BVMS1

• cause infertility (if survive gestation)
• embryonic loss (miscarriage)
• growth and developmental abnormalitites

(most chromosomal abnormalities are NOT compatible w/ survival)

• Karyotypes
• if chromosomes are missing or gained it would be easily noted

• 1) nucleated cells are isolated from animal
• 2) cells are grown in cultures
• 3) cells are arrested in metaphase
• 4) cells are dropped onto slides and stained

• light/dark banding pattern
• due to density of heterochromatic
• characteristic for each chromosome
• used to detect abnormalities

chromosomes are replicated and condensed

• location of centromere
• acrocentric: just off centre
• metacentric: middle
• telocentric: extreme end

using fluorescent probes can help id specific chromosomes (for X and Y or all!)

• humans: 46
• cows: 60
• dog: 78
• cat: 38
• horse: 64
• donkey: 62

• 1) abnormalities in chromosome NUMBER (aneuploidy, polyploidy)
• 2) Abnormalities in chromosome STRUCTURE (deletion, duplication, inversion, translocation, ring)

• presence or absence of one or more chromosomes
• Euploidy: normal
• trisomy: extras (ex: 3 extra X)
• monosomy: missing (ex: 1 X
• causes gene dosage effects
• (ex: trisomy 21)

• 3 well defined disorders known in humans (most autosomal aneuplois are not compatible w/ survival)
• Trisomy 21= downs syndrome
• Trisomy 18= Edwards syndrome
• Trisomy 13= Pataus Syndrome
• (not well documented in animals)

• Trisomy 18 (cows)
• causes lethal brachygnathia in cattle resulting in death in utero

• cause infertility
• most common chromosomal disorder in horses: XO or Monosomy X in mares (63, XO)
• affected mares have a small size, small ovaries
• causes infertility
• similar to human disease Turners syndrome
• (underdeveloped, not diagnosed until much later)

• testicular feminisation in mares
• mares have a male karyotype
• mares can often be large, successful show and performance prior going to stud (they have XX and XY in cells)
• causes infertility

• affected animals show a male phenotype
• underdeveloped male sexual characteristics
• causes infertility
• similar to the human disease Klinefelters syndrome (mental impairment also)

• change in diploid chromosome content (2n)
• ex: triploid- three of each chromosome (3n)
• can be detected in embryo in animals but NOT seen in live births
• causes embryonic loss
• (common in fish and plants)

• failure of chromosomes to separate properly at meiosis I or meiosis II
• random events in the formation of reproductive cells
• they are NOT inherited

chromosomes do not separate propery (meiosis I or II)

• trisomy: extra chromosome
• monosomy: missing chromosome

• unknown!
• old meiotic apparatus MAY cause errors in chromosomal movement???

• arise when chromosomes breaks and are NOT restored to original structure
• Genetically balanced: correct genetic information is present buy may be rearranged
• Genetically unbalanced: due to either deletion or duplication of a region of chromosome

• 1) deletion (breaks)
• 2) duplication (part makes 2 or 3 copies)
• 3) ring chromosomes (break in both arms- losing telomeres and chrom. fuse together)
• 4) inversions (break and inserted in incorrect orientation)
• 5) translocation (reciprical exchange between 2 chromosomes)

• centromere of 2 acrocentric chromosomes fuse together to give one large metacentric chromosome
• (no centromeres lost in next cell division- cannont undergo mitosis)
• *causes embryonic loss in cattle!*

• cause embryonic loss
• 1/29 translocation affects most breeds
• 14/20 translocations affects 1% of simmental cows
• **bulls can be karyotyped if cows serviced by the same bull abort

• some may be inherited
• others occur as random events in the formation or reproductive cells:
• unequal crossing over in meiosis
• breakage of chromosomes
• chemical mutagens
• radiation

• abnormality arises during embryonic development
• only some cells cary abnor.
• in such cases the symptoms are usually less severe

animals w/ 2 or more cells derived from a single zygote

animals w/ 2 or more cell lines derived from 2 zygotes

• Chimeras and are often infertile
• occurs when 2 embryos developing, one male and 1 female
• during preg. placental anastomosis can occur in 90% of cases (exchange of blood cells/hormones)
• blood supply is shared, cells, proteins, hormones
• female calf is then exposed to male hormones
• female calf becomes "masculinized"
• 90% of females born co twin to a male will be infertile freemartins
• check if a female young cow is a freemartin- look for XX/XY chimerism on karyotype analysis (multi cells)

• malformation- error of normal development
• congenital- present at birth but sometimes not diagnosed until later
• 1/3 of all congenital malform. are due to chromosomal abnor.
• other causes: multifactorial, congenital infection, maternal illness, drugs, x rays

