Medical Genetics-Mendelian Genetics Robert F. Waters, Ph.D.

1. Medical Genetics-Mendelian GeneticsRobert F. Waters, Ph.D. • Preparation for Pathology • Preparation for Immunology • Preparation for Epidemiology • Etc.

2. Gametes • Spermatogenesis • Oogenesis

3. Chromosomes (Karyotype)

4. Classification of Chromosomes • Centromeric Classification (Nuclear) • Metacentric (mediocentric) • Center (nearly) • Submetacentric (submediocentric) • Little off center • q-long arm • p-short arm • Acrocentric • Centromere at the terminus

5. Meiosis First meiotic division

6. Meiosis • Second meiotic division

7. Human Spermatogenesis

8. Human Oogenesis • Intrauterine primary Oocyte • First meiotic division • Second meiotic division • 12 to 50 years after start of meiosis • Ova (secondary Oocyte) • Receives most of the cytoplasm • Others become polar bodies • Longer prophase in meiosis in females • Higher probability of meiotic non-disjunction

9. The Pedigree • Propositus • P1 (Parental) • F1, F2, etc. (Filial)

10. Phenylthiocarbamide (PTC) • Taster vs. Non-taster • Homozygous • Heterozygous • Complete dominance • Punnett’s square

11. Genotype and Phenotype • Genotypic ratio and phenotypic ratio

12. Autosomal Dominant • Approximately 50% Males and Females affected • Dentinogenesis imperfecta • Pediatric opalescent brown color • Wear down easily

13. Dentinogenesis imperfecta • Approximately 1:8000

14. Criteria for Autosomal Dominant • Usually not fully expressed in heterozygous state • Appears in every generation with no skipping • Trait transmitted by affected person to half the offspring (average) • Unaffected persons do not transmit the disease (not carriers) • Occurrence and transmission of trait not influenced by sex (males ~ females)

15. Autosomal Recessive • Cystic Fibrosis • Consanguinity and Recessive Inheritance

16. Autosomal Recessive-Cont: • Tay-Sachs Disease • Ashkenazi Jews • Neuro-degenerative disorder • High frequency in North America • Migrations • Tyrosinemia • Usually lethal • Hepatic lethal

17. Autosomal Recessive-Cont: • Criteria • Carrier identification, if possible • Trait characteristically occurs in sibs, not in parents, immediate offspring, and most other close relatives • About 1 in 4 ratio at birth to have trait • Parents of affected child may be consanguineous (unknowingly) • Males and females equally likely to be affected

18. Multiple Alleles • ABO blood type system

19. Sex Linked Inheritance • X-Linked • May be X-linked Recessive • May be X-linked Dominant • When X-Linked gene in male (y) is considered hemizygous not heterozygous

20. X-Linked Recessive • Follow a well defined pattern • Expressed always males and only in females that are homozygous • Example (Hemophilia) • Queen Victoria • Classical Hemophilia A (XR) • Deficiency in antihemophilic globulin • Clinical features • Severe arthritis’ • Internal joint hemorrhages • Difficulty in healing after cuts or abrasions

21. X-Linked Recessive • Normal Female • Hemophiliac male OVA Daughters: 100% carriers (heterozygotes) Sons: 100% normal

22. X-Linked Recessive Cont: • Carrier Female • Normal Male ova Daughters: 50% normal, 50% carriers Sons: 50% normal, 50% affected

23. Criteria for X-Linked Recessive Inheritance • Incidence of trait much higher in males • Trait passed from affected man through all his daughters to half their sons • Trait never passed directly from father to son

24. X-Linked Dominant Inheritance • Traits occur approximately twice as often in females • Affected male transmits the trait to ALL of his daughters and to NONE of his sons

25. X-Linked Dominant Cont: • Example • X-linked blood group system Xg • Xg/Xg x Xga/y Male has Dom. Marker OVA Daughters: Gen: Xga/ Xg Phen: Xg(a+) -- Like father Sons: Gen: Xg/y Phen: Xg(a-) –- like mother

26. X-Linked Dominant Cont: • Heterozygous female and Xg(a-)male • Cross is Xga/ Xg x Xg/y Ova Daughters:Xga/ Xg Xg/Xg – 50% receive dominant allele Sons: Xga /y Xg/y – 50% receive dominant allele

27. Criteria for X-Linked Dominant Inheritance • Affected males transmit trait to all of their daughters but to none of their sons • Affected females who are heterozygous transmit the gene to half the sons and half the daughters • In X-Linked dominant disorders, affected females are twice as common as affected males but will express the condition in a milder form (heterozygous)

28. Penetrance • Ability of any gene to be expressed • When some individuals have the gene but fail to express it are said to have reduced penetrance • Patients who have a gene and do not express it are said to have a nonpenetrant gene

29. Expressivity • The degree of expression of a penetrant gene • Polymorphisms • May be due to modifier genes • E.g. oncorepressor genes repressing oncogenes

30. Pleiotropy • One gene, multiple effects • Stem cells • E.g. galactosemia • Defect in galactose-1-phosphate uridyl transferase • Multiple effects • Cirrhosis of liver • Cataracts • Galactosuria • Mental retardation • Reversed by galactose free diet

31. Sex-Limited and Sex-Influenced Genes • Sex-Limited Trait • Autosomally inherited trait expressed in one sex (e.g., male only) • X-linked ruled out because may be transmitted by females • Precocious puberty • Exhibit adolescent growth spurt around the age of four years

32. Precocious Puberty Pedigree • Autosomal dominant precocious puberty

33. Sex-Limited Expression • Testicular feminization • XY males have testes but are also born with female external genitalia and raised as females (Some female secondary sexual characteristics at puberty)

34. Autosomal Phenotypes with Unequal Male and Female Expression

35. Hemochromatosis • May be less expression in young females • Menstrual cycle • Iron storage disease • Different from Thalassemias • Treatments

36. Latent Genes (Delayed Onset)

37. Huntington’s Chorea • Choreic movement • Unpredictable, jerky, ballistic • Mental deterioration • Dominantly inherited • Gene remains in population • After reproductive age • Variable onset • Usually above 35