Diagnostic Genetics 0308322

Pedigree Analysis
Practical Lab (2)
Dr. Ahmed Abu siniyeh
 Introduction

PedigreeAnalysis
▪ A very important tool for studying human inherited
diseases

▪ These diagrams make it easier to visualize relationships with

in families, particularly large extended families.

▪ Pedigrees are often used to determine the mode of

inheritance(dominant,recessive, etc.) of genetic diseases.
 Introduction

Why do pedigrees?
Punnett squares and chi-square tests work well for
organisms that have large numbers of offspring and
controlled matings, but humans are quite different:

1. Small families, even large humanfamilies have 20 or

fewerchildren.
2. Uncontrolledmatings,oftenwith heterozygotes.
3. Failureto truthfully identify parentage.

3
 Introduction

Individuals may wish to be tested if:

a) Thereisa family history of onespecificdisease.
b) Theyshowsymptoms of a geneticdisorder,
c) They are concerned about passing on a genetic
problem totheir children.

4
Basic symbols

5
 Categories of Inheritance

• Autosomal means inherited on chromosome 1-22 while

sex- linked meansinherited on either XorYchromosome.
• Autosomal recessive
• e.g., PKU, Tay-Sachs, albinism
• Autosomal dominant
• e.g., Huntington’sDisease
• X-linked recessive (meaning this allele isfound on only the X
chromosome:canbe in males or females)
• e.g., Color-blindness, hemophilia

6
 Categories of Inheritance

• X-linked dominant (meaning this allele is found

onX chromosomes; canbe in males or females)
• e.g., hypophosphatemia
• Y-linked (meaning the allele is found on the Y chromosome
and can only be in males.

7
 Autosomal recessive pedigree

• Disease is in homozygotes
• More uniform expression than autosomal dominant
• Often complete penetrance
• Onset usually early in life
• New mutations rarely detected clinically
• Proteins show loss of function
• Include all inborn errors of metabolism
• Much more common that autosomal dominant

8
 Autosomal dominant pedigree

• Trait iscommon in the pedigree

• Trait isfound in everygeneration
• Affected individual also transmit the trait to about
1/2 of their children (regardless of sex).
• There are few autosomal dominant human diseases but
somerare traits havethis inheritancepattern.

• For example: achondroplasia (a skeletal disorder causing

dwarfism)

9
 X-linked recessive pedigree

• Traitisrarein pedigree
• Trait skips generations
• Affected fathers DO NOT passto their sons
• Males are more often affected than females
• Females are carriers(passed from mom to son)

10
 X-linked dominant pedigree

• Trait is common in pedigree

• Affected fathers pass to ALL of their

daughters

• Males and females are equally likely to be affected

• 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)

12
 Y-linked Inheritance

Traits on the Y chromosome areonly found in males,never in

females.

• The father’s traits are passed to all sons.

• Dominance is irrelevant: there is only 1
copyof each
Y-linked gene(hemizygous).

13
 Mitochondrial genes

Mitochondria are only inherited from the

MOTHER.

• If a female has a mitochondrial trait, ALL ofher

offspring inherit it.

• If a male has a mitochondrial trait, NONE of his

offspring inherit it.

14
 Dominant Vs Recessive

1. If two affected people have an unaffected child, it must be a

dominant pedigree:
D is the dominant mutant allele and d is the recessive wild
type allele.
Both parentsareDdandthe normalchild isdd.
2. If two unaffected people have an affected child, it is a recessive
pedigree:
R is the dominant wild type allele and r is the recessive mutant
allele. Both parents areRr andthe affected child isrr.
3. If every affected person has an affected parent it is a dominant
pedigree.
14
 Assigning genotypes for Dominant
pedigree

1. All unaffected are dd.

2. Affected children of an affected parent and an
unaffected parent must be heterozygous Dd, because
they inherited a d allele from the unaffected parent.
3. The affected parents of an unaffected child must be
heterozygotes Dd, since they both passed a d allele to
their child.
4. Outsider rule for dominant autosomal pedigrees: An
affected outsider (a person with no known parents) is
assumed to be heterozygous (Dd).
5. If both parents are heterozygous Dd x Dd, their affected
offspring have a 2/3 chance of being Dd and a 1/3 chance of
beingDD. 15
 Assigning genotypes for Recessive
pedigree

1. all affected are rr.

