Genetic and congenital diseases

Congenital malformations in PEOPLE (live births)

Genetic
Chromosomal: 10 15% Mendelian: 2 10% Multifactorial: 20 25%

Environmental
Maternal infections: 2 3% Maternal diseases: 6 8% Drug and chemical: 1% Irradiation: 1%

Unknown: 40 60%
Diseases of Food Animals and Horses PATB 4110

Diseases with genetic component - human

Autosomal Described Gene known Described Gene unknown 2080 X-linked 192 Y-linked 2 Mitochondrial 26

Genetic diseases characterized at molecular level domestic animals

Cattle 40 Sheep 16 Horses 14 Pigs 30

1948

140

Congenital defects in cattle of unknown origin

Estimated frequency of congenital disorders in cattle

1:100 1:500
21.6%
CNS Muscles Anomalous twins Systemic Body cavity Digestive Urinary Bone Heart Skin Others

Schistosomus reflexus

Contracted tendons

Umbilical hernia multiple genes most common defect in cattle Schistosomas reflexus unknown Two-headed calves - unknown Anencephaly unknown Absence of cerebellum unknown Chromosomal anomalies many unknown

9.7%

10.0%

13.7%

Congenital defects
Genetic
Most commonly, homozygous recessives Selection by inadvertent linkage to a desired trait
Milk production and weaver trait in Brown Swiss Lean carcass and porcine stress syndrome Heavy muscling and HYPP in progeny of Impressive

Suspect genetic defects when

More than one born in season, or several born over multiple seasons Stereotyped appearance and outcome Common blood-line (e.g., to half sisters)

Some dominant Chromosomal abnormalities can result in resorption, early abortion or malformation (esp. dwarfism or infertility)

Environmental
Infectious: BVD; BTV; Neospora Teratogenic plants: lupines and skunk cabbage Nutritional: iodine and vitamin A deficiency

The problem
Many congenital diseases of animals can be due to either genetic or environmental causes
Goiter Arthrogryposis Hydrocephalus Dwarfism Cerebral malformations Many others

Terminology
Out breeding - breeding unrelated or less related animals than average of the p p population Phenotype physical appearance of individual based on genetic + environmental influences Genotype genetic makeup of individual

Congenital (with birth): Present at birth Genetic: Associated with genes genetic diseases usually evident early in life, but some manifest later
GENETIC DISEASE CONGENITAL DISEASE

Congenital non-genetic disease

BVDV encephalopathy Goiter

Low iodine or iodine competitors Congenital viral infection

 Inbreeding - production of offspring from parents more closely related than the average of population Line breeding - inbreeding in which inheritance of a specific ancestor is concentrated by fatherdaughter or granddaughter matings

Types of Mendelean inheritance

Autosomal* recessive Autosomal* dominant X-linked recessive X-linked dominant
* Autosome = one of the numbered genes

Here in Rock Springs, Pop and sis did a lot of line breeding

Typical homozygous recessive pedigree

Ancestral sire

Some genetic diseases are expressed LATER in life

CHAROLAIS ATAXIA Charolais Onset O t at t 6 - 36 mo Progression over 1 2 years CNS disease Ataxia to recumbency Abnormal white matter HEMOCHROMASIS Salers Seriously inbred Homozygous recessive Onset at 1 2 years Excessive uptake of iron Liver iron = hepatic failure with bone disease

Carrier dam

Carrier sire

Affected homozygote

Hemochromatosis

Hemochromatosis in cattle and people

Human Onset: decade Inheritance: AR (HFE Cys282Tyr) Hepatic iron: 11,680 g/g T Transferrin f i sat: >62% 62% Cause of death: Cirrhosis M: F ratio: 7:1 Joint lesions: Chondrocalcinosis Bone lesions: No 4th 5th Bovine 9 22 months Familial 1,500 20,000 g/g >65% 65% Hepatic fibrosis Predominantly F No Yes

Ill-thrift, Ill thrift, loss of incisors, death Breed society unhelpful Comparative disease interest

