Download Understanding Patterns of Inheritance Through Pedigree

Understanding Patterns of Inheritance through Pedigree Analysis
Pamela Engel1, 3 and Julie Hoover-Fong, M.D., Ph.D.2, 3
1. Glen Burnie Senior High School, Glen Burnie, MD
2. Greenberg Center for Skeletal Dysplasias
McKusick-Nathans Institute of Genetic Medicine
Johns Hopkins University
3. Geneticist-Educator Network of Alliances (GENA).
Overview: This lesson was designed to help high school biology students
understand and recognize patterns of inheritance as illustrated by pedigrees.
The usual sequence for determining patterns of inheritance in high school text
books is to teach recognizable Mendelian patterns through Punnett square
analysis, and introduce other, nonmendelian patterns later. After students have
mastered Punnett squares, then they are introduced to pedigree analysis. All too
often students associate pedigrees with the last Punnett square they were
taught, usually sex-linked traits. This lesson was designed to break up this
sequence and link the student understanding of inheritance to pedigrees first,
and then move toward specific analyses of inheritance with Punnett squares. As
students have just finished studying asexual and sexual reproduction/mitosis and
meiosis, it is hoped that students will be able to relate the passing of traits to
their understanding of chromosomal segregation and assortment, and that this
will help them better recognize the relationship between traits, chromosomes,
and genes.
State Standards:
3.3.2 – The student will illustrate and explain how expressed traits are
passed from parent to offspring
1.4.2 – The student will analyze data to make predictions, decisions, or
draw conclusions.
1.4.6 – The student will describe trends revealed by data.
Science Concepts:
1. A gene is a sequence of DNA on chromosome which codes for a
protein or an RNA
2. Each individual receives two copies of a gene.
3. One allele for a gene may always be expressed when present
(dominant).
4. One allele may only be expressed when two copies are present
(recessive).
5. The genes for X-linked traits are located on the X-chromosome.
6. Sons receive only one X-chromosome from their mothers. They
only have one copy of each of the genes on the X-chromosome.
7. Patterns of inheritance over several generations within a family
may be analyzed using pedigrees
Student Misconceptions:
1. Genes and chromosomes are the same thing OR genes and
chromosomes are not related to each other in any way.
2. Inheritance of traits is not related to chromosomes or
chromosomal movements during meiosis.
3. All pedigrees are for determining X-linked traits.
4. Alleles are traits
5. Genotype and phenotype are the same
Learning Outcomes:
1. The learner will be able to analyze pedigrees to determine
phenotype and genotypes of individuals by writing a
justification (claim, evidence, reasoning, rebuttal)
2. The learner will be able to analyze pedigrees to determine
patterns of inheritance (dominant, recessive, X-linked) in writing
(claim, evidence, reasoning, rebuttal)
Curriculum Materials:
1. Biology – Holt Winston Rhinehart 2004 (AACPS Single-text adoption
program)
Prior Knowledge:
1. Students know and understand the terms, homozygous,
heterozygous, dominant, recessive, phenotype, genotype, gene,
allele, and chromosome.
2. Students understand that they inherit one-half of their
chromosomes from each parent.
3. Students understand that genes are carried on chromosomes, and
they code for traits.
Engagement:
Student scenario – They are geneticists and have been asked to
construct a pedigree for their family to understand how family
members are related and how physical traits and genes can be passed
through the family. The pedigree construction and analysis they will
perform in this exercise is introduced as key part of patient care in a
genetics clinic.
a. Students are given a pedigree worksheet used by genetic
counselors and geneticists at JHMI in daily clinical practice.
As the different symbols and notations are explained,
students develop their own pedigree of their family,
identifying themselves as the proband.
b. After the family pedigree is constructed for three
generations, students are asked to pick a trait in their family
and color in all the individuals that carry or express that trait.
Exploration:
1. Students are asked to examine their pedigree to determine how
their trait is inherited. The focus is on identifying how the trait was
passed from parent to offspring, not necessarily dominance or
recessive characteristics, but who do you think gave you this trait,
your mom or your dad? Who did they get it from?
2. This lends to some discussion of new traits that occur in every
family due to spontaneous mutations of previously unaffected
(normal) genes. Thus neither parent may have a trait, but a child
(offspring) does.
