Chromosomes and Randomness

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  1. Karyotype resolution
    • Whole chromosome structure, big problems
    • Banding patterns is low resolution
    • Condensation can produce different resolution
    • Only works on dividing cells
    • Subjective
  2. FISH
    • Fluorescent in Situ hypridization
    • Probe targets specific gene 100kb-1Mb
    • You can to it interphase or dividing cells
    • Need to know gene (philedelphia) microdeletion that you target
    • Can be used for aneuploidies
    • DiGeorge is a microdeletion example
  3. Microarray (aCGH)
    • Array comparative genomic hybridization
    • Sheer green fluorescent patient DNA and put over microarray that contains control DNA red fluorescing
    • Same ratio (normal) yellow
    • Too much patient (duplication) green
    • Too little (deletion) red
  4. Pitfalls of aCGH
    • Not perfect resolution
    • We don't always understand consequences of copy number variants (CNVs)
    • I have 2-15 CNVs
  5. Centromere placement
    • Metacentric at middle
    • Submetatcentric longer q
    • Acrocentric near telomere, has stalk and satellite instead of p arm 13,14,15,21,22
  6. Ideograms
    • Banding patterns
    • International
  7. Isochromosome
    2q arms or 2p arms on one chromosome
  8. Deletions
    Terminal or intersitial
  9. The lyon hypothesis
    • X inactivation to Barr body (not complete inactivation)
    • Random during development but conserved in lineage, producing mosaicism
  10. Genotype frequency
    • Frequency of allelic combinations
    • p2, 2qp, and q2
  11. Allele frequency
    • Frequency of allele in population
    • p or q
  12. Importance of studying allele frequency
    • Calculating risks for genetic counseling
    • Public health screening
    • Understanding of why a condition is common (sickle cell)
  13. Hardy Weinberg Basis
    • Uses statistical probabilities
    • 2pq because p sperm and q egg or q sperm and p egg (add because probability of one or the other)
    • Add all because probability of this or that or that
    • Can be used for x linked disorders (male phenotype is p not p2)
  14. Hardy Weinberg assumptions
    • No new mutation, selection or migration
    • Random mating
    • No stratification, assortative mating, or consaquinity
    • Large population
  15. Genetic drift
    More likely in a small population that it happens to go to one allele of high frequency
  16. Founder effect
    Population has high levels of rare alleles when small population breaks off from larger one
  17. Gene flow
    Migrations bring two populations together and become genetically similar
  18. Mutation and selection
    Advantage of a certain phenotype, including heterozygous advantage
  19. Linkage analysis
    • Studies at level of family
    • Does not look at physical distance
    • More likely with physically close loci
    • 1% recombination is 1 cM (centimorgan)
    • Can trace inheritance or identify unknown disease genes
    • Use logarithm of odds
  20. Linkage disequilibrium
    Region where recombination does not take place almost ever
  21. Association studies
    • Studies at level of population
    • Look for association of alleles at linked loci (haplotype)
    • HapMap project
    • International similarities in 90%
  22. Logarithm of odds
    • For linkage analysis to determine likelihood of observing pedigree data if loci are linked versus likelihood if unliked
    • Greater than 1 favors linkage
    • Less than 1 favors chance
    • LOD score of 3 means 1000x more likely
  23. Androgenetic
    • Both haplotypes are paternal
    • No embryo but good membranes and placenta
    • Hydatidiform mole
  24. Gynogenetic
    • Both haplotypes are maternal
    • Embryo but poor membranes and placenta
    • Teratoma
  25. Hereditary Glomus Tumor
    Always comes from father (imprinting)
  26. Mechanisms of imprinting
