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Human Mendelian Genetics

Human Mendelian Genetics. After rediscovery of Mendel’s principles, an early task was to show that they were true for animals And especially in humans Resistance to this from English geneticists.

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Human Mendelian Genetics

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  1. Human Mendelian Genetics

  2. After rediscovery of Mendel’s principles, an early task was to show that they were true for animalsAnd especially in humansResistance to this from English geneticists

  3. Problems with doing human genetics:Can’t make controlled crosses!Long generation timeSmall number of offspring per crossSo, human genetics uses different methods

  4. Chief method used in human genetics is pedigree analysisI.e., the patterns of distribution of traits in kindreds

  5. Pedigrees give information on:Dominance or recessiveness of allelesRisks (probabilities) of having affected offspring

  6. Standard symbols used in pedigrees

  7. Modes of Inheritance

  8. Autosomal DominantFirst pedigree of this type: Farabee1903Brachydactyly

  9. Autosomal DominantMost dominant traits of clinical significance are very rareSo, most matings that produce affected individuals are of the form:Aa x aa

  10. Autosomal Dominant Requirements for ideal auto. dom. pedigree: Every affected person must have at least 1 affected parent

  11. Autosomal Dominant Requirements for ideal auto. dom. pedigree: Both males and females are affected and capable of transmitting the trait

  12. Autosomal Dominant Requirements for ideal auto. dom. pedigree: No skipping of generations

  13. Autosomal Dominant Requirements for ideal auto. dom. pedigree: No alternation of sexes: we see father to son, father to daughter, mother to son, and mother to daughter

  14. Autosomal Dominant Requirements for ideal auto. dom. pedigree: In the usual mating, expect 1/2 affected, 1/2 unaffected

  15. Example: Achondroplasia

  16. Autosomal recessive Affected persons must be homozygous for the disease alleleThese are likely to be more deleterious than dominant disorders, and so are usually very rareThus, the usual mating is:Aa x Aa

  17. Autosomal recessive Features of recessive pedigrees: Both parents are normal, but may see multiple affected individuals in the sibship, even though the disease is very rare in the population

  18. Autosomal recessive Features of recessive pedigrees: Usually see “skipped” generations. Because most matings are with homozygous normal individuals and no offspring are affected

  19. Autosomal recessive Features of recessive pedigrees: Expect increased consanguinity between the parents. That is, the parents are more likely to be relatives

  20. Autosomal recessive Another example pedigree

  21. Genetic CounselingHave had 1 affected child.Odds of having another?Aa x Aa produces 1/4 aaEach subsequent child has a 25% chance of being affected

  22. Genetic CounselingTougher case:Normal man and normal wife want to have first childEach has an affected sibChance of it being affected?

  23. Genetic CounselingProbability = (Probability that man is hetero) X

  24. Genetic CounselingProbability = (Probability that man is hetero) X(Probability that woman is hetero) X

  25. Genetic CounselingProbability = (Probability that man is hetero) X(Probability that woman is hetero) X(Probability of two hets producing homozygous recessive offspring)

  26. Genetic CounselingProbability that man is heterozygous:Since sib is affected, parents must have been heterozygousAa x Aa > 1 AA : 2 Aa : 1 aa2/3 of the normal offspring are Aa

  27. Genetic CounselingProbability of woman being heterozygous is also 2/3

  28. Genetic CounselingIf both are heterozygous, then the probability of producing an affected offspring is 1/4So, overall probability is:2/3 x 2/3 x 1/4 = 4/36 = 1/9

  29. Examples of autosomal recessive diseasesSickle-cell anemiaCystic fibrosisPhenylketonuria (PKU)

  30. X-linked Recessive

  31. X-linked Recessive Features of X-linked recessive inheritance: Act as recessive traits in females, but dominant traits in males

  32. X-linked Recessive Features of X-linked recessive inheritance: An affected male cannot pass the trait on to his sons, but passes the allele on to all his daughters, who are unaffected carriers

  33. X-linked Recessive Features of X-linked recessive inheritance: A carrier female passes the trait on to 1/2 her sons

  34. X-linked Recessive About 70 pathological traits known in humans Examples: Hemophilia A, fragile X syndrome, Duchenne muscular dystrophy, color blindness

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