Pedigree Analysis SDK November 23, 2012

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 2SDK 2012

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. 3SDK 2012

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. 4SDK 2012

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) 5SDK 2012

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. 6SDK 2012

7  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.  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. What is a Genetic Pedigree?

Goals of Pedigree Analysis 1.Determine the mode of inheritance: 1.Dominant 2.Recessive 3.Sex-linked 4.Autosomal 5.mitochondrial, maternal effect. 2. Determine the probability of an affected offspring for a given cross. 8SDK 2012

Symbols 9SDK 2012

10  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. Symbols

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Symbols 12SDK 2012

13 More Symbols

Generations I II III 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.  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.

“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. I II III SDK 2012

“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 I II III 17SDK 2012

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 II SDK 2012

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 II SDK 2012

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 II SDK 2012

A Punnett square A Punnett square 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

Steps in Pedigree Analysis 1.Analyze whether the pedigree belongs to a dominant or recessive group. 1.Recessive a)Parents will be not affected b)There will be skip generations 2.Dominant a)Affected person must have affected parents b)Every generation will be affected 22SDK 2012

1.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 2.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 Steps in Pedigree Analysis 23SDK 2012

1. Autosomal Dominant Inheritance 24SDK 2012

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

26 Autosomal Dominant Traits

Dd dd Dd DD Dd ddDd dd 27SDK 2012

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 28SDK 2012

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) 29SDK 2012

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 30SDK 2012

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? A.The probability that each of their children will be affected is 1 in 4. B.The probability that their second child will be affected if their first child is affected is 1 in 4. C.The probability that their third child will be affected if their first two children are affected is 1 in 2. D.If their first child is affected then their second child will not be affected. SDK Brain Work C. The probability that their third child will be affected if their first two children are affected is 1 in 2.

2. Autosomal Recessive Traits 32SDK 2012

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

34 Autosomal Recessive

Autosomal Recessive Traits 35SDK 2012

Autosomal Recessive 36SDK 2012

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 Autosomal Recessive Traits 37SDK 2012

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. 38SDK 2012

39 CYSTIC FIBROSIS

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

 Abetalipoproteinemia.  Acute fatty liver of pregnancy  Alkaptonuria.  Congenital hepatic fibrosis.  Cystic Fibrosis.  Cystinosis, Cystinuria.  Dubin-Johnson syndrome.  Fanconi Anemia.  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. Autosomal Recessive Traits 41SDK 2012

How is this trait most likely inherited? 42SDK 2012

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 Brain Work 2

D. Autosomal recessive 1 in 4 A.X linked recessive; 1 in 2 for a son and 1 in 4 for a daughter B.Autosomal recessive; 1 in 2 C.Autosomal dominant; 1 in 2 D.Autosomal recessive; 1 in 4 E.Mitochondrial; 1 in 2 SDK

3. X-Linked Recessive Inheritance 45SDK 2012

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 46SDK 2012

47 X-Linked Recessive T rait

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

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Brain Work II3 in the pedigree below has two brothers with hemophilia A, a bleeding disorder that is inherited as an X ‑ linked recessive trait. What is the risk of hemophilia for her children? SDK

A.1 in 4 for a son, close to zero for a daughter B.1 in 2 both for sons and daughters C.1 in 2 for a son and 1 in 4 for a daughter D.1 in 2 for a son, close to zero for a daughter E.1 in 4 both for sons and daughters SDK A.1 in 4 for a son, close to zero for a daughter

II-3 in the below family has two brothers and three sons with classical hemophilia (factor VIII deficiency). Now she is pregnant again. How likely is it that this child will also have hemophilia? SDK Brain Work 2

A.100% for a son and 50% for a daughter B.100% for a son, zero for a daughter C.50% for a son, zero for a daughter D.50% for both sons and daughters E.25% for a son and zero for a daughter SDK E. 25% for a son and zero for a daughter

4. X-Linked Dominant Inheritance 55SDK 2012

X-Linked Dominant Inheritance Affected males transmit the trait to all of their daughters and none of their sons. Affected females transmit the trait to half of their sons and half of their daughters. 56SDK 2012

57 X-Linked Dominant Inheritance

Affected males transmit the trait to all of their daughters and none of their sons. 58SDK 2012

X-Linked Dominant Inheritance 59SDK 2012

 X Linked Hypophosphotemic Rickets.  Focal Dermal Hypoplasia,  Orofaciodigital syndrome. X-Linked Dominant Inheritance 60SDK 2012

How is this trait most likely inherited ? 61SDK 2012

Y-Linked Inheritance We will now look at how various kinds of traits are inherited from a pedigree point of view. Traits on the Y chromosome are only found in males, never in females. The father’s traits are passed to all sons. 62SDK 2012

 About 20,000 genes in the human genome are located in small compartments in the cell called the mitochonria.  The genes found within the mitochondria contain the information that codes for the production of enzymes that drive the biochemical reactions to produce energy(ATP).  The cells in the body, especially in organs such as the brain, heart, muscle, kidneys and liver, cannot function normally unless they are receiving a constant supply of energy (ATP).  Faulty mitochondrial genes can result in absence of these enzymes, or enzymes that are impaired and do not work properly.  This leads to a reduction in the supply of ATP, and may result in problems with the body’s functions. Mitochondrial Genes 63SDK 2012

64 Mitochondrial Genes  The pattern of inheritance of conditions due to faulty mitochondrial genes is often called maternal inheritance.  This is because a child inherits the great majority of their mitochondria from their mother through the ova.  Usually a mother will have a mixture of mitochondria containing the working gene copy and others containing the faulty gene.  For a condition to develop, the number of mitochondria with the faulty gene must be above a critical level (the threshold).  The pattern of inheritance of conditions due to faulty mitochondrial genes is often called maternal inheritance.  This is because a child inherits the great majority of their mitochondria from their mother through the ova.  Usually a mother will have a mixture of mitochondria containing the working gene copy and others containing the faulty gene.  For a condition to develop, the number of mitochondria with the faulty gene must be above a critical level (the threshold).

SDK Mitochondrial Genes

 As 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.  If the mother is not affected but has the faulty genes, than  Disease will occur depending up on the levels of faulty genes. 66SDK 2012

67 Mitochondrial Genes SDK 2012

Thank You 68SDK 2012