3. Additional discussion about the impossibility of sharing traits and
genes between step siblings, a common part of pedigrees today.
The drawn 3 generation pedigree is an excellent visual aid to
understand the lack of relatedness in this instance.
4. Students try to determine how the trait was passed from generation
to generation.
Explanation:
1. Students are directed to presentation on pedigrees.
2. Clinical descriptions of genetic disorders that represent different
types of inheritance patterns are presented to students along with
typical pedigrees that demonstrate this pattern. Images of the
classic features of these disorders, frequency of the disorders in
the population as well as a typical representative pedigree are
presented to students.
3. Students are shown basic identifying characteristics for each type
of inheritance pattern.
4. Disorders are chosen for their appeal to high school students –
a. Marfan Syndrome
b. Cystic Fibrosis
c. Achondroplasia
d. Fragile X syndrome
5. Students are introduced to Punnett squares as a way to determine
probability of inheritance from parents.
Exploration:
1. Students are directed back to their family pedigrees.
2. Using the identifying characteristics presented to them, students
analyze the pattern of inheritance in their family, and determine if
it is an autosomal dominant, autosomal recessive, or X-linked trait.
In some cases, students picked a “trait” such as wearing glasses.
Since the purpose of this was to focus on identifying the pattern,
they were still able to use the characteristics to find a pattern that
best fit their family.
Extension:
1. After students felt somewhat familiar with pedigrees and
identifying patterns, they were given actual pedigrees to analyze.
2. Working in pairs, the students were given four different pedigrees
to analyze. In each case they were to justify their answer by writing
a paragraph using the Claim Evidence Reasoning rubric. They have
used this rubric for data analysis throughout the school year.
Evaluation: Students were assessed informally by teacher observation,
and formative quizzes on the subject. Summative evaluation was the
Anne Arundel County Benchmark Exam for the third marking period.
Predicting inheritance pattern from pedigree analysis
A man who had purple ears came to the attention of a human geneticist. The
human geneticist did a pedigree analysis and made the following observations:
In this family, purple ears proved to be an inherited trait due to a single genetic
locus. The man's mother and one sister also had purple ears, but his father, his
brother, and two other sisters had normal ears. The man and his normal-eared
wife had seven children, including four boys and three girls. Two girls and two
boys had purple ears.
1.
Draw a pedigree for this family.
2.
Identify the index case/proband.
3.
Is this trait autosomal dominant, autosomal recessive, or X-linked
recessive? Use the CERR Rubric to justify your answer to number.
a.
Claim – what pattern of inheritance is demonstrated in this
pedigree?
b.
Evidence – Identify the individuals in the pedigree on which you
base your claim.
c.
Reasoning – Explain how you arrived at your claim, which particular
parent/offspring inheritance pattern helped you arrive at your
conclusion and why.
d.
Rebuttal – how do you know it is not another pattern of
inheritance?
Individuals who lack an enzyme needed to form the skin pigment melanin are
called albinos. Normal skin pigmentation is the normal phenotype, and is
dominant. N represents a normal allele or version of the pigmentation gene.
Albinism is the abnormal phenotype and is recessive. If the pigmentation gene is
abnormal, it is represented by n. The genotype for albinism is represented as
nn. If you cannot determine if an individual with normal pigmentation is
heterozygous or homozygous, use N_.
ALTERNATIVE SENTENCES for this question:
N represents a normal allele or version of the pigmentation gene. If the
pigmentation gene is abnormal, it is represented by n. nn represents the
genotype for albinism. If you cannot determine if an individual with normal
pigmentation is heterozygous or homozygous, use N_.
Refer to FIGURE II and identify the genotype of each individual.
Draw a chart listing the individuals and their genotypes.
FIGURE II - ALBINISM PEDIGREE
1.
2.
3.
How many individuals had the genotype Nn ?
How many were N_?
Write a response using the CERR Rubric.
a.
Claim – Which individuals do you know were Nn?
b.
Evidence – what evidence in the pedigree helped you determine
this?
c.
Reasoning – Explain your reasoning at arriving at this conclusion.
d.
Rebuttal – why can’t you determine the second allele for the
individuals you labeled as N_?
