1. X-LINKED RECESSIVE INHERITANCE X-LINKED DOMINANT INHERITANCE X-LINKED INHERITANCE dr. Retno Sutomo, Ph.D., Sp.A.

2. X-LINKED RECESSIVE INHERITANCE

3. Segregation of X-linked recessive allele Carrier mother

4. Segregation of X-linked recessive allele Affected father

5. Pedigree of X-linked recessive inheritance

6. X-linked recessive inheritance: Features  Affects mainly males  Affected males are usually born to unaffected parents  Transmission through carrier females  No male-to-male transmission  All daughters of affected males are carriers

7. X-linked recessive disorders

8. De novo mutation in DMD Complication to X linked pedigree De novo mutation

9. X-linked recessive disease in female  is it possible? 1.Mating of an affected father and a carrier mother 2.Non-random X inactivation 3.Female with single X chromosome 4.Translocation of X chromosome 5.Androgen insensitivity syndrome (AIS)

10. XmXm X XmXm X m XmXXmX YXmYXmYXYXY Mother’s gametes Father’s gametes Usually lethal X-linked recessive disorder in female Affected male + carrier female

11. X-linked recessive disorder in female Female with single X chromosome  45, X0  Turner’s syndrome

12. X-linked recessive disorder in female  Only one X chromosome is active in each cell, other X chromosome/chromosomes is/are inactivated  Normally, inactivation of X chromosome occurs randomly (by chance)  random (balanced) X inactivation  The chance for each X chromosome being inactivated in each cell is 50%  In normal female (46, XX), mutation in one X chromosome will be compensated by another active X chromosome  In certain condition, most cells activate the defective X chromosome and only few cells activate the normal one  non-random (imbalanced, skewed) X inactivation Non-random X inactivation

13. X-linked recessive disorder in female  Translocation of X chromosome segments to autosomes  The translocated X chromosome  defective/non-functional  Mimics individual with single X chromosome for the associated gene Translocation of X chromosome

14. X-linked recessive disorder in female  Phenotypically female but genotypically male (pseudo female)  Non-responsiveness of androgen receptor to androgen stimulation  No development of male sex characters  Duchene muscular dystrophy (DMD) in Vietnamese “girl”  Karyotipe: 46, XY  boy  Carries mutation in androgen receptor gene Androgen insensitivity syndrome

15. X-LINKED DOMINANT INHERITANCE

16. X-linked dominant inheritance Characteristics  Affects either sex, F > M  Females are often less severely affected than males  The child of an affected female has a 50% chance of being affected, regardless the sex  For an affected male, all his daughters are affected, but none of his sons  The pedigree resembles autosomal dominant inheritance, except  no male to male transmission  excess of affected females

17. X-linked dominant pedigree

18. Which one is X-inked dominant inheritance? X-linked dominantautosomal dominant

19.  In some disorders the condition appears to be lethal in affected males  Ex: focal dermal hypoplasia (Goltz syndrome), incontinentia pigmenti  There will be fewer males than expected, half of the females will be affected and all surviving males will be unaffected  Some XLD disorders affects girls almost exclusively and usually occurs sporadically, since affected females do not reproduce  Ex: Rett syndrome  gene mapped to Xq24 X-linked dominant inheritance Characteristics

20. X-linked dominant pedigree  lethality in male

22. XmXm X XXXmXXmX YXmYXmYXYXY Mother’s gametes Father’s gametes

24. POLIFACTORIAL INHERITANCE

25. Mendelian versus Galtonian  Mendel  discontinuous characters  Tall vs dwarf  Green peas vs yellow peas  Etc  Galton  continuous characters  Body height  Intelligence  etc Polifactorial inheritance Environment + genetic factors

26. Galtonians Regression to mean  Extremely tall fathers tend to have sons shorter than themselves, extremely short fathers tend to have sons taller than themselves  "Tallness" or "shortness" is not similar to Mendel's pea experiments  The height of the father and the average height of the son are related, but the average height of the son always regresses toward the mean