2. If an affected person (rr) mates with an unaffected person,
any unaffected offspring must be Rr heterozygotes, because
they got a r allele from their affected parent.
3. If two unaffected mate and have an affected child, both
parents must be Rr heterozygotes.
4. Recessive outsider rule: outsiders are those whose parents
areunknown.
5. In a recessive autosomal pedigree, unaffected outsiders are
assumed tobe RR, homozygous normal.

18
 Assigning genotypes for Recessive
pedigree

• Children of RR x Rr have a 1/2 chance of being RR and a 1/2

chanceof being Rr.
• Note that anysiblings who havea rr child must be Rr.

• Unaffected children of Rrx Rrhave a 2/3 chance of being Rrand

a1/3chanceof being RR.

18
 Conditional Probability

• Determining the probability of an affected offspring for

most crosses is quite simple: just determine the parents’
genotypes and follow Mendelian rules to determine the
frequency of the mutant phenotype.
• In some cases, one or both parents has a genotype that is not
completely determined.
• For instance, one parent has a 1/2 chance of being DD and a 1/2
of being Dd.

18
 Conditional Probability

• If the other parent is dd and this is a dominant autosomal

pedigree, here is how to determine the overall probability of
an affectedphenotype:
• Determine the probability of an affected offspring for each
possible set of parental genotypes.
• Combine them using the AND and OR rules of
probability

19
 Conditional Probability

• In our example, one parent has a 1/2 chance of being Dd

and a1/2chanceof being DD,and the other parent isdd.
• There are thus 2possibilities for the cross:
• it could be DDxdd, or it could beDd xdd.
• Wehaveno way of knowing for sure.
• If the cross is DD x dd, all the offspring as Dd, and since the
trait is dominant, all are affected.
• On the other hand, if the cross is Dd x dd, ½ the offspring
are Dd(affected) and ½ are dd (normal).

20
 Conditional Probability

• So, there is a ½ chance that the mating is DD x dd, with all

offspring affected, and a ½ chance that the mating is Dd
x dd, with ½ the offspring affected.
• Or: (1/2 * 1)+(1/2 * 1/2) =overall probability
= 1/2 + 1/4= 3/4

21
 Pedigree Analysis

a. autosomal recessive
b. autosomal dominant
c. autosomal dominant
d. autosomal recessive
e. x-linked recessive
Pedigree Analysis Questions

f. autosomal dominant

g. X-linked recessive OR autosomal recessive

h. autosomal recessive
 Pedigree Analysis Questions

1 In the following human pedigrees, the filled symbols

represent the affected individuals. You may assume that the
disease allele is rare and therefore individuals marrying into the
family are unlikely to have defective allele.

i) The mode of inheritance?

Autosomal dominant
 Pedigree Analysis Questions

ii) State the genotypes of individuals # 1-5 in the following table using the letter ”A”, Use
the uppercase letter to represent the dominant allele and lowercase letter to
represent the recessive allele.
Individual Genotype
#1 aa
#3 aa
#4 Aa
#5 aa
iii) If individuals # 2 and 3 have another son what are the chances that this son will be
affected? 50% (Aa x aa)
 Pedigree Analysis Questions

2- The following human pedigree shows a family affected by a

specific disease.
Assume that the individuals marked with an asterisk (*) do not
carry any allele associated with the affected phenotype and that
no other mutation spontaneously occurs. Also assume complete
penetrance
 Pedigree Analysis Questions

a) State the most likely mode of inheritance for this disease.

autosomal recessive

b) Write all possible genotypes of the following individuals in the pedigree. Use the
uppercase “A” for the allele associated with the dominant phenotype and lowercase “a”
for the allele associated with the recessive phenotype.
Individual Genotype
#1 Aa or aa
#2 Aa or aa
#4 Aa
 Pedigree Analysis Questions

3- Try to analyze the following human pedigree.

Assume that the individual marked with an asterisk (*) does not carry
any allele associated with the affected phenotype and that no other
mutation spontaneously occurs.
Also assume complete penetrance.
Use “R or XR ” for the allele associated with the dominant phenotype,
“r or Xr ” for the allele associated with the recessive phenotype
 Pedigree Analysis Questions

a) What is the most likely mode of inheritance of this disease?

X linked recessive
b) List all possible genotypes of the following individuals in the pedigree.

Individual Genotype
#1 XR XR or XRXr
#3 XRXr