collagen, type VI, alpha-1, and alpha-2 Members of the collagen VI family form distinct networks of microfibrils in connective tissue and interact with other extracellular matrix components

localized at the sarcolemma

Beta-sarcoglycan

Myotilin directly binds F-actin and efficiently cross-links actin filaments and

prevents filament disassembly

integrity of myofibrils

found in muscle fibers

laminin-2

m-Calpain Two CAPN1

MDC1A

Duchene muscular dystrophy

Congenital merosin-deficient muscular dystrophy type 1A;

LGMD1A is caused by heterozygous mutation in the MYOT. It is characterized by adult-onset muscle weakness, progressing from the hip to the

shoulder girdle

type 1C; LGMD1C

type 2F; LGMD2F

Muscular dystrophy, limb-girdle,

genetically heterogeneous disorder characterized by myoclonic jerks affecting mostly proximal muscles

Ullrich congenital muscular

dystrophy 1, Bethlem myopathy

dystrophy 1 Bethlem myopathy 1

1 Dystonia 27

Caveolin 3 Muscular dystrophy, limb-girdle,

Epsilon-sarcoglycan Myoclonus-dystonia is a

COLLAGEN, TYPE VI, ALPHA-3 Ullrich congenital muscular

**trait**

genetic markers are associated with tenderness in Brahman beef [38]

SNPs in MYOT correlate with loin muscle area and intramuscular fat in Qinchuan cattle[39]

**108**

*Details of relevant genes outside of Hosa 17/Bota 19.*



**Table 3.**

*Protein accumulations and deficits in dystrophy.*
