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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