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  1. Mendelian Inheritance
    • Autosomal, X linked and holandric recessive and dominant
    • Independent segregation (of alleles)
    • Independent assortment (of loci) thanks to meiotic recombination
  2. Locus v allele
    • Locus is the site of a gene (basically the gene itself)
    • Allele is a certain form of that locus
  3. Autosomal recessive pedigree
    Negative family history
  4. Autosomal recessive
    • Horizontal transmission
    • Two copies of same allele
    • Risk of recurrence for sibling is 25%
  5. X linked recessive pedigree
    Only males
  6. Autosomal dominant pedigree
    Common and male to male transmission
  7. Maternal pedigree
    Mother gives to all offspring and fathers give to none
  8. Sex limited pedigree
    • Only males with male to male transmission
    • Only females
  9. X linked dominant pedigree
    • Fathers give to all offspring
    • Mothers give to half
  10. Recurrent risk pedigree calculation
    • Take into account if child shows phenotype (or is born)
    • Always start from bottom to identify obligate carriers
    • Bayes theorem can lower
  11. Autosomal dominant
    • Veritcal transmission
    • Parent affected means children have 50% chance
    • Only one allele needed
    • De novo (osteogenesis imperfecta, neurofibromatosis, achondroplasia)
  12. Codominant
    • No dominance or recession of alleles, both expressed
    • ABO blood types
  13. X linked recessive
    • Usually only expressed in males who have normal parents
    • Father makes daughters carriers
    • Carrier moms give to 50%
  14. X linked dominant
    • Male and female expression
    • Mothers to sons and daughters 50%
    • Fathers only to daughters
  15. Gene dosage
    • Only half gene product amount due to loss of allele, but sufficient
    • Results in mosaicism of tissue in females with X linked recessive
  16. Autosomal mosaicism
    Mutation during embyonic development
  17. Lethal x linked stable gene population frequency
    • Males are unfit
    • Approximately 1/3 de Novo frequency required for maintenance
  18. Limitations of linkage analysis
    • Linked markers must be polymorphic
    • 2 individuals with trait in family
    • Meitotic recombination can lead to errors
    • Not always informative
  19. Isozymes
    Distinguishable proteins with same enzymatic activity
  20. Polymorphism
    • Two or more allelic traits in a population with frequencies of at least 1%
    • Many may combine to lead to phenotype
  21. Single nucleotide polymorphisms
    • Single base substitution including synonomous/conservative
    • Occur every 100-200 base pairs
    • Heterozygous every 250-500 base pairs
    • 6-12 million per person
  22. Peptidase
    • Isozymes
    • Dimer and polymorphic
    • Heterozygotes have 3 dimer forms
  23. Cholinesterase
    • Isozymes
    • Only known function is catabolism of benzoylcholine with no observed activity variation
    • Difference in inhibitor effect (dibucaine) dibucaine number is -5 log molar
    • Those with atypical type can wake up paralyzed
  24. Haplotype
    Collection of alleles of linked loci
  25. Apolipoprotein B-100
    • Delivers LDL cholesterol to tissues via LDL receptor
    • Two polymorphic sites of locus (both missense)
    • Two alleles (homologs) of course means 2^4=16 haplotypes
    • Variation in levels of cholesterol
  26. Consequences of polymorphisms
    • No phenotypic effect
    • Normal variation
    • Disease susceptibility
    • Disease
  27. Qualitative trait
    Phenotype is present or absent
  28. Quantitative trait
    Phenotype varies in degree
  29. Multifactorial traits
    • Can be quantitative or qualitative
    • Multiple loci and multiple environmental factors
    • Associated relative risk
    • Cleft lip with or without cleft palate, neural tube defect (spina bifida, anencephaly), pyloric stenosis, congenital heart disease
    • Recurrence risk approximates square root of population (usually 3-10%)
    • Recurrence risk decreases logarithmically with decreasing degree of relationship to proband
  30. Relative risk
    Prevalence for subpopulation of individual/prevalence of population
  31. Teratogenic
    Phenotype due to environmental factor
  32. Cleft lip with or without cleft palate
    • Less common in girls, but if they have it the relative risk is increased
    • More affected individuals in family increases relative risk
    • 35% concordance for monozygotic twins and 6.2% for dizygotic
    • Being related and living in very different environments doesn't completely decrease relative risk
  33. Threshold model
    • For qualitative traits
    • Multiple genes and teratogenic factors increse liability
    • Liability above a threshold results in the trait
    • Various thresholds for severity of trait or things like sex
    • If there is a less affected sex they are more likely to transmit
  34. Heritability
    • Fraction of phenotypic variance attributable to genes
    • Calculate from variance in mono and dizygotic twins
    • Can determine extent to which alleles at different loci contribute to a trait
  35. Limitations of heritability
    • Applicable only to population studied
    • Close relatives often share environment
