Pedigree Analysis

1. Pedigree Analysis SDK November 23, 2012

2. Learning Objectives • Define common terms used in genetic pedigree • What are the goals of pedigree analysis • What a genetic pedigree is • How to read a genetic pedigree • How to draw a human genetic pedigree • Clinical Examples of genetic pedigree SDK 2012

3. Terms • Trait – characteristic of an organism • Gene – a heredity unit that codes for a trait. • Allele – different gene forms • Dominant – the gene that is expressed (shown) whenever it is present • Recessive – the gene that is “hidden”. It is not expressed unless a homozygous condition exists for the gene. SDK 2012

4. Terms • Homozygous – two identical (same) alleles for a given trait (TT) also called purebred. • Heterozygous – two different (opposite) alleles for a given trait (Tt), also called hybrid. • Gamete – sexual reproductive cell (sperm & egg). • Fertilization – the fusion of two gametes. • Phenotype – physical trait of an organism. • Genotype – the genes present in the cell. SDK 2012

5. Remember • Homozygous = AA or aa = purebred • Heterozygous = Aa = hybrid • Dominant = capital letter (A) • Recessive = lower case letter (a) • Genotype = alleles involved (AA, aa, or Aa) • Phenotype = trait expressed (blue or green) SDK 2012

6. What is a Genetic Pedigree? • Pedigree is a diagram of family relationships that uses symbols to represent people and lines to represent genetic relationships • A genetic pedigree is an easy way to track your family traits. • It looks like a family tree, but also contains information about the mode of inheritance (dominant, recessive, etc.) of genetic diseases. SDK 2012

7. What is a Genetic Pedigree? • A doctor or geneticist might draw a family pedigree if some one had a family history of a particular disease. • With this information they could see how the disease is inherited and calculate the probability of passing on the disease to future children. SDK 2012

8. Goals of Pedigree Analysis • Determine the mode of inheritance: • Dominant • Recessive • Sex-linked • Autosomal • mitochondrial, maternal effect. 2. Determine the probability of an affected offspring for a given cross. SDK 2012

9. Symbols SDK 2012

10. Symbols • Each of the individuals indicated by a circle is a woman and each of the squares represents a male family member. • Individual III:1 is a male. • Occasionally, the sex of an individual may not be known. Common reasons for this would be, miscarriages or early death, babies given up for adoption, a child that has not been born yet. • These individuals can be noted by using a diamond symbol ( ) instead of a square or circle. SDK 2012

11. Symbols SDK 2012

12. Symbols SDK 2012

13. More Symbols SDK 2012

14. I 1 2 II 2 3 1 III 1 Generations SDK 2012

15. Generations • This is an example of a family tree showing 3 generations of family members. • The roman numerals (in red) on the left indicate the generation each person belongs to. • Each individual in a generation is then numbered (in green). • Notice it restarts at 1 every new generation. • Older siblings are on the left and younger siblings are on the right in descending order. • Using this system, the individual at the bottom of this pedigree is III:1. SDK 2012

16. I 1 2 II 2 3 1 III 1 “Marriage Lines” • The lines highlighted in red indicate individuals that have had children together. Even though we call them “marriage lines” it does not matter if they are married, were married, or were never married. • It is important to realize that time has no meaning on a genetic pedigree, therefore we do not usually indicate if someone has died or been divorced. SDK 2012

17. I 1 2 II 2 3 1 III 1 “Children Lines” • The lines highlighted in red are • “children lines” • The marriage line that they are connected to from above indicates who gave them their genetic traits rather than who raised them. • If a couple has more than one child together then we split the child line as the green highlighted line shows. More siblings would simply require a longer line with more lines coming down from it. • Thus II:2 and II:3 are children of I:1 and I:2, but II:1 married into the family and has different parents. We also know that II:2 is older than his sister (read left to right). However, we don’t know anything about the relative age of II:1 even though she is on the left since she married into the family. SDK 2012

18. Remarriages Half Siblings • This is an example of how to show a parent who has had children with more than one person. It does NOT mean that they are married to more than one person at the same time. • Remember, time has no meaning in a pedigree. • In this example, II:1 and II:2 are half brother and sister. They share the same mother, but different fathers. I 1 2 3 II 1 2 SDK 2012

19. Adoptions • The red line (dashed) “children lines” to denote a child that is not related biologically (adopted). • In this example, the couple adopted a son. I 1 2 II 1 SDK 2012

20. Twins • Twins are another fairly common occurrence. However, there are two kinds and from a genetic standpoint it is very important to know the difference. • In the case of identical twins, the two siblings have the same DNA. • To show this we split the sibling line at an angle. The red highlighted line is an example of this. • In the case of fraternal twins, although born at the same time, the siblings are no more related than any other siblings. Thus, they are drawn the same as any siblings. The green highlighted lines show this. I 1 2 II 3 4 1 2 SDK 2012

21. A Punnettsquare • A Punnettsquare is a chart which shows/predicts all possible gene combinations in a cross of parents. • Punnett Square looks like a two-dimensional table, where over the square horizontally fit the gametes of one parent, and the left edge of the square in the vertical - the gametes of the other parent. SDK 2012

22. Steps in Pedigree Analysis • Analyze whether the pedigree belongs to a dominant or recessive group. • Recessive • Parents will be not affected • There will be skip generations • Dominant • Affected person must have affected parents • Every generation will be affected SDK 2012

