Genetic Tests for Large Animals

DANIKA L. BANNASCH, Consulting Editor CARRIE J. FINNO

Genetic testing based on deoxyribonucleic acid (DNA) involves the analysis of an animal's DNA to determine its genotype for an inherited disorder, trait, or anonymous marker.

Genetic testing can be used for positive or negative selection in a population, depending on whether it is being used to identify a disease (negative) or a trait (positive). Genetic testing can also be used for permanent individual identification and parentage determination. Many breed registries require parentage verification to ensure the accuracy of their pedigrees.

Using genetic testing results for selection requires an understanding of the mode of inheritance of the disease or trait. Most often, a genetic test will be performed for a recessive disorder to determine if an animal is a carrier. Carriers are asymptomatic but have the potential to produce diseased progeny. Because they have no outward manifestation of disease, a genetic test is extremely valuable for managing their breeding appropriately. Carrier animals can be bred to noncarriers if needed to retain valuable characteristics while not producing diseased offspring. In the case of positive selection for a trait of interest, carrier animals may have higher breeding values because they can produce a trait if bred to other carriers or to animals with the trait. Genetic tests may also be used for dominant disorders if the disease/trait has a late age of onset or if it is inherited in a codominant manner. DNA testing for traits that are controlled by more than one locus (polygenic) may also be used for selection for economically important traits. In these cases, one particular genotype may confer a slight advantage over another and therefore, in a large population, can have a significant effect on production.

Box 52.1 defines key genetic terms; see also Chapter 51.

Individual Identification and Parentage Testing

Researchers use genetic markers distributed along all the chromosomes as tools to identify regions associated with diseases or traits. One type of marker used for individual identification and parentage testing is composed of small nucleotide repeats and is called microsatellite markers or short tandem repeats (STRs). These markers have a feature that makes them extremely useful to geneticists; the markers have been chosen to be “polymorphic” (show differences) between individuals. In other words, individual animals will have different lengths of the nucleotide repeats for each of these markers. The high level of polymorphism of this type of marker makes them useful for “mapping” (identifying the chromosomal location of diseases and traits).

The microsatellite markers are assayed by polymerase chain reaction (PCR) amplification using fluorescent-labeled primers. Primers are short (20 base pairs), single-strand lengths of DNA that are complementary to a specific region of the genome. PCR is the amplification of a section of DNA contained between two primers designed to complement the unique sequence flanking the STR. The PCR products are then resolved by electrophoresis on the basis of their length. Markers with many different alleles are said to be polymorphic and would be a useful marker for individual identification or parentage. Because the markers show differences between individuals, a collection of these markers can be used as a form of identification of an animal. High statistical significance can be obtained with as few as 10 markers, depending on the species and breed. The DNA type of an animal will not change over its lifetime and can therefore be used as a form of permanent identification.

Many purebred registries require parentage verification for registration purposes. To accomplish parentage verification, a DNA sample must be available from both parents, as well as the offspring. DNA samples are taken in the form of hair, blood, or buccal swabs (depending on the species and registry) and submitted at the time registration is requested.

Each animal inherits one copy of each marker from its sire and one copy from its dam, so the markers can also be used to verify parentage. The most useful marker has a high polymorphism rate because that type of marker will be most likely to show differences not only between the sire and the dam but also between the two copies (alleles) of the marker. A set of polymorphic markers (10 to 20) is used to verify parentage to ensure a high probability that the parentage is correct. Table 52.1 shows the allele sizes for a set of markers in a parentage case. For marker A the offspring inherited a 122 allele and a 126 allele. The 122 came from its dam, so the 126 came from the sire. Because sire 1 does not have a 126 allele, it has been excluded. In this example, sire 1 is excluded as the sire of the offspring and sire 2 is verified on the basis of the results for all three markers.

