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2010-11-18 14:26:04
Biomolecular science

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  1. Rare chromosomal abnormatilites are compatible with survival but...
    • cause infertility (if survive gestation)
    • embryonic loss (miscarriage)
    • growth and developmental abnormalitites

    (most chromosomal abnormalities are NOT compatible w/ survival)
  2. chromosomal abnormalities can be detected using...
    • Karyotypes
    • if chromosomes are missing or gained it would be easily noted
  3. How are karyotypes prepared?
    • 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
  4. Staining patterns are unique for each chromosome and aid identification by:
    • light/dark banding pattern
    • due to density of heterochromatic
    • characteristic for each chromosome
    • used to detect abnormalities
  5. Why use metaphase chromosomes for karyotyping?
    chromosomes are replicated and condensed
  6. what else aids in ID of chromosomes?
    • location of centromere
    • acrocentric: just off centre
    • metacentric: middle
    • telocentric: extreme end
  7. chromosomal painting
    using fluorescent probes can help id specific chromosomes (for X and Y or all!)
  8. Each species has a characteristic no. of choromoses
    • humans: 46
    • cows: 60
    • dog: 78
    • cat: 38
    • horse: 64
    • donkey: 62
  9. Types of chromosomal abnormalities (2)
    • 1) abnormalities in chromosome NUMBER (aneuploidy, polyploidy)
    • 2) Abnormalities in chromosome STRUCTURE (deletion, duplication, inversion, translocation, ring)
  10. Aneuploidy
    • 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)
  11. Autosomal aneuplidy diseases:
    • 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)
  12. Best known example of Trisomy in cows?
    • Trisomy 18 (cows)
    • causes lethal brachygnathia in cattle resulting in death in utero
  13. Aneupolidy of sex chromosomes:
    • 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)
  14. XY in mares (64, XY)
    • 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
  15. XXY in cats, dogs, cattle, pig, sheep
    • affected animals show a male phenotype
    • underdeveloped male sexual characteristics
    • causes infertility
    • similar to the human disease Klinefelters syndrome (mental impairment also)
  16. Polyploidy
    • 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)
  17. Numerical chromosomal abnormalities are caused by meitotic non-disjunction
    • failure of chromosomes to separate properly at meiosis I or meiosis II
    • random events in the formation of reproductive cells
    • they are NOT inherited
  18. Non disjunction
    chromosomes do not separate propery (meiosis I or II)
  19. Trisomy vs monosomy
    • trisomy: extra chromosome
    • monosomy: missing chromosome
  20. Why does non-disjuction occur? increase with maternal age?
    • unknown!
    • old meiotic apparatus MAY cause errors in chromosomal movement???
  21. Abnormalities in chromosome structure
    • 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
  22. 5 types of chromosome structural abnormalities
    • 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)
  23. Robertsonian translocations
    • 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!*
  24. Robertsonian Translocation 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
  25. causes of structeral chromosomal abormalities
    • 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
  26. Chromosomal abnormalities in somatic cells
    • abnormality arises during embryonic development
    • only some cells cary abnor.
    • in such cases the symptoms are usually less severe
  27. mosaics
    animals w/ 2 or more cells derived from a single zygote
  28. Chimeras
    animals w/ 2 or more cell lines derived from 2 zygotes
  29. Freemartin cattle
    • 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)
  30. Congenital malformations (chromosomal abnormalities)
    • 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
  31. Mendelian genetics
    • study of inherited single gene disorders
    • >5000 genetic dz known in humans
    • due to mutations in specific genes
    • autosomal inheritance
    • sex linked inheritance
  32. main classes of gene mutations
    • 1) deletions
    • 2) insertions
    • 3) duplications
    • 4) single base substitutions
    • 5) non coding sequence mutation
    • 6) dynamic mutations
  33. single base substitution
    • missense (replace 1 aa w/ another in the gene product= silent)
    • nonsense (replace one aa w/ a stop codon
  34. Non coding sequence mutations
    • splice site mutations: create or destroy signals for exon-intron splicing
    • promoter mutations: affect protein expression
  35. Dynamic (trinucleotide repeat) mutation
    • 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)
  36. germ line mutations verses somatic mutations
    • 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)
  37. Def: Allele
    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
  38. Homozygous
    if an individual has 2 copies of the same allele (aa, AA)
  39. heterozygous
    if the individual has 2 different alleles (Aa)
  40. dominant and recessive
    • if the gene is expressed in the heterozygous state: dominante
    • if expressed only in the homozygous state: recessive
  41. X chromosome inactiviation
    • 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
  42. Tortoiseshell cats
    • 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)
  43. Modes of inheritance
    • autosomal recessive (AR)
    • autosomal dominant (AD)
    • X linked recessive
    • X linked dominant
    • Y linked inheritance (rare)
  44. Autosomal dominant (AD) inheritance
    • 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
  45. Examples of AD disorders
    • in animals tend to be rare (breeders)
    • hyperkalaemic periodic paralysis (HYPP) in horses
    • Polycyctic kidney disease in cats
    • hungtingtons chorea in humans
  46. Hyperkalaemic periodic paralysis in horses
    • 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
  47. Polycyctic kidney dz in cats
    • 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
  48. Hungtingtons Chorea in Humans
    • 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)
  49. Autosomal recessive inheritance
    • 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
  50. Examples of AR disorders
    • severe combined immunodeficiency in horses
    • lethal white syndrome in horses
    • copper toxicosis in dogs
    • pyruvate kinase dificiency in dogs
    • cystic fibrosis in humans
  51. Severe combined immunodeficiency in horses
    • 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
  52. Copper toxicosis in dogs
    • 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)
  53. Overo lethal white syndrome in horses
    • 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
  54. Hemolytic anaemia (Pyruvate kinase deficiency) in dogs
    • 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
  55. Cystic fibrosis in humans
    • 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
  56. X linked Recessive inheritance
    • 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)
  57. Duchenne Muscular dystrophy in humans
    • 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
  58. Haemophilia A (VIII) and B (IX) in humans
    • 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)
  59. X linked dominance
    • 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
  60. Examples of X linked dominant diseases
    • 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**
  61. Sporadic mutations
    • 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
  62. Single gene disorders can be complex:
    • 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!
  63. late onset disorders
    • 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
  64. variable expression
    • 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
  65. incomplete penetrance
    • 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**
  66. Example of incomplete penetrance
    • 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
  67. Incomplete penetrance: scour in piglents
    • 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
  68. Male lethality
    • 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
  69. Mitochondrial genomes
    • 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**
  70. Mitochondrial inheritance
    • 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!!!