Pedigree Workshop

1. Pedigree Workshop

2. Congenital cataracts

3. A pedigree traces the patterns of inheritance of genetic traits from generation to generation within a family.

4. Generations are numbered with Roman numerals. Within each generation, individuals are numbered from oldest to youngest.

5. female marriage proband male consanguineous marriage diseased Dizygotic twins Affected individuals Extra-marital mating carrier progeny identical (monozygotic) twins ? Female carrier of an x-linked trait Stillborn or abortion Unknown phenotype

7. Autosomal Recessive Traits Only expressed in individuals that have two copies of the relevant gene. More frequent with inbreeding, isolated groups. Autosomal Dominant Traits Expressed even if only one copy of the gene is inherited. Effects sometimes show up later in life. Sex-linked Traits Associated with genes on the X chromosome. Chromosomal Abnormalities Deletions, Duplications, Inversions, Translocations Nondisjunction and Aneuploidy Extra or missing chromosomes

8. Complicating factors: -Sex influenced genes -Multi-gene traits -Incomplete penetrance -Imprinting -Phenocopies -Anticipation

9. Penetrance: Fraction of a genotype that show the disease (or trait). Expressivity: Extent to which a trait (disease) shows variablity of expression when present.

11. Characteristics of • autosomal dominant inheritance: -Direct transmission from an affected parent to an affected child. (Affected children always have an affected parent.) -Transmission can occur from affected father to affected son. -Approximately a 1:1 ratio of affected vs. unaffected progeny with one affected parent.

12. Examples of Autosomal Dominant Traits Achondroplastic dwarfism Huntington's disease Polydactly One of the wives of Henry VIII had an extra finger.

13. Characteristics of • autosomal recessive • inheritance: -Affected parents can have affected offspring. (In fact, affected children typically do not have affected parents.) -Affected progeny are both male and female.

14. Examples of autosomal recessive traits: Albinism- the lack of pigmentation in skin, hair, and eyes. Phenylketonuria (PKU) - sufferers lack the ability to synthesize an enzyme to convert the amino acid phenylalanine into tyrosine.

15. Characteristics of • sex-linked recessive traits: • -More affected males than affected females. • -Affected grandfather to affected grandson transmission through a carrier female intermediate. • -No male to male transmission.

16. Examples of sex-linked recessive traits: Red and green color blindness. • Color blindness afflicts 8% of males and 0.04 % of human females. Hemophilia A Duchenne Muscular Dystrophy (DMD)

17. An example of an x-linked dominant trait. Hypophosphatemic Rickets

18. Mitochondrial inheritance: Affected males do not transmit the trait to any of their children. Affected females transmit the trait to all of their children.

19. Pedigree Workshop Handout 1

20. Given the pedigree shown below, answer the following questions.

21. Is the pedigree consistent with autosomal recessive inheritance? Briefly explain why or why not and indicate all individuals who must be heterozygous if this is an AR trait. Yes. What would exclude AR inheritance is 2 affected individuals having unaffected children, which is not the case here. If it is AR, then I-4 and III-2 are aa and II-1, II-2, II-3, II-4, and II-5 must be Aa heterozygotes. (The first because he produced an affected child and the others because their mother was affected.) In addition, either I-1 or I-2 must be Aa.

22. Is it consistent with X-linked recessive inheritance? Briefly explain why or why not. No. The sons of I-4 must be affected if it were XR. An affected female must be homozygous and would have to pass the trait on to all her sons.

23. Is it consistent with autosomal dominant inheritance? If so, what assumption must be made? Yes, if it is incompletely penetrant. Then II-2 could have the dominant allele and pass it on to her son, III-2, but not show the trait herself.

24. Pedigree Practice http://www.cellbio.drake.edu/Cancer/CancerBioMail.html

25. An important goal of science education is to influence students to think like scientists.

26. Case Studies: 1. Queen Victoria, porphoria and hemophilia in the royal families of Europe 2. The Blue People of Kentucky 3. Familial, early-onset Alzheimer's disease 4. Construction of a pedigree from microsatellite analysis 5. Fragile “X” 6. “Anticipation” in Huntington’s Disease 7. Li-Fraumeni Syndrome

27. Your Assignment 1. Prepare a pedigree for your case study. Discuss possible modes of inheritance and a typical genotype of an affected individual. 2. Briefly summarize the disease's main symptoms, and the frequency of occurrence in affected populations or sub-populations. 3. If known, what is the biochemistry behind this trait? 4. If known, what is the chromosomal location of the gene?