Genome Sequence

Whole-genome sequencing and genome assembly of large animal species was completed in the early 2000s (horse September 2007, cow October 2011, sheep February 2010, goat February 2013). The whole-genome sequence of an organism provides the exact base pairs along each chromosome of the individual animal that was sequenced. This “assembly” of DNA sequence then becomes the reference assembly for each organization, and genetic variation is compared with that reference providing a frame of reference for all DNA sequencing. In the horse, a Thoroughbred mare (Twilight) was selected for sequencing because of her low heterozygosity rate (1/1380 base pairs). In 2010, a Quarter Horse mare underwent whole-genome sequencing and was aligned to Twilight.¹ In cattle, a single partially inbred Hereford cow was selected to contribute 6? whole-genome shotgun (WGS) reads and another 1.5? came from individual animals of the Holstein, Angus, Jersey, Limousin, Brahman, and Norwegian Red breeds for detection of single nucleotide polymorphisms (SNPs). Following sequencing of each species, over 20,000 protein-coding genes were annotated on the sequences by virtue of previously sequenced cDNAs and also by prediction software that compared known genome

■ BOX 52.1

Definitions of Genetic Terms

Allele One of the variant forms of a gene at a particular locus, or location, on a chromosome.

Base pairs Two bases that form a “rung of the DNA ladder.” A DNA nucleotide is made of a molecule of sugar, a molecule of phosphoric acid, and a molecule called a “base” The bases are the “letters” that spell out the genetic code. In DNA the code letters are A, T, G, and C, which stand for the chemicals adenine, thymine, guanine, and cytosine, respectively.

Genotype Genetic makeup, either at a single locus or at all loci. Genome wide association study A study that uses genomewide markers, typically microsatellites or single nucleotide polymorphisms (SNPs) to determine an association between a phenotype and region of particular chromosome.

Linked Association of genes and markers that lie near each other on a chromosome; linked genes and markers tend to be inherited together.

Locus Place on a chromosome where a specific gene is located; a type of “address” for the gene.

Marker Segment of DNA with an identifiable physical location on a chromosome, the inheritance of which can be followed. A marker can be a gene or some section of DNA with no known function. Also known as a genetic marker.

Microsatellite Repetitive stretches of short sequences of DNA used as genetic markers to track inheritance in families.

Phenotype Observable traits or characteristics of an animal (e.g., coat color, weight, presence or absence of a disease).

Recombination Genetic transmission process by which the combinations of alleles observed at different loci in two parental individuals become shuffled in offspring individuals.

Single nucleotide polymorphism (SNP) Differences in a single base pair of DNA (A, C, T, G) often used as genetic markers for linkage and association studies sequences in other species with newly sequenced genomes. Since these initial assemblies, revisions have occurred within species. These initial and updated annotated genome databases are publicly available (Table 52.2).

With the advent of whole-genome sequencing and assemblies, there has been a rapid expansion in the number of SNPs discovered in the genomes of large animal species.

SNPs are single base pairs of DNA with differences between individuals. They generally have only two alleles and are therefore less informative than the STR markers mentioned earlier. They have distinct advantages, however, when it comes to ease of genotyping. Very large numbers of SNP markers can be genotyped for a fraction of the cost of microsatellite markers. SNPs are now considered the next generation of markers to conduct breed diversity and to map disease-causing traits. The availability of such a tool as an SNP chip facilitates rapid mapping of diseases to specific chromosomal regions and analysis of candidate genes. SNP arrays are currently available on many large animal species (Table 52.2) and are currently being used in mapping studies of various complex disorders. Haplotype structures are being identified across species with targeted resequencing and, most recently, whole-genome next-generation sequencing, of animals from different breeds.

In addition to genomic mapping, functional genomic tools have become more readily available and affordable to researchers. More recently, sequencing of the transcriptome, through technologies such as RNA-Seq, have allowed researchers to evaluate gene expression differences among tissues and between animals of different disease states.