The Blue People Of Troublesome Creek
Six generations after a French orphan named Martin Fugate settled on the banks
of eastern Kentucky's Troublesome Creek with his redheaded American bride, his
great-great-great great grandson was born in a modern hospital not far from
where the creek still runs. The boy inherited his father's lankiness and his
mother's slightly nasal way of speaking. What he got from Martin Fugate was
dark blue skin. "It was almost purple," his father recalls. Doctors were so
astonished by the color of Benjy Stacy's skin that they raced him by ambulance
from the maternity ward in the hospital near Hazard to a medical clinic in
Lexington. Two days of tests produced no explanation for skin the color of a
bruised plum. A transfusion was being prepared when Benjy's grandmother
spoke up. "Have you ever heard of the blue Fugates of Troublesome Creek?" she
asked the doctors. "My grandmother Luna on my dad's side was a blue Fugate.
It was real bad in her," Alva Stacy, the boy's father, explained. "The doctors
finally came to the conclusion that Benjy's color was due to blood inherited from
generations back." Benjy lost his blue tint within a few weeks, and now he is
about as normal looking a seven-year-old boy as you could hope to find. His lips
and fingernails still turn a shade of purpleblue when he gets cold or angry a quirk
that so intrigued medical students after Benjy's birth that they would crowd
around the baby and try to make him cry. "Benjy was a pretty big item in the
hospital," his mother says with a grin. Dark blue lips and fingernails are the only
traces of Martin Fugate's legacy left in the boy; that, and the recessive gene that
has shaded many of the Fugates and their kin blue for the past 162 years.
Given below is a pedigree of some of the blue people of Troublesome Creek
I
II
III
IV
1.
Is this trait autosomal dominant, autosomal recessive, or X-linked?
2. Identify the carriers in generation three for the “Blue” trait by completing the
pedigree. Can’t confirm all the carriers in the youngest generation b/c may be Bb
or BB.
3. If B = normal skin, and b = blue skin, what is the genotype of the affected
individuals?
Examine the pedigree below.
1. Identify the index case in this pedigree
2.
Is this trait autosomal dominant, autosomal recessive, or X-linked
recessive? Justify your response using the CERR Rubric.
a.
Claim – which pattern of inheritance is illustrated in this pedigree?
b.
Evidence – what evidence for this is seen in the pedigree.
c.
Reasoning – Explain why this evidence helped you arrive at your
conclusion.
d.
Rebuttal – why isn’t this a pedigree for another pattern of
inheritance?
Characteristics of Pedigree Analysis
Autosomal Dominant
1. Every affected individual has an affected biological parent. There is no
skipping of generations.
2. Males and females have an equally likely chance of being affected. The
recurrence risk of each child of an affected parent is 1/2.
3
Normal siblings of affected individuals do not transmit the trait to their
offspring.
Autosomal Recessive.
1.
Males and females are equally likely to be affected.
2.
On average, the recurrence risk to the unborn sibling of an affected
individual is 1/4.
3.
The trait is characteristically found in siblings, not parents of affected or
the offspring of affected.
4.
Parents of affected children may be related. The rarer the trait in the
general population, the more likely a consanguineous mating is involved.
X-Linked Recessive
1. As with any X-linked trait, the disease is never passed from father to son.
2. Males are much more likely to be affected than females. If affected males
cannot reproduce, only males will be affected.
3.
All affected males in a family are related through their mothers.
4.
Trait or disease is typically passed from an affected grandfather, through
his carrier daughters, to half of his grandsons.
Sources for Pedigrees
http://www.biology.arizona.edu/Human_bio/problem_sets/human_genetics/10Q.
html
//www.biology.arizona.edu/Human_bio/problem_sets/human_genetics/05Q.html
http://www.horton.ednet.ns.ca/staff/selig/handouts/bio12/mengenetics/pedigree
s.pdf
http://www.uic.edu/classes/bms/bms655/lesson7.html
http://www.uic.edu/classes/bms/bms655/lesson5.html
http://www.uic.edu/classes/bms/bms655/lesson4.html
NB: While the questions and pedigrees were originally obtained from the sites
above, modifications were made to help students focus on key ideas, and to
clarify the information for students understanding.
Vocabulary Introduced during Explanation.