• study of inherited single gene disorders
• >5000 genetic dz known in humans
• due to mutations in specific genes
• autosomal inheritance
• sex linked inheritance

• 1) deletions
• 2) insertions
• 3) duplications
• 4) single base substitutions
• 5) non coding sequence mutation
• 6) dynamic mutations

• missense (replace 1 aa w/ another in the gene product= silent)
• nonsense (replace one aa w/ a stop codon

• splice site mutations: create or destroy signals for exon-intron splicing
• promoter mutations: affect protein expression

• excessive number of CAG repeats (huntington chorea)
• progressive neural degeneration, uncontrolled tremors, leading to convulsions and premature death
• late age of onset disorder (35-45 years)
• (glutamine= makes really sticky- used for nerve cell protection)

• significance of mutations depends on whether the mutation arises in germ cells (sperm or egg) or somatic cells
• Germline mutations: following fertilisation, every cell of the gamete formed from an egg/sperm w/ a mutation will carry the mutation
• offspring of the formed adult will also carry the mutation in EVERY CELL!
• somatic cell mutations: mutations arises in ONE CELL and is passed on only to the DAUGHTER cells (cell may die or give rise to a tumor)

if a disease (or trait) is controlled by a single gene, each individual has 2 copies of the gene: the 2 copies are termed alleles

if an individual has 2 copies of the same allele (aa, AA)

if the individual has 2 different alleles (Aa)

• if the gene is expressed in the heterozygous state: dominante
• if expressed only in the homozygous state: recessive

• Y chromosome: contains few genes, mostly genes governing male sexual function
• X chromosome: contains many genes that play a vital role in both sexes
• X-chromosome inactivation: one chromosome is inactivated in every female somatic cell- random (paternal or maternal)
• ensures product levels for genes on the X chromosome are similar in both sexes allows for dosage compensation

• must be heterozygous Xa Xb- must be female
• random inactivation of one X chromosome
• approx 50% cells inactivate Xa (orange)
• 50% cells inactivate Xb (non-orange)

• autosomal recessive (AR)
• autosomal dominant (AD)
• X linked recessive
• X linked dominant
• Y linked inheritance (rare)

• an individual ingeriting 1 mutant allel will be affected
• *this assumes the affected parent in heterozyhous- usually true for rare conditions*
• 1)males and females have the condition with equal freq.
• 2) each child of an affected individual has 50% chance of being affected
• 3) affected offspring have an affected parent (every generation affected)- vertical pattern
• 4)unaffected individuals do not have children w/ the condition

• in animals tend to be rare (breeders)
• hyperkalaemic periodic paralysis (HYPP) in horses
• Polycyctic kidney disease in cats
• hungtingtons chorea in humans

• causative mutation: missense mutation in sodium ion channel gene on muscle cells
• causes uncontrolled sodium influx-muscle twiching/profound muscle weakness
• high levels of potassium in the blood usually are present
• effects: heavy musculature, paralysis, intermittent muscle weakness and spasms, profuse sweating, increased respiratory rate

• Causative mutation: genetic defect not ID to date
• effect: can cause death due to kidney failure (usually later in life)
• most cats are heterozygous (homozygotes die before birth-lethal)
• common in some breeds: persians, exotic short hairs, 1/3 cats affected

• causative mutation: metabolism associated gene
• excessive number of CAG repeats (glutamine)
• trinucleotide repeat disorder
• extra glut makes cells sticky
• effect: progressive neural degeneration, uncontrolled tremors, leading to convulsions and premature death
• late onset (age 35-45yrs)

• an individual must inherit two mutant allels
• BOTH parents must be carriers
• 1) males and females have the condition w/ equal frequency
• 2) 1/4 chance of offspring being affected
• 3) appears in one generation and not the parents (horizontal)
• 4) parents of affected offspring must be carriers

• severe combined immunodeficiency in horses
• lethal white syndrome in horses
• copper toxicosis in dogs
• pyruvate kinase dificiency in dogs
• cystic fibrosis in humans

• causative mutation: DNA-dependent kinase gene mutation
• framshift deletion mutation of 5 nucleotides
• effects: gene function to manufactures B and T lymphocytes mutation totally inactivates function
• results in lack of immunity
• lethal inability to fight infections causing death w/in first few months of life

• causative mutation: not ID to date
• appears to differ in different breeds
• effects: lethal inability to control copper accumulation in the liver
• particularly common in bedington terriers and west island white terriers
• DNA test available for bedington terriers (test for disease marker)

• affected foals have all white or nearly all white coats and blue eyes
• affected foals have a non-funtioning colon
• w/in a few hours= develop colic
• die w/in a few days
• causation: endothelin receptor gene, cell signaling (G protein receptor)
• similar to hirsprung disease in humans (bowel obstruction, enlargement of the colon)
• DNA tests available to test for carriers
• common in american paint horses