Vet Pathol 38: 372 389, 2001

Homozygous recessive disease

N C N NN NC C NC CC

Dominant traits
ONE affected parent required to transmit 1:1 ratio of normal:affected offspring Carrier x carrier = 3 affected, , 1 normal In every generation If 1:1 ratio males:females = autosomal dominant If mostly females = sex linked dominant EXAMPLE: HYPP

When carrier bred to carrier, 25% chance that offspring will have disease When carrier bred to a non-carrier, no affected offspring. But

50% of offspring will be carriers In the herd, it may seem to skip generations Used to be tested by sire-daughter or sire-carrier mating if 32 and 16 normal offspring, <1:100 chance he is carrier

Polygenic traits
Multiple genes involved Usually, small effect per gene Genes x + y + z + environmental effect = disease Example: Brisket disease

Chromosomal disorders
Poorly characterized in cattle and horses Due to:
Translocation and deletions of parts of chromosomes Trisomy states

Less common than in people? ~11% of aborted and stillborn calves

Types of chromosomal disorders

Abnormal chromosome number - aneuploidy Extra chromosome trisomy Loss of one chromosome monosomy

Congenital malformations in livestock and horses

Breed societies vary in record-keeping
Some have good genetic disease records available to members
Expect AI animals to be tested for diseases of concern If a carrier is found, family tree should be tested

Others secretive

Difficult to investigate with many owners

Stigma Economic effect on sale of seed stock Difficult to trace back sires and dams

Horse industry progressive about investigating suspect genetic disease and underwriting genetic test development

If you think you have a deleterious genetic trait in herd or flock

1. Blood or hair DNA type to confirm parents, esp. if AI e.g., UC Davis genetics laboratory or private laboratory determined by breed society 2 Contact breed association to see if record of defect in 2. breed 3. Submit typical affected animals for necropsy to characterize defect 4. Work with geneticist to generate pedigree 5. Avoid and/or cull affected blood lines 6. If major problem, work with breed association to develop genetic test to pick up carriers

Genetic tests
Probe for normal gene Probe for abnormal gene

1 35 Kb 1.35

1.35 Kb

NN Nn nn

NN Nn nn

PCR amplification using allele-specific oligonucleotides

Hyperelastosis cutis in AQH

Formal name: HEDRA Hereditary equine regional dermal asthenia AQH, Paints and Appaloosas 1978 Homozygous recessive Poco Bueno sireline Damaged dorsal trunk skin hematomas, seromas, scars Horses 6 months 2 years old in sites of trauma and wear Poorly healing ulcers Hematoma and seroma formation White hairs at sites of healed skin Lifespan 2 4 years Genetic test available
N/N vs. N/HRD vs HRD/HRD

HYPP
Hyperkalemic periodic paralysis
K+ Progeny of Impressive Uncontrolled muscle twitching, especially neck, shoulders, ribs, hips and flanks Breeding for heavy muscles? Potentially fatal in H/H less in H/N DOMINANT trait PCR test available ~30% of positive horses no signs Older horses less affected Dietary control: keep K+ in diet low

Osteopetrosis
Marble bone disease Black and Red Angus Small premature calves Dead at birth Failure to resorb bone Undershot jaw Malformed skull and brain Homozygous recessive? No genetic test -yet Notify breed association

Dwarfism
Multiple forms
Genetic Growth retardation

Proportionate vs. short limbs Recessive vs. dominant Each breed has its own

Syndactyly mule foot

Relatively common
Holstein Angus Many others

Porcine stress syndrome

Selection for lean carcass/efficient growth Single founder Pietran pig Esp. Landrace; also Large White, Duroc In 1970s, prevalence of 70- 90% in some European countries
Major: PSE pork Minor: death

Autosomal recessive Associated with hyperthermia

Genetic test Manage to reduce stress

Overo lethal white syndrome

Breeding paint horses: overo x overo Aganglionisis = paralyzed LI D th within Death ithi 2 days d - colic li Overo x Overo horses = 50% overo foal, 25% lethal white and 25% non-overo foal Overo x non-Overo = 50% chance of overo foal and no chance of lethal white foal Genetic test available for trait Genetic test available