Pedigree
A family tree describing the occurrence of a heritable character in
parents and offspring across many generations
Autosome A chromosome that is not involved in determining sex. Humans
have 22 pairs of autosomes and 1 pair of sex chromosomes (X and Y)
Carrier
An individual who is heterozygous for a given gene, with one
normal allele and one potentially harmful recessive allele. They are normal but
can pass on the harmful allele to their offspring.
Affected individual
Person who has the heritable trait in a pedigree
Index case/proband
investigation
Initial member of a family being studied in a genetics
X-linked trait
A trait that is determined by a gene on the X chromosome.
•
Females receive two copies of the X chromosome, one from the mother
and one from the father, so they have two alleles for the trait.
•
Males only receive one X chromosome from their mothers, and only have
one allele for the trait. They receive the Y chromosome from their father.
Summary
GENA project
Images from Google and some
text from GeneTests.org
3 Types of Inheritance
• Autosomal dominant
• Autosomal recessive
• X-linked inheritance
•Characteristics
•Pitfalls
•Diseases examples
3 Types of Inheritance
• Autosomal dominant
• Autosomal recessive
• X-linked inheritance
Autosomal Dominant
Marfan Syndrome
•Abnormal connective tissue
•Eyes: myopia (near sighted, lens
Dislocation
•Skeletal: bone overgrowth (pectus),
laxity, limbs too long for trunk
•Heart: dilation, abnormal valves
Autosomal Dominant
Marfan Syndrome
•25% de novo; 75% inherited
•1 out of 5,000 people
Autosomal Dominant
Marfan Syndrome
Autosomal Dominant:
Pedigree Characteristics
•
Each child of an affected
person has a 50% risk of
inheriting the gene mutation.
•
Males and females are equally
likely to be affected.
•
The condition is seen in
sequential generations,
affecting 50% of individuals in
each generation on average.
Marfan Syndrome
Marfan Syndrome
Autosomal Dominant: Pitfalls in
recognizing this inheritance
•
Incomplete penetrance. Some people who have
the gene mutation do not show the clinical effects.
•
Penetrance limited to one gender. If prostate
cancer risk inherited in autosomal dominant
manner, women who inherit the mutation are not
affected, but can pass the mutation on to their
sons.
Marfan Syndrome
Marfan Syndrome
•
Variable expressivity. The gene mutation has
variable clinical manifestations: the disorder may
range from mild to severe or a range of problems
may occur in people with the mutation.
•
New mutation. An affected person may be the
first person in the family with the condition, from
mutation arising for 1st time in sperm, egg, or
embryo
•
Germline mosaicism. A new mutation may arise
in testis or ovary, resulting in an unaffected parent
transmitting the condition to two or more children
Another Autosomal Dominant
Condition: Achondroplasia
Average
•80% born to average stature
parents
•One mutation in the FGFR3
gene is responsible for 99%
of all achondroplasia
What if both parents have
achondroplasia? Are their children
affected too?
What if both parents have
achondroplasia? Are their children
affected too?
R*
R*
R*R*
r
R*r
r
R*r
rr
What if both parents have
achondroplasia? Are their children
affected too?
R*
R*
R*R*
r
R*r
r
R*r
rr
What if both parents have
achondroplasia? Are their children
affected too?
R*
R*
R*R*
r
R*r
r
R*r
rr
What if both parents have
achondroplasia? Are their children
affected too?
R*
R*
R*R*
r
R*r
r
R*r
rr
AVERAGE
STATURE
What if both parents have
achondroplasia? Are their children
affected too?
R*
R*
R*R*
r
R*r
LETHAL
r
R*r
rr
3 Types of Inheritance
• Autosomal dominant
• Autosomal recessive
• X-linked inheritance
What is cystic fibrosis?
•Lung disease
•Lots of lung secretions &
infections
•Deficient digestive enzymes
•Excess salt in sweat
•Failure to thrive
•Male infertility
•Sinus disease
Autosomal Recessive:
Pedigree Characteristics
Cystic Fibrosis
•
Have features of the disease
when mutations are present in
both copies of a gene pair.
•
When parents are both carriers
- that is, each carries a gene
mutation in one gene and has a
normal copy of the other gene their children each have a 25%
chance of being affected. Of
the children who are
unaffected, 2/3 will be carriers.
Cystic fibrosis carrier
Cystic fibrosis affected
•
If only one parent is a carrier,
children will not be affected.