• causative mutation: nonsense mutation in pyruvate kinase gene (stop codon)
• effect: protein is required for energy metabolism in RBC, mutations shortens the life span of RBC
• csevere hemolytic anaemia

• Causative mutation: cystic fibrosis transmembrane conductance regulator gene chloride channel protein (lungs, pancreas, colon, genitourinary tract)
• defective protein that transports chloride ions across the cell membrane (> 1000 different mutations reported)
• effect: salt imbalance alters the lung mucus
• secretion of large amounts of mucus into the lungs

• affected males CAN NOT transmit the disease to sons- all sons must inherit Y from the father
• Females can be affected if the father is affected and the mother is a carrier
• 1) disease is NEVER passed from FATHER to SON
• 2) males are much more likely to be affected than females- only need one copy
• 3) all affected males in the family are related through their mothers
• 4) trait or disease is typically passed from an affected grandfather through his carrier daughters
• (skips male generation)

• causative mutation: dystophin gene mutation
• > 1000 single nucleotide changes have been reported
• normal protein stablizes the protect muscle fibers
• effect: no dystrophin protein produced
• progressive muscle weakness and wasting
• increased creatine kinase (indicator of muscle, brain, heart damage)
• muscular dystrophy also documented in cats and dogs

• causative mutation: factor VIII or IX gene
• range of different mutations reported
• normal protein required for blood clotting cascade
• Effect: different mutations have different effects- molecular heterogeneity
• impaired coagulation of the blood
• strong tendency to bleed
• (haemolphilia A also documented in dogs)

• affected males CAN NOT transmit the disease to SONS
• all sons must inherit Y from father
• 1) the disease is NEVER passed from Father to SON
• 2) all daughters of an affected male and a normal female are affected
• 3) matings of affected females and normal males produces 1/2 the sons affected and 1/2 the daughters affected
• 4) males are usually more severely affected than females- but more affected females than males

• very few known
• vitamin D resistant rickets (characterized by softening and weakening of the bones)
• incontinenti pigmenti (characterized by unusaual patterns of discolored skin- melanin)
• **rare in animals**

• most genetic diseases are inherited
• some are due to sporadic mutations ("new mutations")
• sporadic mutations arise from random genetic event in the sperm or egg that formed the embryo

• 1) late age of onset
• 2) variable expression
• 3) incomplete penetrance
• 4) male lethality (X linked disorders)
• these factors can cause complications when trying to interpret pedigrees!

• some autosomal diseases are not expressed until late life
• mutant allels can be passed on before disease symptoms arise (huntingtons chorea, poylcyctic kidney dz)
• helps to maintain mutant allel w/in a pop

• only affects dominant conditions
• individuals w/ the same gene mutation can show variable clinical expression
• symptoms can range from mildly affected to severely affected
• causes: modifying effects of other genes
• environmental factors
• help maintain mutant allele w/in a population

• only affect dominant conditions
• 100% penetrance: if an individual carries the disease gene and exhibits the disease phenotype
• incomplete penetrance: the individual carries the disease gene but does NOT express the disease
• (ALL or NONE phenomena)
• not to be confused with variable expression**

• Retinoblastoma
• common childhood tumor of the retina (AD)
• 10% of carriers never develop the disease (incomplete penetrance of 90%)
• two hit model of dz:
• 1) inherit a mutant allele from either parent
• 2) other allele is muated in the developing retinoblast cell in the fetus
• 10% of carriers never experience the second muation

• caused by infection w/ E.coli K88
• if a piglet inherits the dominant allele for K88 receptor, the piglet will express the receptor (Bb)
• pigs that have the recessive allele are immune to infection (bb)
• BUT! the mothers that pass the dominant allele to piglets will have antibodies to E.coli
• immunity is passed through colostrum to piglets
• only piglets that inherit the dominant allele from Boars are at risk

• X linked dominant conditions
• in some cases loss of normal allel is lethal before birth
• affected males are NOT born
• disease affects females who pass it on to half their daughters but non of their sons

• human mitochondrial genomes is circular double-stranded DNA
• human cells usually contain 1000s of compies of mtDNA
• During zygote formation, sperm contribute nuclear DNA NOT mtDNA
• nuclear AND mtDNA is from the unfertilized egg
• **mitochondrial DNA is maternally inherited**

• Non-mendelian inheritance
• very small (13 genes)
• mutations also contribute to genetic dz
• highly mutable due to replication being more error prone
• number of replications is higher
• mitochondrial encoded dz matrilineal inheritance
• *all offspring of an affected female have dz!!
• *none of the offspring of an affected male have the disease!!!