Identifying Genetic Mutations

Initial genetic mutations in large animal species were discovered through the use of comparative genomics. Genes involved in a specific disease were targeted because of equivalent diseases in other species, namely humans. In the horse, the genetic mutations for many diseases that have genetic tests currently available, including hyperkalemic periodic paralysis (HYPP)² and severe combined immunodeficiency (SCID),³ were uncovered by evaluating candidate genes that had been associated with similar diseases in humans (Table 52.3). With the sequencing and annotation of whole genome maps, other diseases were discovered through whole-genome linkage mapping (hereditary equine regional dermal asthenia [HERDA]4), genome-wide association studies with microsatellites (Type I polysaccharide storage myopathy [PSSM]⁵) and genome-wide association studies using SNP array technology (Lavender foal syndrome⁶).

A similar theme is evident in cattle. Initial genetic mutations were discovered based on sequencing of candidate genes known to cause similar disease in humans (bovine leukocyte adhesion deficiency [BLAD]⁷). Later studies used microsatellite markers and performed linkage analysis (complex vertebral malformation⁸) and, most recently, the use of SNP-based genome-wide association studies has identified recessive defects (congenital muscular dystony types 1 and 29). At the time of publication,

■ TABLE 52.1

Parentage Verification Using Microsatellite Markers

AUele Sizes for 4 Markers

Individuals	A	B	C	D
Dam	122/124	110	131/133	80/82
Offspring	122/126	110/112	133	82/86
Sire 1	128	112/114	131	84
Sire 2	126	112/114	131	86/90

■ TABLE 52.2

Map Status and Genomic Resource for Large Animal Species

Horse Cattle Sheep Goat

^eIlluminaInc., San Diego, Calif. ^fAHymetrix, Inc., Santa Clara, Calif.

■ TABLE 52.3

Genetic Tests for Horses

Disease/Trait	Gene	Mode of Inheritance	Reference
Androgen insensitivity syndrome (AIS)	AR	X-linked recessive	18
Cerebellar abiotrophy (CA)	TOE1/MUTYH	Autosomal recessive	19
Curly coat	KRT25	Autosomal dominant	20
Dwarfism, ACAN related	ACAN	Autosomal incompletely dominant	21,22
Dwarfism, Friesian	B4GALT7	Autosomal recessive	23
Hereditary regional dermal asthenia (HERDA)	PPIB	Autosomal recessive	4
Junctional epidermolysis bullosa (JEB)	LAMA3	Autosomal recessive	24
JEB.	LAMC2	Autosomal recessive	25
Foal immunodeficiency syndrome (immunodeficiency	SLC5A3	Autosomal recessive	26
of Fell ponies)
Gaitedness	DMRT3	Multifactorial	27
Glycogen storage disease IV (glycogen branching	GBE1	Autosomal recessive	28
enzyme deficiency)
Hoof wall separation disease (HWSD)	SERPINB11	Autosomal recessive	29
Hydrocephalus	B3GALNT2	Autosomal recessive	30
Immune-mediated myositis	MYH1	Autosomal semidominant	31
Incontinentiapigmenti	IKBKG	X-linked semidominant	32
Lavender foal syndrome (LFS)	MYO5A	Autosomal recessive	6
Malignant hyperthermia (MH)	RYR1	Autosomal dominant	33
Megacolon (ileocolonicaganglionosis or lethal white	EDNRB3	Autosomal semidominant	10-12
foal syndrome)
Multiple ocular defects	PMEL17	Autosomal semidominant	34
Myotonia	CLCN1	Autosomal recessive	35
Naked foal syndrome	ST14	Autosomal recessive	36
Night blindness, congenital stationary	TRPM1	Autosomal recessive	37
Occipitoatlantoaxial malformation (OAAM)	HOXD3	Autosomal recessive	38
Ocular squamous cell carcinoma	DDB2	Autosomal recessive	39
Ovotesticular disorder of sexual development	SRY	Y-linked	40
Periodic paralysis II (hyperkalemic periodic paralysis;	SCN4A	Autosomal semidominant	2
HYPP)
Polysaccharide storage myopathy type I (PSSM I)	GYS1	Autosomal dominant	5
Severe combined immunodeficiency	DNAPKcs	Autosomal recessive	3
Skeletal atavism	SHOX	Autosomal recessive	41
Thrombasthenia (Glanzmann thrombasthenia)	ITGA2B	Autosomal recessive	42,43
Warmblood fragile foal syndrome	PLOD1	Autosomal recessive	44