    • Methylation/demethylation of cytosine, which is inherited and environmental
    • (De)acetylation/(de)methylation of histone tails
    • Interference RNA
  27. Prader-Willi
    • Failure to thrive then obesity
    • Characteristic facies
    • Small hands, feet, genetalia
    • Deletion of paternal 15q11-13 in 70%
    • Uniparental disomy missing paternal 15 is other cause
  28. Angelman syndrome
    • Postnatal growth deficiency
    • Severe intellectual disability
    • Inappropriate movements (ataxia, jerky, seizures), laughter
    • Dletion of maternal 15q11-13 in 70%
    • Uniparental disomy loss of maternal 15
    • Point mutations in UBE3A ~10%
  29. Imprinting re-programming
    • Occurs in gamete formation
    • Paternal and maternal imprtinting erased (demethylation)
    • Reimprinted based on sex
  30. Beckwith-Wiedemann Syndrome
    • Usually loss of methylation of IC2 on maternal chromosome 11 but also uniparental disomy ~20% or other mutations and methylations of maternal
    • Macrosomia (giantism)
    • Macroglossia, visceromegally
    • Omphalocele
    • Renal abnormalities
    • Ear creases
    • Neonatal hypoglycemia
    • Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
  31. Uniparental disomies
    • Heterodisomy is from meiosis I error
    • Isodisomy is from meiosis II error
  32. Epigenetic determinants
    Smoking, nutrition, environmental exposures like pesticides, alcohol, medications, early experience with parent behavior
  33. Dutch hunger
    • Famine during conception lead to reduced IGF2 methylation (detectable 60 years later)
    • Offspring insulin resistant, obese, coronary artery disease
    • Grandchildren smaller than expected
  34. Bariatric surgery epigenetics
    • Children after dramatic maternal weight loss are less prone to obesity than siblings born prior
    • Increased maternal weight gain between pregnancy results in increased weight of second child
  35. Overkalix Study
    • Food shortage during father's slow growth period (SGP) (prepubescence) protected children from cardiovascular disease mortality and diabetes
    • Food abundance in SGP increased diabetes risk in grandchildren
  36. Vinclozolin
    Anti androgenic fungicide early in gestation reduced generations spermatogenesis
  37. Licking and grooming
    • High licking and grooming mothers have demethylated Nr3c1
    • Increased serotonin, increased NFG1-A expression, increased hippocampal glucocorticoid receptor
    • Children have increased hippocampal glucocorticoid receptor and decreased glucocorticoid levels in response to stress, and they lick and groom
    • Low licking and grooming mothers have opposite
    • Methionine infusion in high licking and grooming adults their levels reflected low licking and grooming
  38. Aquired epigenetic diseases
    • Asthma, allergy
    • Obesity, diabetes
    • Cancer
    • Fetal alcohol effects, autism
  39. Populations of increased risk
    • African-sickle cell
    • Ashekenazi-Tay sachs, gaucher, canavan, others
    • Mediterraneans-beta thalassemia
    • SE asians-alpha thalassemia, hemoglobin E
  40. Contributions to increased frequency of a disorder
    • Founder effect, genetic drift, inbreeding, heterozygote advantage
    • NOT high mutation rate
  41. Newborn screening
    • Robert guthrie with bacterial inhibition assay for PKU
    • State laws within 24 hours
    • Heel stick
    • Core panel and secondary targets
  42. Principles of newborn screening
    • Should be important health problem
    • Accepted treatment
    • Treatment facilities available
    • Latent or early symptomatic state
    • Suitable test that is acceptable
    • Understood natural history
    • Agreed policy for whom to treat
    • Cost expenditure
    • Continually updated list
  43. Neurofibromatosis 1
    • Autosomal dominant
    • Varying expressivitiy
    • 50% de novo
    • 6 or more cafe-au-lait spots (linked loci,
    • often present at birth increase in first 2-3 years)
