Transcript Gene350 Animal Genetics

Gene350 Animal Genetics
Lecture 2
23 July 2009
Last Time
•
•
•
•
•
Functions of animals
Define Animal Genetics
Branches of genetics
Domestication
Methods used in animal genetics
Today
•
•
•
•
Single gene disorders
Gene action and single gene disorders
Mutations causing single gene disorders
Examples of single gene disorders in animals
Inborn errors of metabolism
• If a polypeptide acts as an enzyme or is part of an
enzyme, a mutation in its gene results in a
deficiency of that enzyme
• Consequent blockage in biochemical pathway
where that enzyme is required
• Diseases resulting from such blockages are called
inborn errors of metabolism
• Types of gene action (dominant, recessive, codominant or incompletely dominant) are
important
Genetic disorders
• Autosomal recessive disorders
– Disorder caused by a single, recessive gene that is
not sex-linked
– Caused by enzyme deficiencies
• Autosomal dominant disorders
– Disorder caused by a single dominant gene that is
not sex-linked
– More likely caused by non-enzymatic polypeptides
Enzymes required in small quantities that 50% normal activity (as in heterozygotes) is
sufficient for normal function. Polypeptides are often required in relatively large quantities
and therefore heterozygotes show clinical signs
Genetic disorders
• Sex-linked disorders
– Recessive will be defective
• Polygenic disorders
– Caused by more than one pair of genes
Single gene disorders
• Potential number of single gene disorders is far
greater than the total number of genes
• A deficiency in any polypeptide is likely to give
rise to either :
1. Embryonic lethality (spontaneous abortion) or
2. Clinical signs
• Different mutations in the same gene can give
rise to different sets of clinical signs
Phenocopies
• Phenotype of a single gene disorder can occur
due to an environmental cause
• Such occurence is called phenocopy
• e.g α-mannosidosis (lysosomal storage disease)
in cats and cattle caused by mutation in the
gene for α-mannosidase.
• Cattle grazing on pasture containing legume
Darling Pea often develop α-mannosidase
Mutations producing embryonic
lethals
• Are difficult to detect
• Recalling that number of genes is large
(>30000), it is evident that list of single-gene
disorders that will be detected is likely to be
very long
• Only small fraction have been documented in
domestic animals
Molecular technology
• Increasing use in investigation has uncovered
several interesting examples of different types
of mutations
• Example – mis-sense mutation by canine
haemophilia B
– Caused by substitution of A for G at nucleotide
1477 in the gene for canine factor IX
– Results in the substitution of glutamic acid for
glycine at position 379 in the factor-IX molecule
Mis-sense mutations
• Single amino-acid substitution alters tertiary
structure of the factor-IX molecule
• No functional factor-IX is detected
• Mis-sense mutations also cause bovine
leucocyte adehesion deficiency (BLAD),
hyperkalaemic periodic paralysis in horses,
malignant hyperthemia syndrome in pigs &
behavioural defect called shaking in dogs
Nonsense mutations
• Also occur
– e.g in Afrikander cattle, inherited goitre is due to a
nonsense mutation in thyroglobulin gene
– Citrullinaemia in cattle, deficiency of uridine
monophosphate synthase (DUMPS) in cattle,
hypotrophic axonopathy in quail etc
• DUMPS is also an example of embyonic lethal
that has been detected
• Detection was through studies of inheritance and
molecular genetics techniques
DUMPS
• Deficiency of uridine monophosphate (UMP)
synthase
• enzyme converts orotic acid to UMP
• UMP is essential component of pyridine
nucleotides
• Vast quantities required during embryonic
growth
• Homozygosity for nonsense mutation causes
embyonic death around 40 days in utero
DUMPS
• Practical effect of disorder is that carrier cows
show a higher rate of return to service> some
pregnancies end in early natural abortion
• Difficult to identify mutation from
reproductive records because return to service
has several possible reasons
• Discovered from nutritional study: milk orotic
acid levels in cattle were very high
• Possible explanation: deficiency of UMP
Point mutations in intron
• Introns are excised before translation
• Disrupts the RNA splicing mechanism if point
mutation occurs in the first few or last bases of
an intron e.g is muscular dystrophy in dogs is due
to base substitution in the 3’ splice-acceptor site
of intron 6 of dystrophin gene
• Riboflavinuria in chickens caused by point
mutation in 5’ splice-donor sequence GT in intron
2 of the gene for riboflavin-binding protein
becoming AT
Insertion mutation
• e.g henny feathering in chickens.