■I TABLE 52.4

Genetic Tests for Cattle

bgcolor=white>

Disease/Trait	Gene	Mode of Inheritance	Reference(s)
Abortion/Stillbirth	MIMT1	Maternally imprinted	45
Abortion	ANXA10	Autosomal incompletely dominant	46
	EXOSC4	Autosomal recessive lethal	47
	MED22	Autosomal recessive lethal	47
	MYH6	Autosomal recessive lethal	47
	OBFC1	Autosomal recessive lethal	47
	RABGGTB	Autosomal recessive lethal	47
	RNF20	Autosomal recessive lethal	47
	RPIA	Autosomal recessive lethal	47
	SNAPC4	Autosomal recessive lethal	47
	TTF1	Autosomal recessive lethal	47
	APAF1	Autosomal recessive lethal	48
	CWC15	Autosomal recessive lethal	49
	SLC39A4	Autosomal recessive	50
	EDA	X-linked recessive	51
	TUBD1	Autosomal recessive lethal	52
	SUGT1	Autosomal recessive lethal	53
	SMC2	Autosomal recessive lethal	54
	GART	Autosomal recessive lethal	55
	TFB1M	Autosomal recessive lethal	56
	PFAS	Autosomal recessive lethal	57
	SLC37A2	Autosomal recessive lethal	55
	RNASEH2B	Autosomal recessive lethal	58
Achondrogenesis, type II	COL2A1	Autosomal dominant	54,59,60
Acrodermatitisenteropathica	SLC39A4	Autosomal recessive	50
Anhidrotic ectodermal dysplasia	EDA	X-linked recessive	51,61-64
Anhidrotic ectodermal dysplasia	EDAR	Autosomal recessive	60
Arachnomelia (spider limbs)	MOCS1	Autosomal recessive	65
Arachnomelia (spider limbs)	SUOX	Autosomal recessive	66
Arthrogryposis	AGRN	Autosomal recessive lethal	67
	CHRNB1	Autosomal recessive	68
	MYBPC1	De novo	69
	PIGH	Autosomal recessive	70
Axonopathy (Demetz syndrome)	MFN2	Autosomal recessive	71
Brachyspina	FANCI	Autosomal recessive	72
Caprine-like generalized hypoplasia	CEP250	Autosomal recessive	73
Cardiomyopathy and woolly haircoat syndrome	PPP1R13L	Autosomal recessive	74
Cardiomyopathy, dilated	OPA3	Autosomal recessive	75
Cataract	CPAMD8	Autosomal recessive	76
	NID1	Autosomal recessive	77
Chediak-Higashi syndrome	LYST	Autosomal recessive	78
Chondrodysplasia	EVC2	Autosomal	79
Citrullinemia	ASS1	Recessive	80
Complex vertebral malformation	SLC35A3	Autosomal recessive	8
Congenital muscular dystonia 1	ATP2A1	Autosomal recessive	9
Congenital muscular dystonia 2	SCL6A5	Autosomal recessive	9
Contractural arachnodactyly (Fawn calf syndrome)	ADAMTSL3	Autosomal recessive	81
Curly hair, karakul-type	KRT27	Autosomal dominant	54
Deficiency of uridine monophosphate synthase (DUMPS)	UMPS	Autosomal recessive	82
Depigmentation with microphthalmia	MITF	Autosomal dominant	83
Developmental duplications	NHLRC2	Multifactorial	84
Dominant white with bilateral deafness	MITF	Autosomal dominant	83
Dwarfism Angus	PRKG2	Autosomal recessive	85
Fleckvieh	GON4L	Autosomal recessive	86
ACAN-related	ACAN	Autosomal recessive lethal	87
Growth hormone deficiency	GH1	Autosomal recessive	88
Proportionate, with inflammatory lesions	RNF11	Autosomal recessive	89
Ears crop	HMX1	Autosomal dominant with variable expressivity	90
Ehlers-Danlos syndrome Holstein variant	EPYC	Autosomal recessive	91
Type VII (dermatosparaxis)	ADAMTS2	Autosomal recessive	92
Epidermolysis bullosa	KRT5	Autosomal dominant	93
Dystrophic	ITGB4	Autosomal recessive	94
LAMA3	Autosomal recessive	95
	LAMC2	Autosomal recessive	96
	COL7A1	Autosomal recessive	97
Facial dysplasia syndrome	FGFR2	Autosomal dominant	98

