Sample pedigree - cystic fibrosis

2. female male affected individuals Sample pedigree - cystic fibrosis

3. Autosomal recessive traits • Trait is rare in pedigree • Trait often skips generations (hidden in heterozygous carriers) • Trait affects males and females equally

4. Autosomal recessive diseases in humans • Most common ones • Cystic fibrosis • Sickle cell anemia • Phenylketonuria (PKU) • Tay-Sachs disease

5. Autosomal dominant pedigrees • Trait is common in the pedigree • Trait is found in every generation • Affected individuals transmit the trait to ~1/2 of their children (regardless of sex) • Assume individuals with trait are heterozygous

6. Autosomal dominant traits • There are few autosomal dominant human diseases (why?), but some rare traits have this inheritance pattern ex. achondroplasia (a sketelal disorder causing dwarfism)

7. X-linked recessive pedigrees • Trait is rare in pedigree • Trait skips generations • Affected fathers DO NOT pass to their sons, • Males are more often affected than females

8. X-linked recessive traits ex. Hemophilia in European royalty

9. X-linked recessive traits ex. Glucose-6-Phosphate Dehydrogenase deficiency • hemolytic disorder causes jaundice in infants and (often fatal) sensitivity to fava beans in adults • the most common enzyme disorder worldwide, especially in those of Mediterranean ancestry

10. X-linked recessive traits ex. Glucose-6-Phosphate-Dehydrogenase deficiency

11. X-linked dominant pedigrees • Trait is common in pedigree • Affected fathers pass to ALL of their daughters • Males and females are equally likely to be affected

12. X-linked dominant diseases • X-linked dominant diseases are extremely unusual • Often, they are lethal (before birth) in males and only seen in females ex. incontinentia pigmenti (skin lesions) ex. X-linked rickets (bone lesions)

13. Mitochondrial Genes • Mitochondria are only inherited from the mother. • If a female has a mitochondrial trait, all of her offspring inherit it. • If a male has a mitochondrial trait, none of his offspring inherit it. • Note that only 1 allele is present in each individual, so dominance is not an issue.

14. Pedigree Analysis in real life • Remember: • dominant traits may be rare in population • recessive traits may be common in population • alleles may come into the pedigree from 2 sources • mutation happens • often traits are more complex • affected by environment & other genes

15. Dominant vs. Recessive • Is it a dominant pedigree or a recessive pedigree? • 1. If two affected people have an unaffected child, it must be a dominant pedigree: D is the dominant mutant allele and d is the recessive wild type allele. Both parents are Dd and the normal child is dd. • 2. If two unaffected people have an affected child, it is a recessive pedigree: R is the dominant wild type allele and r is the recessive mutant allele. Both parents are Rr and the affected child is rr. • 3. If every affected person has an affected parent it is a dominant pedigree.

16. I 2 1 II 1 2 3 4 5 6 III 1 2 3 4 5 6 7 8 9 10 Dominant Autosomal Pedigree

17. Assigning Genotypes for Dominant Pedigrees • 1. All unaffected are dd. • 2. Affected children of an affected parent and an unaffected parent must be heterozygous Dd, because they inherited a d allele from the unaffected parent. • 3. The affected parents of an unaffected child must be heterozygotes Dd, since they both passed a d allele to their child. • 4. Outsider rule for dominant autosomal pedigrees: An affected outsider (a person with no known parents) is assumed to be heterozygous (Dd). • 5. If both parents are heterozygous Dd x Dd, their affected offspring have a 2/3 chance of being Dd and a 1/3 chance of being DD.

18. Recessive Autosomal Pedigree

19. Assigning Genotypes for Recessive Pedigrees • 1. all affected are rr. • 2. If an affected person (rr) mates with an unaffected person, any unaffected offspring must be Rr heterozygotes, because they got a r allele from their affected parent. • 3. If two unaffected mate and have an affected child, both parents must be Rr heterozygotes. • 4. Recessive outsider rule: outsiders are those whose parents are unknown. In a recessive autosomal pedigree, unaffected outsiders are assumed to be RR, homozygous normal. • 5. Children of RR x Rr have a 1/2 chance of being RR and a 1/2 chance of being Rr. Note that any siblings who have an rr child must be Rr. • 6. Unaffected children of Rr x Rr have a 2/3 chance of being Rr and a 1/3 chance of being RR.

20. What is the pattern of inheritance? What are IV-2’s odds of being a carrier?

21. Sample pedigree - cystic fibrosis What can we say about I-1 and I-2? What can we say about II-4 and II-5? What are the odds that III-5 is a carrier? What can we say about gene frequency?

22. What is the inheritance pattern? What is the genotype of III-1, III-2, and II-3? What are the odds that IV-5 would have an affected son?

23. III-1 has 12 kids with an unaffected wife 8 sons - 1 affected 4 daughters - 2 affected Does he have reason to be concerned about paternity?

24. Problem Your grandfather’s sister had cystic fibrosis (rare, autosomal recessive). That’s the only case in your family. (A) What’s the chance that you are a carrier of CF? 2/3 B. 1/2 C. 1/4 D. 1/6 E.1/8

25. Your grandfather’s sister had CF but he, his parents, and his descendants are unaffected, as are those who married into the family A B 2/3 1/2 1/4 1/6 1/8 D C E F G H you

26. D d A B DD Dd D d 2/3 Dd dd D C E F G H you

27. IF D E F G THEN ? H you

28. ANSWERS A. 1/4 = Chance that you got any particular allele from from grandpa B. 1/6 = correct answer = 1/4 (see A) x 2/3 (chances that grandpa was a carrier)