    • axilary (crowe's sign) or inguinal freckling
    • 2 or more neurofibromas (appear at puberty, Schwann/nerve/fibroblast cutaneous are button hole and subcutaneous are firm, can cause spinal compression) or 1 plexiform NF (present at birth, wormy, hyperpigmentation often, large
    • Optic pathway tumor
    • 2 or more iris lisch nodules
    • Osseus lesion (tibial psuedoarthosis or craniofacial sphenoid dysplasia)
    • Slight decrease in cognitive function
    • Clumsy children
  44. Neurofibromin
    • One of the largest genes
    • Expressed in all cells, sometimes acting as tumor suppressor (dominant disease though) by downregulating Ras
    • No common mutation or genotype-phenotype relationship (varying expressivity)
    • First degree relative with NF-1
    • Very high mutation rate
  45. Down Syndrome
    • 1 in 600
    • Life expentacy to 50 or 60
    • Brachycephaly (flat short head) upward slanting palpebral fissures, epicanthal folds, brushfield spots small pinnae (ear) with overfolding of upper helix
    • Transverse palmar crease, short fingers
    • Wide gap between first and second toe
    • Failure of bowel to form (corrected at birth)
    • A or V septal defect, AV-canal
    • Small penis, male infertility
    • Cutis marmorata (pinkish skin variations)
    • Hypotonia, small round mouth with tongue, mental retardation
  46. Most common chromosomal rearrangement
  47. Trisomy 13
    • 1 in 5000
    • Malformations in more than 50% of cases
    • Incomplete forebrain
    • Severe mental deficiency, seizures, apnea (often causes mortality), deafness
    • 55% 1 mo, 70% 6 mo, 82% 1 year
    • Microcephaly, wide frontalles and skull sutures, redudant neck skin, small eyes colobomata of iris, cleft lip with or without cleft palate
    • Transverse palmar crease, polydactyly prominent heels
    • Heart defects
    • Undescended testes, bicornate uterus
  48. Trisomy 18
    • 1 in 3000
    • Malformations in more than 50% of cases
    • 30% 1 mo, 50% 2 mo, 90% 12 mo
    • Abnormal gestational age and small babies/placenta with polyhydramnios (too much amniotic fluid) single umbilic artery
    • Increased muscle tone (rigid)
    • Severe mental retardation
    • Thin ribs, short sternum
    • Limited hip abduction
    • Clenched overlapping hand, rocker bottom feet
    • Narrow head with low set ears small mouth
    • Heart defects
    • Exta skin, cutis marmorata
  49. Turner syndrome
    • 1 X female
    • Short, delayed motor skills and slightly lower IQ, poor social skills
    • Streak ovaries (infertile) and no secondary sex characteristics without hormones
    • Wide carrying angle (arms)
    • Epicanthal folds and abnormal ears redundant neck skin
    • Edema of hands and feet as babies
    • Hearing impairment
    • Coarcation of aorta/horseshoe kidney
  50. Williams-Beuren Syndrome
    • Microdeletion 7q11.23
    • Test with FISH
    • Mental retardation but talk a lot
    • Hypercalcemia
    • Supravalvular aortic stenosis
  51. Mitochondrial genome
    • All coding, tRNA separates genes
    • Unique codons
    • 2-10 copies per mitochondrion
    • High mutation rate
  52. Mitochondrial disorders
    • Due to nuclear or mitochondrial gene mutation
    • Multisystemic (nervous system and skeletal/cardiac muscle first)
    • Randomly diabetes is a problem
    • Signs/symptoms/age of onset vary greatly even in family
  53. MELAS
    • mitochondrial encephalompyopathy with lactic acidosis and stroke like episodes
    • tRNA point mutation
    • Onset 2-10 years, seizures, recurrent headaches, vomiting, myopathy (muscle disorder)
    • Stoke like episodes do not follow vasculature
  54. Mitochondrial disorders
    MELAS, MERRF, NARP, Kearns-sayre syndrome (KSS, deletions) Alpers-huttenlocher syndrome
  55. Alpers-huttenlocher
    • Childhood onset
    • Mutation in POLG for alpha subunit of polymerse gamma so you can't replicate mtDNA