■ TABLE 52.4

Genetic Tests for Cattle—cont'd

bgcolor=white>Sperm, short tail

Disease/Trait	Gene	Mode of Inheritance	Reference(s)
Factor XI deficiency	F11	Autosomal recessive	99
Fanconi syndrome	SLC2A2	Autosomal recessive	100
Forelimb-girdle muscular anomaly	GFRA1	Autosomal recessive	101
Glycogen storage disease II (Pompe’s disease)	GAA	Recessive	102
Glycogen storage disease V	PYGM	Autosomal recessive	103
Goiter, familial	TG	Autosomal	104
Gonadal hypoplasia	KIT	Autosomal recessive	105
Hairy	PRL	Autosomal dominant	106
Hemophilia A	F8	X-linked	107
Holstein cholesterol deficiency	APOB	Autosomal recessive lethal	108
Hydrallantois	SLC12A1	Autosomal recessive	109
Hypotrichosis	HEPHL1	Autosomal recessive	110
Streaked	KRT71	Unknown	111
	TSR2	X-linked semidominant	112
Ichthyosis congenital	ABCA12	Autosomal recessive	9
Lethal multiorgan developmental dysplasia	KDM2B	Autosomal recessive	113
Leukocyte adhesion deficiency, type I	ITGB2	Autosomal recessive	7
Male subfertility	TMEM95	Autosomal recessive	114
Mannosidosis alpha	MAN2B1	Autosomal recessive	115
Mannosidosis beta	MANBA	Autosomal recessive	116
Maple syrup urine disease	BCKDHA	Autosomal recessive	117
Marfan syndrome	FBN1	Autosomal dominant	118
Mucopolysaccharidosis IIIB	NAGLU	Autosomal recessive	119
Multiple ocular defects	WFDC1	Autosomal recessive	120
Muscular hypertrophy (double muscling)	MSTN	Autosomal recessive	13-15
Myasthenic syndrome, congenital	CHRNE	Autosomal	121
Myoclonus	GLRA1	Autosomal recessive	122
Myopathy of the diaphragmatic muscles	HSPA1A	Autosomal recessive	123
Neurocristopathy	CHD7	Autosomal dominant	60
Neuronal ceroid lipofuscinosis 5	CLN5	Autosomal recessive	124
Osteogenesis imperfecta, type II	COL1A1	Autosomal dominant	60
Osteopetrosis	SLC4A2	Autosomal recessive	125
Osteopetrosis with gingival hamartomas	CLCN7	Autosomal recessive	126
Ovotesticular disorder of sexual development	SRY	Y-linked	127
Perinatal weak calf syndrome	IARS	Autosomal recessive	128
Polled	POLL^a	Dominant	129,130
Progressive degenerative myeloencephalopathy (Weaver syndrome)	PNPLA8	Autosomal recessive	131
Protoporphyria	FECH	Autosomal	132
Pseudomyotonia, congenital	ATP2A1	Autosomal recessive	133
Ptosis, intellectual disability, retarded growth and mortality (PIRM) syndrome	UBE3B	Autosomal recessive	134
Renal dysplasia	CLDN16	Autosomal recessive	135
ResistanceZsusceptibility to Mannheimia hemolytica leukotoxin	ITGB2	Autosomal recessive	136
Retinitis pigmentosa 1	RP1	Autosomal recessive	137
Scurs, type 2	TWIST1	Autosomal dominant	138
Slick hair	PRLR	Autosomal dominant	106,139
ARMC3	Autosomal recessive	140
Spherocytosis	SLC4A1	Autosomal incompletely dominant	141
Spinal dysmyelination	SPAST	Autosomal recessive	142
Spinal muscular atrophy	KDSR	Autosomal recessive	143
Spongiform encephalopathy	PRNP	N/A	144
Syndactyly	LRP4	Autosomal recessive	145,146
Tail, crooked	MRC2	Autosomal recessive	147
Tibialhemimelia	ALX4	Autosomal recessive	67,149
Tricho-dento-osseous-like syndrome	DLX3	De novo autosomal dominant	150
Thrombopathia	RASGRP2	Unknown	151
Trimethylaminuria	FMO3	Autosomal recessive	152
Vertebral and spinal dysplasia	T	Autosomal incompletely dominant	153
Xanthinuria, type II	MOCOS	Autosomal recessive	154,155
Yellow fat	BCO2	Unknown	156
Zinc deficiency-like syndrome	PLD4	Autosomal recessive	157
A2 milk	CSN2	Autosomal codominant	158
Beta-lactoglobulin, low expression	PAEP	Autosomal	159
Milk yield and composition	GHR	Polygenic	160

