Download Pedigrees – Important Points are in BLUE

Pedigrees – Important Points
are in BLUE
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Analysis of inheritance in human families
Typically small number of offspring
-> Mendelian ratios rarely observed
Allow inferences concerning genotypes and
predictions concerning phenotypes of
offspring (genetic counseling)
Studying human genetics
• You cannot make humans of different types
breed together
• Pedigree charts offer an ethical way of
studying human genetics
• Today genetic engineering has new tools to
offer doctors studying genetic diseases
• A genetic counselor will still use pedigree
charts to help determine the distribution of a
disease in an affected family
Symbols used in pedigree
charts
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Normal male
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Affected male
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Normal female
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Affected female
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Marriage
• Arranged Oldest to youngest – L to R
Most common
signs and symbols
used in pedigree
analysis
Organizing the pedigree chart
– Generations are identified by Roman numerals
I
II
III
IV
Organizing the pedigree chart
• Individuals in each generation are identified by Roman
numerals numbered from the left
• Therefore the affected individuals are II3, IV2 and IV3
I
II
III
IV
Categories of inheritance
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Autosomal (non sex-linked) recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Y-linked
Organelle
Pedigree analysis: case 1
P/p
pp
PP or Pp PP or Pp
P/p
pp
PP or Pp
• Two children, one of each sex, show the trait but trait was
not shown in the parents
• Conclusions:
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–
must be autosomal recessive trait (example: PKU)
parents must be heterozygous (Pp)
2/3 chance for each unafflicted child to be heterozygous (Pp)
1/3 chance for each unafflicted child to be homozygous (PP)
Autosomal recessive inheritance in
pedigrees
• Trait is rare in pedigree
• Trait often skips generations (hidden in
heterozygous carriers)
• Trait affects males and females equally
Most common ones
• Cystic fibrosis
• Sickle cell anemia
• Phenylketonuria (PKU)
• Tay-Sachs disease
Pedigrees: Case 2
A/a
a/a
A/a
a/a a/a
a/a
A/a
A/a
a/a
a/a
a/a
a/a
A/a
a/a
a/a
A/a
a/a
A/a
a/a
Autosomal dominant disorders
• Trait is common in the pedigree
• Trait is found in every generation
• Affected individuals transmit the trait to ~1/2
of their children (regardless of sex)
(Note: In fact, in some AD diseases the
homozygous genotype is incompatible
with life)
Typical pedigree for AD disorder
A/a
a/a
A/a
a/a a/a
a/a
A/a
A/a
a/a
a/a
a/a
a/a
A/a
a/a
a/a
A/a
a/a
A/a
a/a
Autosomal dominant traits
There are few autosomal
dominant human
diseases (why?), but
some rare traits have this
inheritance pattern
ex. achondroplasia (a
sketelal disorder
causing dwarfism)
Huntington’s disease: an example of AD disorder
- Half the people in the
Venezuelan village of
Barranquitas are
affected
- A large-scale pedigree
analysis was conducted
including 10,000 people
- Example for one
particular family:
X-linked recessive disorders
• Trait is rare in pedigree
• Trait skips generations
• Affected fathers DO NOT pass to their sons,
• Males are more often affected than females
ex. Hemophilia, ColorBlindness
Pedigree of an X-linked recessive disorder
Father
affected
Son non
affected
1/2
grandsons
affected
Daugther
carrier
Hemophilia: an example of X-linked recessive
disorder
Partial pedigree analysis of hemophilia in royal
families of Europe
Only males develop the disease!
Partial pedigree analysis of hemophilia in royal
families of Europe
Spontaneous mutation gave
rise to defective allele of
Factor VIII gene (XfXF)
X fY
XfXF
X fY
XfXF
XfXF
X fX F
XfXF XfY
X fY
X fY
X fY
XfXF
X fY X fY
Is it possible that the present British family
still harbors the recessive allele?
X fY
X fY
Partial pedigree analysis of hemophilia in royal
families of Europe
Spontaneous mutation gave
rise to defective allele of
Factor VIII gene (XfXF)
X fY
XfXF
XfXF ?
XfXF\?
X fY
XfXF
XfXF
X fX F
XfXF XfY
X fY
X fY
X fY
Must be XFY, even if mother was XfXF
(otherwise he would be sick) so Xf allele was
lost in this branch of the family
XfXF
X fY X fY
X fY
X fY
X-linked dominant disorders
• 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)
ex. X-linked rickets (bone lesions)
Case 4: X-linked dominant disorders
Pedigree Analysis in real life: complications
Incomplete Penetrance of autosomal dominant traits
=> not everyone with genotype expresses trait at all
Ex. Breast cancer genes BRCA-1 and BRCA-2
& many “genetic tendencies” for human diseases
Pedigree Analysis in real life
Remember:
• dominant traits may be rare in population
• recessive traits may be common in population
• alleles may come into the pedigree from 2 sources
• mutation happens
• often traits are more complex
• affected by environment & other genes