Pedigree Analysis ONE

1. Pedigree AnalysisONE SDK November 5, 2013

2. Learning Objectives • Pattern of Inheritance • 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

3. Pattern of inheritance • Pattern of inheritance is broken in to two major parts. Classical mendelian • Autosomal • Dominant • Recessive • Sex(X)Linked • Dominant • Recessive • Non classical----------Mitochondrail

4. 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. • In this case one of the gene at one loci is defective and this will disturb(decrease) the action of the other normal gene of the other chromosome and brought upon abnormal phenotype. • Recessive – the gene that is “hidden”. It is not expressed unless a homozygous condition exists for the gene. • In this case also one of the gene at one loci is defective but this will not disturb(decrease) the action of the other normal gene of the other chromosome rather other gene will function normally and give a normal phenotype

5. Terms • In general the • Dominant Gene : Code for Structural protein such as receptors, defect in one allele is enough to produce disease • Recessive Gene: Code for Functional proteins such as Enzymes .defect in one allele is do not produce disease

6. 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.

7. 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)

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.

9. Basic Symbols

10. More Symbols

11. 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. • 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.

12. I 1 2 II 2 3 1 III 1 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.

13. 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.

14. 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.

15. 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.

16. 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

17. 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

18. 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

19. Penetrance • Penetrance - the frequency of expression of an allele when it is present in the genotype of the organism. • If 9/10 of individuals carrying an allele express the trait, the trait is said to be 90% penetrant. Or 10% reduce penetrance.

20. Variable Expressivity • Expressivity is the variation in allelic expression when the allele is penetrant. • Not all phenotypes that are expressed are manifested to the same degree. • For polydactyly, an extra digit may occur on one or more appendages, and the digit can be full size or just a stub. • Therefore, when the P allele is present it expresses variable expressivity.

21. Pleomorphisim • Gnees acuses disese in more than one sysytem. Such as Marfan Syndrome It involve • Occular abnormality • CVS problems and • Skeletal abnormalities.

22. The Punnet Square • Simple method of depicting the possible genotypes one could get from various matings. • It is used in predicting the genotypic ratios in the offspring. • Suppose a father is heterozygous for an autosomal dominant gene Dd. • D = the mutant dominant allele & • d = the recessive normal allele. • Suppose his wife is homozygous normal, having both d alleles dd. • The Punnett Square will be as follows

23. 1. The Punnet Square • This disease is inherited as a autosomal dominant disease • Autosomal dominant means that any person with a dominant allele will be affected. • A heterozygous male marries a homozygous recessive female. • Heterozygous male Aa (heterozygous means one of each allele) • Homozygous recessive female aa (homozygous means two of the same allele, here two of recessive alleles) • Draw a Punnett square of the possible offspring • Set up the Punnett square with the genotypes of the above two parents. • What is the chance they will have an unaffected child? • In Ahmad family Disease (A) is inherited as a autosomal dominant disease. • In this family, a heterozygous male marries a homozygous recessive female. • Draw a Punnett square of the possible offspring. • What is the chance they will have an unaffected child?

24. Aa are affected because they have a dominant gene • So 2 of 4 (2/4 = ½), there is a 50% chance that any child would have the disease and 50% will be normal.

25. 2. The Punnet Square • Explanation • This disease is inherited as a autosomal recessive disease • Autosomal recessive means that any person with a two recessive allele will be affected. • A heterozygous male marries a heterozygous recessive female. • Heterozygous male Aa • (heterozygous means one of each allele) • Heterozygous recessive female Aa • Draw a Punnett square of the possible offspring • What is the chance they will have an unaffected child? • This disease is inherited as a autosomal recessive disease. • A heterozygous male marries a heterozygous female. • Draw a Punnett square of the possible offspring. What is the chance they will have an unaffected child?

26. What is the chance they will have an unaffected child? • aa are affected because they have two recessive gene • So 1 of 4 (1/4) AA Completely normal • So 1 of 4 (1/4) aa homozygous Completely abnormal • So 2 of 4 (1/4) Aa heterozygous carrier •   There is a 25% chance that any child would have the disease.

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

28. Steps in Pedigree Analysis • Autosomal . Both boys and girls will be involved. • Dominant • Disease must be 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

30. 1. Autosomal Dominant Inheritance

31. Autosomal Dominant • Appears in both sexes with equal frequency • Both sexes transmit the trait to their offspring • Does not skip generations • Affected offspring must have an affected parent unless they posses a new mutation • When one parent is affected (het.) and the other parent is unaffected, approx. 1/2 of the offspring will be affected • Unaffected parents do not transmit the trait

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

36. 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)

37. 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

38. Group Work

40. Autosomal Dominant Traits Dd dd dd dd Dd Dd Dd Dd Dd DD dd dd Dd

41. 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

42. 2. Autosomal Recessive Traits

43. Autosomal Recessive • Appears in both sexes with equal frequency • Trait tend to skip generations • Affected offspring are usually born to unaffected parents • When both parents are hetrozygout, approx. 1/4 of the progeny will be affected • Appears more frequently among the children of consanguine marriages. • The punnet square will be like this

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

45. Autosomal Recessive Traits

46. 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.

47. Group Work

49. Autosomal Recessive DD dd Dd Dd Dd Dd Dd Dd dd dd dd DD dd

50. Autosomal Recessive DD dd Dd Dd Dd Dd Dd Dd dd dd dd DD dd