Continued

■ TABLE 52.4

there are 147 genetic tests available in cattle (Table 52.4). It is worth noting that the majority of genetic tests currently available are for diseases/traits that are inherited as autosomal recessive traits. With the current technologies available through SNP-association mapping and next-generation sequencing, we should expect to further our understanding of polygenic traits and diseases.

Disease Testing

Clinicians can use DNA testing in disease diagnosis or to determine an animal’s potential for producing diseased progeny. Generally, disease diagnosis is based on clinical signs and other diagnostic tests, but occasionally DNA testing is used, in particular for later-onset diseases or diseases for which diagnosis by traditional methods is difficult or invasive. To offer a genetic test, the gene responsible must be known. Ideally, the actual mutation that causes the disease has been identified. Rather than knowing the exact gene or mutation, only a region of a chromosome may have been implicated in a particular disease. DNA tests can be divided into two categories: mutation tests and linked-marker or haplotype tests. Mutation tests are based on an actual mutation that causes disease, whereas the linked- marker or haplotype test is based on the region of the chromosome that is known to cause disease but not necessarily the actual mutation. Usually, haplotype tests are offered instead of a mutation test because the mutation has not yet been identified. With the current tools available in large animals, the identification of disease causing mutations is so efficient that marker-based tests are rarely used.

Mutations that cause disease appear in many different forms. A change of a single base pair from one base to another can cause a disease by changing an amino acid (“missense” mutation), truncating the amino acid chain (“nonsense” mutation), or altering expression or proper splicing. For example, missense mutations have been shown to cause lethal white foal syndrome in the American Paint horse.^10-12 Insertions or deletions of a single base pair (bp) can cause mutations in the coding sequence by altering the translational frame, which ultimately causes protein truncation. An 11-bp deletion in the myostatin gene causes a frameshift mutation and protein truncation in Belgian blue and Peidmontese cattle with the double-muscle phenotype.^13-15 Large deletions or insertions that remove hundreds and thousands of base pairs can also cause disease. For example, the polled intersexuality mutation in goats is caused by an 11.7-kilobase deletion that removes a regulatory element that controls the expression of two genes.¹⁶ This endless array of possible changes in the DNA that result in disease makes each individual DNA-based genetic test different.

The basis for DNA testing is PCR. Primers can be designed specifically to amplify either the disease-causing allele or the

normal allele. Alternatively, the PCR product can be digested with a restriction enzyme that cleaves the DNA at a particular sequence of bases. A restriction enzyme is chosen that shows a different cleavage pattern between the mutant and the normal version of the PCR product. Direct sequencing of a section of DNA can also be used to determine the animal’s genotype. Many different methods are available to assay changes in DNA that lead to disease. Each company that offers a test may choose a different type of assay for the same mutation.