28. Case 1: A Royal Carrier

29. Case Study Li-Fraumeni Syndrome: MA was worried. There was just too much cancer in her family and was she next. Her older sister was only 18 years old when she developed a brain tumor, which required surgical intervention followed by radiation and chemotherapy. Her younger brother had died at five years of age from rhabdomyosarcoma (cancer of muscle) despite being treated by pre- as well as post-operative chemotherapy accompanied with resection. Her mother had died of breast cancer at 43 years of age despite mastectomy and chemotherapy at the time of diagnosis four years earlier. Her anxiety was only heightened when she considered her maternal family's history: an aunt with acute leukemia in adolescence, a grandfather who died from melanoma, and two first cousins who developed osteosarcomas in adolescence.

30. The diagnostic criteria for Li-Fraumeni syndrome are: Presence of sarcoma in proband at <45 years of age; AND, sarcoma, breast cancer, primary brain tumor, leukemia or adrenocortical carcinoma in a first degree relative <45 years of age; AND cancer diagnosed in another close relative at <45 years old or sarcoma at any age.

31. http://www.medinfo.cam.ac.uk/phgu/info_database/Diseases/

32. Case 4: Microsatellite marker analysis Which microsatellite allele is likely linked to the disease allele? http://nitro.biosci.arizona.edu/courses/EEB320/EEB320.html#notes

33. Genetics Familial, early-onset Alzheimer's disease About 5% of people with Alzheimer's disease have a strong family history of the disease, with several affected family members and an early age of onset (under the age of 60). Mutations in three different genes - the amyloid precursor protein (APP) gene, and the presenilin 1 and 2 (PS1 and PS2) genes - have been found in different families afflicted with early-onset familial Alzheimer's disease. The mutations are dominant, that is, the child of a sufferer has a 50% chance of inheriting the disease susceptibility. With the possible exception of PS2, mutations in these genes are highly penetrant, though the severity of the disease is variable. Together, mutations in the three genes account for about 20-50% of familial cases, suggesting that other gene(s) implicated in familial Alzheimer's still remain to be found.

34. The APP gene encodes the beta-amyloid protein, which shows abnormal accumulation in the brains of Alzheimer's disease sufferers. The normal functions of the PS1 and PS2 genes are not well understood, but the protein products of these genes interact with proteins known to be involved in signaling processes within and between cells.There is some evidence that presenilins may play a role in targeting some of these proteins to their correct destinations in the cell.

35. Fragile X syndrome affects about 1 in 4000 males and 1 in 8000 females. The major features are learning disability of varying severity, behavioural problems such as hyperactivity and autistic tendencies, and physical characteristics including long face, protruding ears, lax joints and (in males) enlarged testes. There is no cure but there is some evidence that treatment of the associated behavioural and educational problems can be beneficial.

36. Genetics Fragile X syndrome is caused by mutation of the FMR-1 gene on the X chromosome. The FMR-1 gene contains a sequence that consists of a variable number of repeats of the trinucleotide CGG. This sequence occurs in a part of the gene that is transcribed but is not translated into protein. The normal number of CGG repeats varies between 5 and about 50 (average around 30). Individuals with fragile X syndrome typically have more than 200 of these repeats, a condition known as a full mutation (FM). The full mutation prevents transcription of the FMR-1 gene, so that none of its protein product is made. Males have only one X chromosome, so if they carry a FM they are always affected. Females have two X chromosomes and the result of a FM in one chromosome can be very variable: about 50% of such females show some symptoms of the syndrome and 20% are severely affected.

37. The unaffected mothers of fragile X individuals are invariably found to have an FMR-1 gene containing between 50 and 199 CGG repeats; this intermediate number is known as a premutation (PM). The population frequency of the PM is about 1 in 250. For reasons that are as yet not understood, the number of repeats in a PM is potentially unstable and can increase into the FM range in a child that inherits the affected chromosome from its mother. The chances of a PM in a mother expanding to a FM in her child have been estimated at about 10% in the general population and about 60-80% in known fragile X families. In contrast to the potential instability of a PM transmitted from the mother, a PM transmitted from the father does not expand to a FM in his daughters. This means that all the children of a male with a PM are unaffected (his sons do not inherit his X chromosome), but because all of his daughters inherit the PM they are at risk of having a child with a FM.

38. HD Pedigree showing anticipation. The age of onset is younger with each generation. How does this happen?