•
Siblings of a person with the
condition have a 25% chance of
being affected.
Autosomal Recessive:
Pedigree Characteristics
R
R
RR
r*
R r*
When parents are both carriers
- that is, each carries a gene
mutation in one gene and has a
normal copy of the other gene their children each have a 25%
chance of being affected.
r*
R r*
r* r*
Of the children who are
unaffected, 2/3 will be carriers.
Autosomal Recessive: Pitfalls to
detect this type of inheritance
Cystic Fibrosis
Lack of family history. Usually no family
history of other affected family members
Cystic fibrosis carrier
since AR conditions are most likely to occur
in siblings rather than in earlier generations.
Cystic fibrosis affected In small families, multiple affected siblings
are uncommon.
Autosomal recessive disease in sequential
generations. Occasionally autosomal
recessive conditions occur in sequential
generations: if the autosomal recessive
condition allows a person to reach
adulthood and to have children, and if
Uniparental disomy. If a couple in which only
the carrier rate for the condition is high,
one partner is a carrier has an affected child,
a person with the condition may marry a
it may rarely be due to uniparental disomy: in
carrier; their children would have a 50%
this case both gene mutations are inherited from
chance of inheriting the condition.
the parent who is a carrier, due to an error in the
Misassigned paternity. If the biologic father of
formation of sperm or ovum.
an affected individual is someone other
than the person assumed to be the father,
De novo mutations. Although rare, de novo
incorrect carrier test results might occur
mutations account for ~1% of gene mutations
(the apparent father would usually not be a
carrier) and risk of additional affected
and provide another explanation for the birth
of an affected child when only one parent is a carrier. children could be misstated.
Typical Recessive
inheritance
What are the chances
her child will have CF?
●
●
●
●
?
r*
•This brother and sister have CF
•She can have children; less likely
for him
r*
R
Rr* Rr*
R
Rr* Rr*
All carriers
No children affected
Typical Recessive
inheritance
What are the chances
her child will have CF?
●
●
●
●
?
r*
•This brother and sister have CF
•She can have children; less likely
for him
r*
R
Rr* Rr*
R
Rr* Rr*
All carriers
No children affected
Typical Recessive
inheritance
What are the chances
her child will have CF?
●
●
●
●
?
r*
•This brother and sister have CF
•She can have children; less likely
for him
r*
R
Rr* Rr*
R
Rr* Rr*
All carriers
No children affected
What happens if her
partner is a carrier?
●
What are the chances
her child will have CF?
●
●
●
●
?
?
r*
R
r*
Rr*
r*
r*
Rr*
R
R
r*r*
r*r*
r*
Rr* Rr*
Rr* Rr*
All carriers
No children affected
1/24 carrier rate of CF in Caucasians
What happens if her
partner is a carrier?
●
What are the chances
her child will have CF?
●
●
●
●
?
?
r*
R
r*
Rr*
r*r*
r*
Rr*
r*r*
2 carrier children
2 with CF!!
50% chance of
having a carrier
50% chance of
having a child
with CF
r*
R
R
r*
Rr* Rr*
Rr* Rr*
All carriers
No children affected
1/24 carrier rate of CF in Caucasians
What happens if her
partner is a carrier?
●
What are the chances
her child will have CF?
●
●
●
●
?
?
r*
R
r*
Rr*
r*r*
r*
Rr*
r*r*
2 carrier children
2 with CF!!
50% chance of
having a carrier
50% chance of
having a child
with CF
r*
R
R
r*
Rr* Rr*
Rr* Rr*
All carriers
No children affected
1/24 carrier rate of CF in Caucasians
What happens if her
partner is a carrier?
●
●
●
R
r*
r*
r*
Rr*
Rr*
r*r*
r*r*
2 carrier children
2 with CF!!
50% chance of
having a carrier
50% chance of
having a child
with CF
If the child is affected,
the pedigree may look
dominant
even though it is
a recessive
condition.
3 Types of Inheritance
• Autosomal dominant
• Autosomal recessive
• X-linked inheritance
X-linked inheritance:
Pedigree Characteristics
X-linked recessive disease usually occurs in
males who have inherited a recessive Xlinked mutation from their mother. Rarely, the
disease may be seen in females who have
inherited mutations in the same gene X-linked
from both parents. More typically, the mother
is a carrier and is unaffected, although it is not
uncommon for female carriers of X-linked
disorders to have mild clinical manifestations
related to the disorder — for example, carriers of
hemophilia may have mild bleeding problems.