There are limits to all genetic testing. For mutation tests, the specific mutation being assayed is the only factor being evaluated. An animal may have a different mutation in that gene or a mutation in a different gene that causes the same phenotype (phenocopy). It is therefore correct to state that an animal has been “DNA tested negative” for this specific mutation rather than “DNA tested clear” of the disease. In addition, more complicated modes of inheritance do not provide a direct disease or trait prediction. For example, some loci have incomplete penetrance and not all animals with the affected genotype will get the disease or trait. Other genetic tests are for susceptibility loci and merely confer a disease risk.

No association or committee evaluates quality control of DNA tests that are available in animals. Most tests are published in the scientific literature not as tests but as articles describing the discovery of the mutation. Because some cases involve patent issues, some tests are offered before publication. Much of the research done to identify the mutations involved in the tests is performed at universities and funded by granting agencies that have both financial and intellectual interest in patenting the tests.

Tables 52.3, 52.4, 52.5, and 52.6 list available genetic tests for traits and diseases other than coat color in horses, cattle, and sheep and goats, respectively. Only tests published in peer-reviewed journals are listed. Additional tests available in cattle for various forms of the milk proteins also are not listed in Table 52.4. The breeds of cattle are not listed because rapid changes in testing mean that tests are always being validated for new breeds. It is therefore recommended that a search be performed for the availability of a test for a particular breed each time the need arises. Coat color genetic tests are listed in Table 52.7, with each particular species in which the genetic mutation has been identified referenced.

The diseases or traits that are tested can be divided into two categories: those that have straightforward Mendelian inheritance patterns (recessive, dominant, and sex-linked) and those that are more complicated because many genes are involved with conferring the phenotype (polygenic). Quantitative trait loci (QTL) are the genes that contribute to a polygenic disease. In cattle, a vast number of QTL have been placed in specific regions of chromosome for quantitative traits such as dairy form, milk production, and fertility.¹⁷ Selection for these traits can be done with DNA testing (Table 52.4). Because so

Genetic Tests for Cattle—cont'd

Disease/Trait	Gene	Mode of Inheritance	Reference(s)
Milk yield and composition Meat tenderness	DGAT1	Polygenic	161
Milk yield and composition	Leptin	Polygenic	162,163
Meat tenderness	Calpastatin	Polygenic	164,165
	μ-Calpain	Polygenic	166,167

^aConsidered a locus and not a gene.

■ TABLE 52.5

Genetic Tests for Sheep

bgcolor=white>CLN5

Disease/Trait	Gene	Mode of Inheritance	Reference(s)
Achromatopsia-2	CNGA3	Autosomal recessive	168
Ataxia, familial episodic spinocerebellar	FGF14	Autosomal incompletely dominant	169
Chondrodysplasia (spider lamb)	FGFR3	Autosomal recessive	170
Chondrodysplasia, Texel	SLC13A1	Autosomal recessive	171
Ehlers-Danlos syndrome, type VII (dermatosparaxis)	ADAMTS2	Autosomal recessive	172
Epidermolysis bullosa, junctionalis	LAMC2	Autosomal recessive	173
	ITGB4	Autosomal recessive	174
Fecundity Barbarine	BMP15	X-linked	175
Belclare	BMP15	X-linked	176
Belcalre/Irish Cambridge	GDF9	Autosomal	176
Booroola	BMPR1B	Autosomal semidominant	177-179
Embrapa	GDF9	Autosomal	180
Galway	BMP15	X-linked	176
Grivette	BMP15	X-linked	181
Hanna	BMP15	X-linked	182
Inverdale	BMP15	X-linked	182
Lacaune	B4GALNT2	Autosomal codominant	183
	BMP15	X-linked	182
Norwegian	GDF9	Unknown	184
Olkuska	BMP15	X-linked	181
RaseAragonesa	BMP15	X-linked	185
Small tail Han	BMPR1B BMP15	Autosomal	186
Thoka	GDF9	Autosomal	187
Vacaria	GDF9	Autosomal	188
Fleece variation	IRF2BP2	Not reported	189
Gangliosidosis, GM1	GLB1	Autosomal recessive	190
Gangliosidosis, GM2, type 1	HEXA	Autosomal recessive	191
Gaucher disease, type I	GBA	Autosomal recessive	192
Glycogen storage disease V	PYGM	Autosomal recessive	193
Hemophilia A	F8	X-linked	194
Hypophosphatemic rickets	DMP1	Autosomal recessive	195
Hypotrichosis	HR	Autosomal recessive	196
Lissencephaly and cerebellar hypoplasia	RELN	Autosomal recessive	197
Microphthalmia	PITX3	Autosomal recessive	198
Motor neuron disease lower	AGTPBP1	Autosomal recessive	199
Muscular hypertrophy (double muscling)

