1. Gene350 Animal Genetics Lecture 5 3 August 2009

2. Last Time Study chromosomes – The normal karyotypes of animals – Chromosomal abnormalities – Chromosomal abnormalities of animals

3. Today Pedigree analysis  How to read pedigrees  Basic patterns of inheritance autosomal, recessive autosomal, dominant X-linked, recessive X-linked, dominant (very rare)  Applying pedigree analysis - practice

4.  Extensions of Mendelian inheritance Goal: understand the diversity of genotype =>phenotype relationships  Pedigree analysis Goal: recognize and predict pedigrees for four common patterns of trait inheritance

5. Pedigree analysis  In humans and many animals, pedigree analysis is an important tool for studying inherited diseases and other traits  Pedigree analysis uses family trees and information about affected individuals to:  figure out the genetic basis of a disease or trait from its inheritance pattern  predict the risk of disease in future offspring in a family (genetic counseling)

6. Most common signs and symbols used in pedigree analysis

7. Categories of inheritance Autosomal recessive – e.g., PKU, Tay-Sachs, albinism Autosomal dominant – e.g., Huntington’s Disease X-linked recessive – e.g., color-blindness, hemophilia X-linked dominant – e.g., hypophosphatemia Y-linked Organelle

8. An autosomal recessive disorder is revealed by the appearance of the phenotype in both male and female progeny of unaffected individuals, who may be inferred to be heterozygous carriers Autosomal recessive inheritance in pedigrees

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

10. Sample pedigree - cystic fibrosis female male affected individuals

11. Autosomal dominant (AD) disorders are those in which both heterozygotes and homozygous dominant individuals show the abnormal phenotype. One copy of the mutant gene is sufficient for expression of the abnormal phenotype = haplo-insufficiency (Note: In fact, in some AD diseases the homozygous genotype is incompatible with life) Autosomal dominant disorders

12. 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 progen (regardless of sex)

13. - Every individual developing the disease must have an affected parent (except in cases of de novo mutations) - Males and females are equally likely to inherit the allele and be affected (autosomal disorder) - Recurrence risk (the probability that a genetic disorder that is present in a patient will recur in another member of the family) for each child of an affected parent is 1⁄2. If one parent is a heterozygote for a particular gene, their offspring will either inherit the gene or they will not, with each outcome equally likely. - Normal siblings of affected individuals cannot pass the trait on to their offspring. If an affected individual’s siblings are not affected, they do not carry the mutation and cannot pass it on to their own offspring (thus a dominant mutant allele should be lost rapidly from the population if it affects greatly the fitness of the carrier). Characteristics of pedigrees for AD disorders:

14. Autosomal recessive diseases in humans & animals For each of these, overdominance (heterozygote superiority) has been suggested as a factor in maintaining the disease alleles at high frequency in some populations

15. are characterized by the following pedigree pattern: (1) Many more males than females develop the disease (ie. show the phenotype) (2) None of the offspring of an affected male are affected, but all of its daughters must be heterozygous carriers (half the sons born to these carrier daughters are affected) X-linked recessive disorders

16. 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

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

18. are characterized by the following pedigree pattern: (1) Affected males pass the condition on to all their daughters but none of their sons (unlike dominant autosomal disorders where daugthers and sons have an equal probability to inherit the disease) (2) Affected females are mostly heterozygotes. When mated to unaffected males, they pass the condition on to 1/2 of their sons and 1/2 of their daughters (same pattern than for autosomal dominant disorder) X-linked dominant disorders Note: X-linked dominant disorder are rare traits in human and animals (ex: hypophosphatemia: low levels of inorganic phosphate in the blood.) Diagnose is complicated by the process of X inactivation in females.

19. 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)

20. 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

21. Organelle inheritance Mitochondria and chloroplasts – small number of genes on circular chromosome – mostly inherited through maternal lineage via egg cytoplasm Examples – white green variegation in plants – poky mutant in Neurospora – Maternal inheritance also shown to primarily occur in humans and animals but some controversy on possible paternal contributions as well (and possible recombination between maternal and paternal mitochondrial genomes)

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

23. Strategy for interpreting pedigrees: systematically rule out each of the options

24. Based on this pedigree, how is cystic fibrosis inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive

25. Based on this pedigree, how is cystic fibrosis inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive

26. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with info provided.

27. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with info provided.

28. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with information provided.

29. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with information provided.

30. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with information provided.

31. Based on this pedigree, how is this trait inherited? (a) Autosomal dominant (b) Autosomal recessive (c) X-linked dominant (d) X-linked recessive (e) Can’t tell with information provided.

32. Pedigree Analysis in real life: complications Sex-limited expression => trait only found in males OR females