Genetics of Disease and Simple Disorders

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Genetics of Disease and Simple Disorders

• N. Matthew Ellinwood, D.V.M., Ph.D.
• Spring 2009

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Genetics of Disease

• Modes of Inheritance
• Dominant
• Recessive
• Complex

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Genetics of Disease

• Modes of Inheritance
• Dominant
• Late onset diseases
• Recessive
• Complex

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Dog and Cat Genetic Diseases

• Mechanism of genetic disease
• Mutations
• Random and spontaneous
• Mutations become concentrated in the population
  over many generations
• Two mechanisms
• Founder effect
• Popular sire or dam effect

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Founder Effect

• Often a misused term
• A disease allele is concentrated in a small or
  new population (foundation population) at a
  higher relative frequency from the originating
  population
• Original population, 1/1,000
• New population 1/10
• Example Angus cattle in Australia and New
  Zealand and alpha-mannosidosis
• Portuguese Water Dogs (15 animals founded the
  population)
• Initial development of breeds was likely
  foundation event

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Popular Sire or Dam Effect

• Dog and cat fancy breeding often involves heavy
  use of popular sires or dams
• This effectively concentrates desirable alleles
  in the population
• If the heavily used animal is carrying a mutant
  allele, it will also increase that allele in the
  population

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Founder and Popular Effect

• Founder effect is often a misused term
• Most common recessive genetic diseases are the
  result of
• Popular sire or dam effect
• Popular sire or dam effect and founder effect

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Pedigree Example

• Founder effect compounded by popular sire/dam
  effect

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How old is a mutation

• Difficult to say
• If it is a common allele, one assumes not a
  recent mutation
• Serious or biomedically important diseases
  receive scrutiny not inline with being clinically
  common conditions
• Example is mucopolysaccharidosis type VII in
  German shepherd dogs
• First seen in mixed-breed dog
• 25 years later published case in German shepherd
  dog

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Age of Mutations in a Population

• Mutant alleles seen in different, but closely
  related breeds of dogs
• Examples
• West Highland white and Cairn terriers
• Krabbe disease (globoid cell luekodystrophy)
• German shorthair and wirehair pointers
• Von Willebrand disease
• Assuming no mixing of breeds, mutations occurred
  before breeds were formed in mid-late 19th century

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Recessive Genetic Disease in Dogs and Cats

• Dozens of genetic disease in dogs and cats for
  which genetic tests exist
• Involve serious inherited recessive diseases of
  various body systems
• Vision
• Lysosomal Storage Diseases
• Hematological Disorders

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Commercial DNA Based Testing

• Testing for diseases
• Testing for traits (hair coat color)
• Testing for parentage
• University based, single tests
• Usually developer of tests
• University based, multiple tests and services
• Commercial laboratories, University spin-offs
• Commercial laboratories, usually little to no
  development
• Price 75-150

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Vet Gen Coat Color Tests

• The B and b alleles of the dog
• Three mutations in Tyrosinase Related Protein-1
  (TRP1) involved in the chocolate coat color in
  bb Labrador retrievers (and dogs of many other
  breeds).
• The E and e alleles of the dog
• One mutation in the the Melanocortin-1 Receptor
  (MC1R) gene that causes the the yellow coat color
  in ee dogs.

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Tests Available for 33 different Breed Tests
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Lysosomal Storage Disease in Veterinary Patients

• Documented in virtually every major veterinary
  species except the horse
• Usually severe disease seen in the young animal
• At least 21 different forms identified in over
  two dozen breeds of dogs and cats
• Mixed breed dogs and cats also documented
• Molecular (DNA) defect known in at least 20 cases
• Documentation of certain breeds affected with
  more than one form of lysosomal storage disease
  (English Springer Spaniel (2), and Siamese Cat
  (3))

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Breed Specific Tests

• Airdale Terrier
• American Cocker Spaniels
• Australian Cattle Dogs
• Australian Shepherd
• Basenji
• Basset Hound
• Bedlington Terrier
• Bernese Mountain Dog
• Briard
• Brittany Spaniel
• Bull Terrier
• Bullmastiffs
• Cairn Terrier
• Cardigan Welsh Corgi
• Chesapeake Bay Retrievers
• Curly-Coated Retriever
• Dachshunds
• Dalmatian
• Doberman Pinscher

• English Cocker Spaniels
• English Pointer
• English Setter
• English Springer Spaniel
• Field Spaniel
• Flat-coated Retriever
• German Short-haired Pointer
• German Wire-haired Pointer
• Golden Retriever
• Great Dane
• Greyhound
• Irish Setters
• Irish Red White Setters
• Kerry Blue Terrier
• Labrador Retriever
• Large Munsterlander
• Lhasa Apso
• Manchester Terrier
• Mastiffs

• Miniature Poodle
• Miniature Schnauzer
• Newfoundland
• Nova Scotia Duck Tolling Retrievers
• Papillon
• Pembroke Welsh Corgi
• Poodles (all varieties)
• Portuguese Water Dog
• Samoyeds
• Schipperke
• Scottish Terrier
• Shetland Sheepdog
• Shih Tzu
• Siberian Huskies
• Sloughis
• Toy Poodles
• West Highland White Terrier
• Wheaten Terrier
• Whippet

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Canine Scientific Investigation(CSI)

• DNA Sample collection and submission
• Blood
• Requires a veterinarian to collect and ship
• What kind of blood sample?
• Cytology brushes
• Can be collected by owner

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DNA Testing Results

• Carrier versus Normal versus Affected
• Allows carriers to be used safely
• Should carrier animals be continued to breed?
• How common are carrier animals in some of these
  disorders?

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DNA Tests and Breeding

• Carrier animals can be safely bred, and in some
  cases, the genetic health of the breed may depend
  on using such animals
• Carrier rates can reach over 20 in some breeds
  and some diseases.