Polysaccharide storage myopathy and tying up syndrome

AQH, Paints, Appaloosas Similar unrelated? disease in draught horses Form of tying tying up: up: Start of training Stiff muscles Shifting lameness Tense abdomen No genetic test but biopsy

Cryptorchidism
Common Testicle(s) fail to descend to scrotum in last month gestation Infertile if internal Inherited but mechanism unclear If castrated, acts as a rig May be seat of neoplasia

Complex vertebral malformation of Holsteins

New disease - 1999 Genetic defect identified/test developed 2001 Originally Scandinavia now worldwide USA/Scand/Japan About 23% bulls carriers (Sweden) Abortions; stillbirth; perinatal death Misshapen/fused vertebrae at cervicothoracic junction crooked calves cleft palate stunted cardiac anomalies Holstein Assoc USA lists of carriers and non-carriers

Scoliois and synostosis J Vet Med Sci 64: 1107-1112

Spider lamb
Bulldog calves
All breeds b d Common in WY Homozygous recessive Often have cleft palate and cardiac anomalies No genetic test Abnormal growth of cartilage
Suffolk breed emerged mid-1980s selection for tall sheep? Affected lambs:
Most born alive with skeletal deformities Some not evident till 3 8 weeks post-natal life Aborted Ab t d or stillborn tillb

Limbs disproportionately long and deformed knock-kneed Other abnormalities: scoliosis, kyphosis, Roman nose Homozygous recessive Genetic test available

BLAD
Bovine Leukocyte Adhesion Deficiency Holsteins Recognized 1980s now largely eliminated Homozygous recessive Inability of WBCs to stick to blood vessels and kill pathogens due to integrin deficiency Common sires tract back to Osborndale Ivanhoe Carrier rate was 15% of AI bulls and 8% of cows Affected rate was 6% of all calves born (16,000-20,000 calves) Sickly calves death due to susceptibility to infection Genetic test available

Parrot mouth
Overbite Excessive length of maxilla (or mandible too short) Inherited but mechanism unclear Care with feed

Brain and spinal cord disorders

Multiple Relatively common Generally y fatal
Hydrocephalus Anencephaly Cerebellar hypoplasia Often concurrent ocular and spinal defects

Cardiac disease in calves

1. Multiple cardiac defects:
Septal defects PDA Anomalies of great vessels

2. Later onset cardiac disease hypertrophic yp p cardiomyopathy

Multiple genetic patterns

Freemartins
NOT genetic Blood test Due to anastomoses of twins placental circulation Male hormones inhibit development of female reproductive tract + chimera Detect by physical examination of cervix in female calves twin to male 92% of such females are sterile 200,000 sets of twin calves born annually in US Also in sheep

Polydactyly and syndactyly

Poly- = too many Syn- = fused -dactyly = related to digits Excessive numbers of digits and fused digits COMMON Holstein, Angus, Hereford, Simmental among others Homozygous recessive for syn-; unclear for poly-

Hypotrichosis - hairlessness
Multiple breeds including Angus and Hereford Common

Brisket
Heart failure secondary to pulmonary hypertension

Usually y recessive
May be dominant or sex linked Can be linked to anemia and anodontia Other causes: BVDV

Common esp. in Angus and >6,000 feet Incidence 0.5 2.0% P l Polygenic i inheritance i h i Compounded by exposure to locoweed Heart failure and diarrhea Test bulls for PAP <35 mg Hg Affected calves bring to lower altitude

Summary: genetic disease

Considered small problem but in individual herds affects reputation Have it CHARACTERIZED esp. in intensive line breeding operations Simple fix: identify sire by DNA testing, and eliminate Serious for AI/high dollar sires and breeds with narrow genetic base May be congenital or later onset Importance as animal models of human disease
GENETIC DISEASE CONGENITAL DISEASE