    • Low mitochondrial count
    • Seizures, progressive brain function loss, liver failure
  56. Heteroplasmy
    • Different types of mitochondria (mutant or not) within cell, or different types of cells (above or below mutant threshold) within individual
    • Proportion of cells above threshold and tissue sensitivity (different thresholds) affect phenotype
  57. Mitochondrial founder effect
    The heteroplasmy level of the mitochondria in the egg
  58. Mitochondrial genetic drift
    Mitochondria randomly segregate at mitosis
  59. Fragile X
    • CGG expansion causing hypermethylation of CpG island, reducing FMR1 gene expression
    • Premutation 55-200, mutation>200 (all boys and 53% of girls)
    • Southern analysis of region to diagnose
    • Premutation unstable in oogenesis (stable sperm and mitosis)
    • Mutation unstable oogenesis and mitosis (leads to mosaicism)
    • Affects males, mental retardation, strong jaw, macroorchidism and ears
  60. The Sherman paradox
    • Anticipation
    • Increasing risk of penetrance with generations that have disease
  61. Permutation carriers of fragile x
    • 40% of male premutation carriers develop tremors or ataxia after 50 with memory difficulties
    • 20% of females hit menopause before 40 (little ataxia or tremor)
  62. Friedreich's Ataxia
    • Autosomal recessive
    • GAA expansion in 1st intron of ataxia
    • Onset before 20 (longer repeat means earlier)
    • Most common inherited ataxia
    • 4 limb ataxia, diabetes, cerebellar dysarthia (difficulty pronouncing words), absent reflexes senses
  63. Myotonic dystrophy
    • Autosomal dominant gain of function
    • CTG expansion in 3 prime untranslated of protein kinase
    • Cardiac and skeletal deformities, progresive weakness and cognitive impairment to death
    • Male pattern baldness
    • Severity due to repeat length 99-1000 classic and 1000-2000 congenital (flacid baby respiratory failure death)
  64. Complete androgen insensitivity syndrome
    • X linked recessive
    • Female external genetalia and secondary sexual characteristics due to aromatization of androgen to estrogen
    • No pubic or axilary hair or facial hair
    • Blind vagina, internal testes
    • No nuerological symptoms
  65. SBMA-Kennedy disease
    • X linked recessive gain of function
    • CAG (polyglutamine tract of exon 1 androgen receptor)
    • Expansion more often in male meioses
    • Normal 11-34 Disease 40-62
    • Slowly progressive from onset in 30s spinal cord and bulbar motor neuron loss (skeletal and facial musculature weakness)
    • Reduced fertility, testicular atrophy
  66. Gene therapy targets disease groups
    • Genetic (born with)
    • Aquired (cancer, HIV...) require only brief treatment
  67. In vivo gene therapy
    • Directly administer virus or DNA to blood or tissue
    • Non dividing or dividing
    • Episomal, so it is unstable and needs repeat
  68. Ex vivo gene therapy
    • Requires dividing cells, cultured and lab manipulated then returned
    • Integrates into genome
    • Persists for life, but wears off because gets turned off for being foreign
  69. Psuedotypes
    Changing envelope protein from native to something else in order to change the cell tropism
  70. Cell tropism
    Virus or pathogen targets certain host species or cell types
  71. General scheme of gene therapy
    • Remove ALL essential genes from viral vector so that it cannot replicate on its own
    • Essential genes are provided in trans using packaging viruses for AAV
  72. First gene therapy
    • 2 children with ADA-SCID (adenosine deaminase with severe combined immunodeficiency using ex vivo
    • Complicated results because also received normal treatment
  73. Germline gene therapy
    Cannot do yet
Card Set:
Chromosomes and Randomness
2014-09-27 06:32:20
Foundations fnd1 chromosomes inheritance genetics tubberly

Lamarck ain't dead
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