X-linked inheritance:
Pedigree Characteristics
•
A male child of a woman who is a carrier has a 50% risk of inheriting
the disorder.
•
A female child of a woman who is a carrier has a 50% risk of
inheriting the gene mutation and thus being a carrier herself.
•
An affected male - if able to reproduce - will pass on the gene
mutation to all daughters, who are therefore obligate carriers. The
affected male never passes the disease on to a son.
•
The typical family history for an X-linked recessive condition is of
disease in maternal uncles. A woman who has both a brother and a
son affected with an X-linked disease is also an obligate carrier.
X-linked inheritance:
Pitfalls
• Small families. Small family size and few male children
may make the pattern of an X-linked recessive disorder
difficult to discern.
• New mutation. An affected male may be the first person
in the family with the condition, due to a mutation arising
for the first time in sperm, egg or embryo.
• Germline mosaicism. A new mutation may arise in
testis or ovary, resulting in a parent who can pass on the
condition or the carrier state to children, without being
either affected (in the case of a male parent) or a carrier
(in the case of a female parent).
Fragile X
• Fragile X syndrome is the most common single-gene
cause of inherited mental retardation. It is caused by a
CGG trinucleotide repeat expansion in the FMR1 gene
on the X chromosome.
• Any child with developmental delay of unknown etiology
should be considered for fragile X syndrome testing.
Family history of mental retardation and/or suggestive
physical features can make the diagnosis more likely.
• A diagnosis of fragile X syndrome can inform the family
about a child's prognosis and enable the child to receive
needed services; this information also informs the family
about their future reproductive risk as well as risk to
other family members.
Fragile X
• Fragile X syndrome is inherited as an X-linked
disorder.
• Family history is often unremarkable.
• In some families, however, males on the
maternal side of the family, such as maternal
uncles or male cousins, have mental retardation.
WHY WE DO PEDIGREES!
• Females can show milder features of fragile X
syndrome, including developmental disability.
Why is it called Fragile X?
The repeats makes the structure fragile
Fragile X
•
•
•
•
Suspected in males and
females with unexplained
developmental delay or mental
retardation
Hyperactivity, social anxiety,
perseverative speech common
large head circumference
long face
prominent forehead
large ears
prominent jaw
macroorchidism
**not always present in young
Females can have similar
characteristics, but typically
milder
1 in 5000 males have fragile X
Fragile X
Fragile X syndrome is associated
with increased CGG repeats in
the FMR1 gene on the X chromosome
Excess repeats methylate
the FMR1 gene
That turns off the FMR1 gene
That causes features of Fragile X
Description
CGG repeat
size
Normal range
6 to 40
Intermediate
range
41 to 58
Premutation
range
59 to 200
Affected
range
Greater than
200
CGG repeats
Description
CGG repeat
size
Normal range
6 to 40
Intermediate
range
41 to 58
Premutation
range
59 to 200
Affected
range
Greater than
200
But those with >35 repeats have ↑ risk
of premature ovarian failure (POF);
20% with >35 repeats have POF
All males here have fragile X associated
tremor/ataxia Syndrome (FXTAS); pass to all
daughters and she will become carrier to
pass on to male children. No mental retardation.
Risk to increase size when pass on
ANTICIPATION, but
can pass premutation on for generations.
Affected male with mental retardation
and facial features. A female with full mutation
is typically more mild, but 50% chance to pass on.
Other genetic conditions
Turner Syndrome
• Short stature
• Sometimes spatial
and language
difficulties
• Usually infertile
• Abnormal pubertal
development
• Normal IQ
• 98% die before birth
• 1 in 5000
Klinefelter Syndrome
• Male sex organs
• Small testes, sterile
• Breast enlargement
and other feminine
body characteristics
• Normal intelligence
• 1 in 500 to 1,000
22q11 Deletion
Facial anomalies
Congenital heart defect
Speech, learning difficulties
Hypocalcemia
T-cell deficiency
Palate anomalies (cleft)
Asymmetric crying face
FISH for
deletion
Deletion by karyotype
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