• Terminal repeat sequence of a retrovirus is
inserted into the 5’ promoter region of the
aromatase gene
• Causes aromatase gene to be switched on in
atypical places of both sexes giving rise to
henny-feathering trait in males
Unstable trinucleotide repeats
• Discovered in humans & likely to be discovered in
animals in the future
• They arise in some genes that contain
microsatellites in which repeat unit is a triplet
• Repeats sometimes rapidly expand in numbers
between generations causing clinical signs to
appear
• Expanded number of repeats methylates
surrounding DNA which inactivates the gene
Examples of single gene disorders
in animals
Name
Deficiency or
abnormal
expression
Causative mutation Species
or linked marker
Goitre
Thyroglobulin (TG)
Cattle & goat:
nonsense mutation
in TG gene
Cattle, goat
Haemophilia B
Coagulation factor
IX
Dog: mis-sense
mutation in factor
IX gene
Cat(X), dog (X)
Dog: point
mutation in 3’
splice-acceptor site
of intron 6 that
introduces a stop
codon into exon 8
Cat(X), dog (X)
Muscular dystrophy Dystrophin
Diseases with a linked marker
Name
Deficiency or
abnormal
expression
Causative mutation Species
or linked marker
Horns (polledness)
Cattle: linked
microsatellite
marker (15 cM)
Cattle, goat, sheep
Muscular
hypertrophy
Sheep (callipyge
gene): linked VNTR
marker (20cM)
Cattle, sheep
Narcolepsy
linked to µ
Dog
immunoglobin gene
Weaver disease
Linked
microsatellite
marker (3 cM)
Cattle
Disorders with known deficiency or
abnormal expression
Name
Deficiency or
abnormal
expression
Causative mutation Species
or linked marker
Albinism
Tyrosinase
Cat, cattle, chicken
Analphalipoprotein
aemia
High-density
lipoprotein
deficiency
Chicken (Z)
Arginaemia
Arginase
Sheep
Dwarfism
Thyroxine and triiodithyroxine
cat
Factor XI deficiency
Coagulation factor
XI
Cattle, dog
Glycogen storage
disease type II
(Pompe disease)
α-glucosidase
Cat, cattle, dog,
quail, sheep
Other single-gene disorders
Name
Deficiency or
abnormal
expression
Causative mutation Species
or linked marker
Ceroid
lipofuscinosis
(Batten’s disease)
Goat, sheep, cat,
cattle, fox
Dwarfism, pituitary
Cattle
Hypotrychosis
(hairlessness)
Dog, cattle
Blindness
Chicken
Naked neck
chicken
Sperm
degeneration
Cattle
Vertical fibre hide
defect
Cattle
Access Online Mendelian Inheritance in Animals
(OMIA) on:
http://omia.angis.org.au
Assignment 1
Trait name
The most standard name for each trait, using (wherever
relevant) terms that reflect homology with other species
MIA number
A unique non-informative 6-digit identifier
References
Arranged chronologically (so as to provide a brief ‘history’ of
knowledge of each trait)
MIM number
If it appears that the animal trait has a human homologue,
the unique 6-digit identifer of the homologous human
trait is included here, providing a hotlink to OMIM
Across-species
synonyms
Other terms by which the trait is known across species
Across-species
summary
A brief summary of the features of the trait that are common
across species
Species synonyms Terms by which the trait is known in a particular species
Species summary
A brief summary of the features of the trait that are peculiar
to a particular species
History
A brief summary of the history of the trait
Clinical summary
A brief summary of clinical signs