27.  RA Fisher (1918):continuous characters governed by a large number of independent mendelian factors (polygenic characters)  Polygenic characters  Polyfactorial characters

28.  Tradition in human genetics  Mendelian genetics  Non-mendelian genetics  The spectacular advances of 1970-1990 were entirely in mendelian genetics  Investigation of nonmendelian characters remained largely limited to statistical studies of family resemblances

29.  Complex statistical methodology  Feeling of a poor investment of research effort compared to mapping and cloning genes for mendelian characters  Many studies concerned sensitive areas of behavioral genetics  such as the heritability of IQ  violent controversies and a distastefully confrontational style of argument often reigned Poor advancement of study on multifactorial characters

30. Multifactorial inheritance Characteristics  Several, but not an unlimited number, loci are involved in the expression of the trait  There is no dominance or recessivity at each locus  The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype.  The environment interacts with the genotype to produce the final phenotype.

31.  Most affected children have normal parents  Most geniuses come from normal parents, most mentally challenged come from normal parents  Recurrence risk increases with the number of affected children in a family  Recurrence risk increases with severity of the defect  A more severely affected parent is more likely to produce an affected child  Consanguinity slightly increases the risk for an affected child Multifactorial inheritance Characteristics

32. Multifactorial determination of disease The balance between angels and devils

33. Influence of environment on phenotypic distribution

34. INBREEDING

35. Inbreeding  Mating between related individuals  Consanguinity  "mixing of the blood.“  Although some plants successfully self-fertilize (the most extreme case of inbreeding), biological mechanisms encourage cross-fertilization

36. Inbreeding in human  In general, inbreeding in human populations is rare  Many customs and laws prevent marriages between closely related individuals  when two partners are related their chance to have a baby with a disease or birth defect is higher than the background risk in the general population.

37. Effect of inbreeding  Many genetic diseases are recessive  only people inherit two disease alleles develop the disease  All individuals carry several single alleles for genetic diseases  Close relatives have more genes in common than unrelated individuals  higher chance of inbred parents have the same disease alleles  higher risk for their child inherits homozygous for a recessive disease

38. Case study  At any locus the chance that cousins share an allele inherited from a common parent is one-eighth  If each parent has one copy of the allele % offspring to inherit this allele from both parents = 1/4  Thus, the risk the offspring inherit two copies of the same allele is 1/8 × 1/4, or 1/32, about 3 percent  Overall, the risk associated with having a child affected with a recessive disease as a result of a first cousin mating is approximately 3 percent, in addition to a baseline risk of 3 to 4 % all couples face

39. Inbreeding coefficient (F)  Probability that two genes at any locus in one individual are identical by descent (common ancestor)  The larger the F the more closely related the parents are  Homozygosity  Allozygosity  two alleles are alike but unrelated (not copies of the same ancestral allele)  Autozygosity  two alleles have identity by descent (i.e., are copies of the same ancestral allele)  Thus, inbreeding coefficient:  The probability of autozygosity  May range from zero (no inbreeding) to one (it is certain an individual is autozygous)

40. Any benefit of inbreeding?  Improve specific characteristics  Facilitate genetic study  gene mapping

41. Any benefit of inbreeding? Improve specific characteristics  Inbreeding commonly practiced in animal breeding to enhance specific characteristics (e.g. milk production)  But, if genes controlling unselected traits are also influenced  deleterious effects  Moreover, inbreeding results in decreased genetic diversity

42.  Inbred populations  relatively homogeneous in both genetics and environment  rich resource for genetic studies  Homozygosity mapping  identify several recessive mutations in inbred groups  Search for regions of alleles at genetic loci that are linked to one another and are homozygous  In affected individual  the two alleles at the disease locus will have descended from a common ancestor  Tightly linked markers (identifiable DNA segments) surrounding the disease locus tend to come from the same ancestral chromosome and identical on both homologous chromosomes. Any benefit of inbreeding? Valuable resource for genetic study

43. Human inbreeding Just don’t do it! Finally…….