    • Even genetic traits can be altered by environment (PKU for example)
  36. Mixed model
    • One or two genes are the major contributor to a phenotype
    • There are many other genes that interact as well as teratogenic factors
  37. Estimating recurrence risk
    • Good model is ideal
    • If no good model, empiric data, but must be same population and multifactorial in nature
  38. Hexosaminidase A
    • Visible gene dosage and quantitative distribution, with slight overlap
    • Missing in Tay Sachs
    • Cleaves GM2
    • alpha and beta dimer from HEXA and HEXB
    • Requires GM2A activator because GM2 is not soluble like enzymes are
    • Allelic heterogeneity in different populations
  39. Tay Sachs
    • Autosomal recessive
    • Macular cherry red spot
    • Lysosomes store ganglioside GM2 as lamelular bodies/onion bodies
    • Normal 3-5 months then gradual slowing and digression, weakness, startled
    • 8-10 months decrease in activity and awareness to vegetative state
    • Deaf and blindness, death by 5
  40. AB variant Tay sachs
    • HEXA and HEXB without activator
    • Cleaves Gm2 in detergent
  41. Sandhoff
    • No hexosaminidase A or B
    • Activator is present
  42. Mucopolysaccharidosis I
    • Autosomal recessive
    • Hurler
    • Stiff joints, claw hand, visceromegaly, coarse facies, corneal clouding, beaking of spine (dystosis multiplex)
    • Mucopolysacharides in urine (glycosaminoglycans)
  43. Mucopolysaccharidosis tests
    • Tagged radioactive sulfurs
    • Monitored incorporation
    • Hunter plus Hurler look normal (as do disease plus normal)
    • Lead to new classifications due to locus heterozygocity
    • Also same locus different alleles were discovered leading to different phenotypes, allelic heterozygosity
  44. I cell disease
    • Autosomal recessive
    • High levels of many non functioning enzymes in serum
    • N-acetylglucosamine 1 phosphotransfase deficiency
    • Responsible for adding phospho acetyl glucosamines (P-GlcNAc) to various enzymes so that they can enter lysosome
  45. Urea cycle deficiency
    • Autosomal recessive
    • Onset around 3 days
    • Ammonia build up from any point in cycle deficiency
    • Treat with arginine and excrete other stuff
  46. Propinyl CoA carboxylase deficiency
    • Autosomal recessive
    • Odd chain fatty acids, ITVM, side chain of cholesterol, all go to propionyl CoA, which cannot be converted to methylmalonyl CoA so they go to alternate reactions all of the organic acids
    • Onset around 3 days
    • Treatment is diet to reduce substrates
  47. Biotinidase deficiency
    • Autosomal recessive
    • Biotin cannot be cleaved to recycle
    • Many enzymes don't work
    • Take biotin
  48. Galactosemia
    • Deficiency in kinase or transferase in galactose metabolism
    • Galctose goes to galactitol which builds up in the lens and clouds it
  49. Dominant mutation types
    • Haploinsufficiency (loss of function)
    • Dominant negative (protein suicide) (also loss of function)
    • Gain of function
  50. Familial Hypercholesterolemia
    • Autosomal dominant, haploinsufficiency
    • Heterozygous has reduced number of functional LDL cholesterol receptors corresponding to cholesterol levels of 250-500 mg/dl
    • Homozygous has 600-1000 mg/dL cholesterol which can be fatal, fatty deposits
  51. Insulin chicago
    • Autosomal dominant, haploinsufficiency
    • Point mutation causes insulin chicago to bind to insulin receptors without activating
    • Rare cause of diabetes
  52. Autosomal dominant heterodimers
    • Haploinsufficiency if one allele causes dimer to not work 1:2:1 where only 1 works
    • If binding of mutant is decreased it is better but still maybe haploinsufficiency
    • If binding of mutant is better then it is greater haploinsufficiency
  53. Osteogenesis imperfecta
    • Collagen Type I
    • 2 alpha1 and 1 alpha2 subunits bind
    • Three bad ways to form and one good way 1:2:1
    • Degradation of nonfunctioning collagen
    • Protein suicide
    • Blue sclerae
    • Severe perinatal lethal when not degraded
    • Prenatal fracturing and respiratory failure
  54. Ehlers-Danlos Syndrome
    • Haploinsufficiency of not collagen type 5
    • COL5A1 or COL5A2 mutations
    • Flexible, soft, flappy skin
    • Cigarette paper scars
    • Molluscoid psuedo tumors
    • Pes planus (flat feet)
    • Delayed motor skills
  55. Achondroplasia
    • Gain of function of FGFR3, fibroblast growth factor 3 receptor always active
    • Shortening of the humurous and femur
    • Narrow base of skull but regular sized
    • Trident hand
  56. Wolf-Hrishhorn Syndrome
    • Deletion of terminal 4p (includes FGFR3 gene)
    • Very different phenotype from achondroplasia
    • Mental retardation, growth deficiency with a small head
    • Celft lip with or without palate hypertelorism (wide spaced eyes)
  57. Male precocious puberty
    • Autosomal dominant sex limited
    • Leutenizing hormone receptors are active despite no LH, causes cAMP to go up
    • In girls LH is not sufficient to begin puberty
Card Set:
2014-09-27 02:58:17
Foundations fnd1 inheritance tubberly

It's my parents' fault I don't understand this stuff
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