Callipyge	DLK1	Polar overdominant	200
Texel	MSTN	Autosomal	201
Myotonia Neuronal ceroid lipofuscinosis	CLCN1	Autosomal recessive	202
10	LOC443060	Autosomal recessive	203
5	Autosomal recessive	204
6	CLN6	Autosomal recessive	205
Polled/Horns	RXFP2	Autosomal	206
Porphyria cutaneatarda	UROD	Autosomal recessive	207
Resistance/susceptibility to lentivirus	TMEM154	Multifactorial	208
Spongiform encephalopathy (scrapie susceptibility)	PRNP	Autosomal recessive	209
Waardenburg syndrome, type 4A	EDNRB	Autosomal recessive	210
Yellow fat	BCO2	Autosomal recessive	211

■ TABLE 52.6

Genetic Tests for Goats

Disease/Trait	Gene	Mode of Inheritance	Reference(s)
Casein, α-S1, reduced concentration	CSN1S1	Autosomal	212
Casein, α-S2, null allele	CSN1S2	Autosomal recessive	213
Casein, β, null allele	CSN2	Autosomal	214
Goiter, familial	TG	Autosomal recessive	215
Horns/Polled	PISRT1, FOXL2	Autosomal	16,216
Mannosidosis, β	MANBA	Autosomal recessive	217
Mucopolysaccharidosis IIID	GNS	Autosomal recessive	218
Myotonia	CLCN1	Autosomal dominant	219

■ TABLE 52.7

Genetic Tests for Coat Color

Coat Color	Gene	Species	Reference(s)
Albinism	TYR	Cattle	220
Albinism (oculocutaneous type IV)	SCL45A2	Cattle	221
Albinism (oculocutaneous type VI)	SLC24A5	Horse	222
Agouti	ASIP	Horse	223
		Cow	224
		Sheep	225
Appaloosa	TRPM1	Horse	37
Brown (Dun)	TYRP1	Cow	226
Brown (Dun)		Sheep	227
Champagne	SLC36A1	Horse	228
Cool gray	MLPH	Cattle	229
Cream dilution	SLC45A2	Horse	230
Dilution	PMEL	Cow	231
Dominant red	COPA	Cow	60
Dominant white	KIT	Horse	232
		Cow	233
Extension	MC1R	Horse	234
		Cow	235
		Sheep	236
		Goat	237
Gray	STX17	Horse	238
Macchiato	MITF	Horse	239
Roan	KITLG	Cow	240
Silver	PMEL17	Horse	241
White belt	TWIST2	Cow	242
White spotting	MITF (Horse, cow)	Horse	239
	PAX3 (Horse)	Cow	233
	EDNRA (Goat)	Goat	243

many different QTL exist, however, selection can be challenging, and trade-offs need to be made.

Genetic testing relies on advances made in the field of genomics. Veterinarians and owners are fortunate that large animal species were chosen as economically important species for whole-genome sequencing. With the tools currently available, the number of disease-based or trait-based tests available in the future will markedly increase.

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The complete list of references can be found at www.expertconsult.com.

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Source: Smith Bradford P., Van Metre David C., Pusterla Nicola (eds.). Large Animal Internal Medicine. Part 2. 6th edition. — Elsevier,2020. — 2279 p.. 2020

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