23. Steps in Pedigree Analysis • Autosomal . Both boys and girls will be involved. • Dominant • Disease must b in multiple generation. • Disease person must have an affected parents. • Male & female are equally affected • Recessive. • Disease have skip generation. • Disease person must not have an affected parents. • Because autosomes are involved , Male & female are equally affected • X-linked • Dominant • Affected male will transmit the character to all daughters but not to sons • Affected female will transmit the character to Half sons and Half daughters. • Recessive. • No male to male transfer • Affected male will be more than female SDK 2012

24. 1. Autosomal Dominant Inheritance SDK 2012

25. Autosomal Dominant Traits • A dominant condition is transmitted in unbroken descent from each generation to the next. • A typical pedigree might look like this: SDK 2012

26. Autosomal Dominant Traits SDK 2012

27. Autosomal Dominant Traits Dd dd dd dd Dd Dd Dd Dd Dd DD dd dd Dd SDK 2012

28. Autosomal Dominant Traits • Huntington disease is a progressive nerve degeneration, usually beginning about middle age, that results in severe physical and mental disability and ultimately in death • Every affected person has an affected parent • ~1/2 the offspring of an affected individual are affected SDK 2012

29. Autosomal Dominant Traits • Huntington's disease • Marfan syndrome • Neurofibromatosis • Retinoblastoma • Familial hypercholestrolemia (LDL receptor defect Type IIa) • Adult polycystic kidney disease • Hereditory spherocytosis • Hypertrophic Obstructive Cardiomyopathy (HOCM) SDK 2012

30. How is this trait most likely inherited? If individual III4 and III6 have a child, what’s the probability that the child will be affected? Zero SDK 2012

31. Brain Work • Neurofibromatosis type 1 is one of the most common autosomal dominant disorders. A woman with neurofibromatosis type 1 has an unaffected partner. Which of the following is correct regarding their children? • The probability that each of their children will be affected is 1 in 4. • The probability that their second child will be affected if their first child is affected is 1 in 4. • The probability that their third child will be affected if their first two children are affected is 1 in 2. • If their first child is affected then their second child will not be affected. • C. The probability that their third child will be affected if their first two children are affected is 1 in 2. SDK 2012

32. 2. Autosomal Recessive Traits SDK 2012

33. Autosomal Recessive • A recessive trait will only show up when homozygous. • Most people are heterozygous carriers SDK 2012

34. Autosomal Recessive SDK 2012

35. Autosomal Recessive Traits SDK 2012

36. Autosomal Recessive SDK 2012

37. Autosomal Recessive Traits • Albinism = absence of pigment in the skin, hair, and iris of the eyes • Most affected persons have parents who are not themselves affected; the parents are heterozygous for the recessive allele and are called carriers • Approximately 1/4 of the children of carriers are affected SDK 2012

38. CYSTIC FIBROSIS • Cystic fibrosis (CF) is a genetic condition that affects many organs in the body: especially the lungs, pancreas and sweat glands. • A build-up of thick, sticky mucus in these organs leads to respiratory problems, incomplete digestion and increased salt loss from the sweat glands. • CF most commonly affects people who are of Northern European or UK descent, is also fairly frequent in people whose ancestry is Southern European and Middle Eastern. • In CF the CFTR gene(salt-transport’ gene) that contains the information for the production of the protein that transports salt in and out of the cells is absent that result in thick secretions loaded with salt. • The CFTR gene is located on chromosome 7, an autosome • This thick secretions block air passages, pancreatic and intestinal ducts will impair the function of these organs, Indigestion wt loss and increased loss of Salts. SDK 2012

39. CYSTIC FIBROSIS SDK 2012

40. Presentation of Disease Mucous in the airways cannot be easily cleared from the lungs. SDK 2012

41. Autosomal Recessive Traits Leukocyte Adhesion Defect. Nieman Pick Disease. Rotor syndrome. Situs Inversus. Sickle cell Disease and Trait. Thalasemia. Wilson's Disease. Xeroderma pigmentosa Friedrech's Ataxia. Glycogen storage diseases. • Abetalipoproteinemia. • Acute fatty liver of pregnancy • Alkaptonuria. • Congenital hepatic fibrosis. • Cystic Fibrosis. • Cystinosis, Cystinuria. • Dubin-Johnson syndrome. • FanconiAnemia. SDK 2012

42. How is this trait most likely inherited? SDK 2012

43. Brain Work 2 • In the below family, a child has been born with Acheiropodia (congenital absence of hands and feet). • Assuming that this is a genetic problem, what is the MOST LIKELY inheritance pattern and how likely is it that a next child of III3 and III4 will be affected? SDK 2012

44. D. Autosomal recessive 1 in 4 • X linked recessive; 1 in 2 for a son and 1 in 4 for a daughter • Autosomal recessive; 1 in 2 • Autosomal dominant; 1 in 2 • Autosomal recessive; 1 in 4 • Mitochondrial; 1 in 2 SDK 2012

45. 3. X-Linked Recessive Inheritance SDK 2012

46. X-Linked Recessive T rait • Characteristics of an X-linked recessive trait include: • More affected males than affected females • No male to male transmission • Male transmission through female SDK 2012

47. X-Linked Recessive T rait SDK 2012

48. X-Linked Recessive Trait SDK 2012

49. X-Linked Recessive Trait Fabry's Disease Bruton's Aggamaglobulinemia Color Blindness Complete Androgen Insensitivity Congenital Aqueductal stenosis (hydrocephalus) Inherited Nephrogenic Diabetes Insipidus • Lesch-Nyhan Syndrome • Duchene Muscular Dystrophy • Glucose 6 Phosphate Dehydrogenase Deficiency • Hemophilia A and B SDK 2012

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