Human Genetic Diseases

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Pedigree analysis

Pedigree analysis reveals Mendelian

patterns in human inheritance

= male

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data mapped on a family tree

= female

= male w/ trait

= female w/ trait

Simple pedigree analysis

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33

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Whats the
likely inheritance
pattern?

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Genetic counseling
Pedigree can help us understand the past
& predict the future
Thousands of genetic disorders are
inherited as simple recessive traits

from benign conditions to deadly diseases

albinism
cystic fibrosis
Tay sachs
sickle cell anemia
PKU

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Genetic testing
*Test fetal cells
*Test adult cells
sequence
individual genes

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Recessive diseases

The diseases are recessive because the

allele codes for either a malfunctioning
protein or no protein at all

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Heterozygotes (Aa)

carriers

have a normal phenotype because one

normal allele produces enough of the
required protein

Heterozygote crosses

Heterozygotes as carriers of recessive alleles

Aa x Aa

female / eggs

male / sperm

A
a

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AA
AA

Aa
Aa

A
Aa
a

carrier

Aa
Aa

aa

carrier

disease

A
Aa
a

Cystic fibrosis (recessive)

Primarily whites of
European descent

strikes 1 in 2500 births

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normal lung tissue

normal allele codes for a membrane protein

that transports Cl- across cell membrane

1 in 25 whites is a carrier (Aa)

defective or absent channels limit transport of Cl- & H2O

across cell membrane
thicker & stickier mucus coats around cells
mucus build-up in the pancreas, lungs, digestive tract &
causes bacterial infections

without treatment children die before 5;

with treatment can live past their late 20s

Chloride channel

Effect on Lungs
normal lungs

airway

Cl

transports salt through protein

channel out of cell
Osmosis: H2O follows Cl
Cl channel

H2O
cells lining
lungs
cystic fibrosis

Cl
H2O

bacteria & mucus build up

thickened mucus
hard to secrete

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mucus secreting glands

delta F508

loss of one
amino acid
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Tay-Sachs (recessive)

Primarily Jews of eastern European (Ashkenazi)

descent & Cajuns (Louisiana)
strikes 1 in 3600 births

non-functional enzyme fails to breakdown lipids

in brain cells

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100 times greater than incidence among

non-Jews

fats collect in cells destroying their function

symptoms begin few months
after birth
seizures, blindness &
degeneration of muscle &
mental performance
child usually dies before 5yo

Sickle cell anemia (recessive)

Primarily

Africans

strikes 1 out of 400 African Americans

high frequency

caused by substitution of a single amino

acid in hemoglobin
when oxygen levels are low, sickle-cell
hemoglobin crystallizes into long rods

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deforms red blood cells into

sickle shape
sickling creates pleiotropic
effects = cascade of other
symptoms

Sickle cell anemia

Substitution of one amino acid in

polypeptide chain

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hydrophilic
amino acid

hydrophobic
amino acid

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Sickle cell phenotype

2 alleles are codominant

both normal & mutant hemoglobins are
synthesized in heterozygote (Aa)
50% cells sickle; 50% cells normal
carriers usually healthy
sickle-cell disease
triggered under blood
oxygen stress

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exercise

Heterozygote advantage

Malaria

single-celled eukaryote parasite spends part of its

life cycle in red blood cells

In tropical Africa, where malaria is common:

homozygous dominant individuals die of malaria

homozygous recessive individuals die of sickle cell
anemia
heterozygote carriers are relatively free of both

reproductive advantage

High frequency of sickle

cell allele in African
Americans is vestige of
African roots

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Prevalence of Malaria

Prevalence of Sickle
Cell Anemia

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Huntingtons chorea (dominant)

Dominant inheritance

repeated mutation on end of

chromosome 4

Testing
Would you
want to
know?

mutation = CAG repeats

glutamine amino acid repeats in protein
one of 1st genes to be identified

build up of huntingtin protein in brain causing cell

death

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1872

memory loss
muscle tremors, jerky movements
chorea
starts at age 30-50
early death
10-20 years after start

Genetics & culture

Why do all cultures have a taboo against incest?

laws or cultural taboos forbidding marriages

between close relatives are fairly universal

Fairly unlikely that 2 unrelated carriers of same

rare harmful recessive allele will meet & mate

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but matings between close relatives increase risk

consanguineous (same blood) matings
individuals who share a
recent common ancestor
are more likely to carry
same recessive alleles

A hidden disease reveals itself

Aa

AA x Aa

AA

AA

Aa

Aa

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female / eggs

female / eggs

Aa

male / sperm

male / sperm

AA

Aa

Aa

aa

increase carriers in population

hidden disease is revealed

The Blue People

of Troublesome
Creek
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Anne Beaumont

Blue People of Troublesome Creek

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Blue People of Troublesome Creek

1820 - French orphan Martin Fugate

settled in Troublesome Creek
Married Elizabeth Smith - 7 children of
whom 4 reported to be blue
Many consanguineous marriages
(normally cousin - cousin)
One of their sons married an aunt

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Blue People of Troublesome Creek

Dd

Generation
1 and Dad
Generation
1: Mom

Dd

mother/father

DD + Dd + Dd + dd
DD

DD

DD

DD

DD + DD + DD + Dd
DD DD DD Dd
DD Dd
Dd Dd
Dd Dd
DD Dd
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Generation 2: 2
Siblings
Generation
brothers/sisters

Reproduce with
Reproduce with non-carrier
non-carrier
Generation 3: Cousins

Generation 3
Cousins

Blue People of Troublesome Creek

6 generations later Ben Stacy born

(1975)
Bens skin blue - no apparent cause
(1998) lips and fingernails still blue
when stressed
What is the cause? Treatment?
Madison Cawein (1960 ) proposed
answers

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Blue People of Troublesome Creek

Haemoglobin (Fe(II))

Diaphorase
Met-Haemoglobin (Fe(III))
(blueness)

Oxyhaemoglobin (Fe(II))

Methylene Blue
Reduction
in Body

Reduced Methylene
Blue (colourless)
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Side Effects

Haemoglobin (Fe(II))

Diaphorase
Met-Haemoglobin (Fe(III))
(blueness)

Oxyhaemoglobin (Fe(II))

Methylene Blue
Reduction
in Body

Reduced Methylene
Blue (colourless)
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Any questions?

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Woody Guthrie & Arlo Guthrie

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