1. Human Genetic Diseases1 2 3 4 5 6

2. Pedigree analysis
Pedigree analysis reveals Mendelian patterns in human inheritance
data mapped on a family tree
= male
= female
= male w/ trait
= female w/ trait

3. Simple pedigree analysis
What’s the likely inheritance pattern?
Simple pedigree analysis 1 2 3 4 5 6 1 2 3 4 5 6

4. 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

5. sequence individual genes
Genetic testing
sequence individual genes

6. Chromosomal Abnormalities
Errors of Meiosis
Chromosomal Abnormalities

7. Chromosomal abnormalities
Incorrect number of chromosomes
nondisjunction
chromosomes don’t separate properly during meiosis
breakage of chromosomes
deletion
duplication
inversion
translocation

8. Nondisjunction
Problems with meiotic spindle cause errors in daughter cells
homologous chromosomes do not separate properly during Meiosis 1
sister chromatids fail to separate during Meiosis 2
too many or too few chromosomes 2n
n-1 n
n+1

9. Alteration of chromosome number
error in Meiosis 1
error in Meiosis 2
all with incorrect number
1/2 with incorrect number

10. Nondisjunction Baby has wrong chromosome number trisomy monosomy
cells have 3 copies of a chromosome
monosomy
cells have only 1 copy of a chromosome
n+1 n
n-1 n
trisomy
2n+1
monosomy
2n-1

11. Human chromosome disorders
High frequency in humans
most embryos are spontaneously aborted
alterations are too disastrous
developmental problems result from biochemical imbalance
imbalance in regulatory molecules?
hormones?
transcription factors?
Certain conditions are tolerated
upset the balance less = survivable
but characteristic set of symptoms = syndrome

12. Down syndrome
Trisomy 21
3 copies of chromosome 21
1 in 700 children born in U.S.
Chromosome 21 is the smallest human chromosome
but still severe effects
Frequency of Down syndrome correlates with the age of the mother
Trisomy 13 occurs in about 1 out of every 5,000 live births. It is a syndrome with multiple abnormalities, many of which are not compatible with life. More than 80% of children with trisomy 13 die in the first month. Trisomy 13 is associated with multiple abnormalities, including defects of the brain that lead to seizures, apnea, deafness, and eye abnormalities. The eyes are small with defects in the iris (coloboma ). Most infants have a cleft lip and cleft palate, and low-set ears. Congenital heart disease is present in approximately 80% of affected infants. Hernias and genital abnormalities are common.
Trisomy 18 is a relatively common syndrome affecting approximately 1 out of 3,000 live births, and affecting girls more than three times as often as boys. The presence of an extra number 18 chromosome leads to multiple abnormalities. Many of these abnormalities make it hard for infants to live longer than a few months.
The cri du chat syndrome is caused by the deletion of information on chromosome 5. It is likely that multiple genes on chromosome 5 are deleted. One deleted gene, called TERT (telomerase reverse transcriptase) is involved in control of cell growth, and may play a role in how some of the features of cri cu chat develop. The cause of this rare chromosomal deletion is not known, but it is expected that the majority of cases are due to spontaneous loss of a piece of chromosome 5 during development of an egg or sperm. A minority of cases result from one parent carrying a rearrangement of chromosome 5 called a translocation. Between 1 in 20,000 and 1 in 50,000 babies are affected. This disease may account for up to 1% of individuals with severe mental retardation. Infants with cri du chat syndrome commonly have a distinctive cat-like cry. They also have an extensive grouping of abnormalities, with severe mental retardation being the most important.

13. Down syndrome & age of mother
Mother’s age
Incidence of Down Syndrome
Under 30
<1 in 1000 30
1 in 900 35
1 in 400 36
1 in 300 37
1 in 230 38
1 in 180 39
1 in 135 40
1 in 105 42
1 in 60 44
1 in 35 46
1 in 20 48
1 in 16 49
1 in 12
Rate of miscarriage due to amniocentesis:
1970s data 0.5%, or 1 in 200 pregnancies
2006 data <0.1%, or 1 in 1600 pregnancies

14. Genetic testing Amniocentesis in 2nd trimester Analysis of karyotype
sample of embryo cells
stain & photograph chromosomes
Analysis of karyotype

15. Sex chromosomes abnormalities
Human development more tolerant of wrong numbers in sex chromosome
But produces a variety of distinct syndromes in humans
XXY = Klinefelter’s syndrome male
XXX = Trisomy X female
XYY = Jacob’s syndrome male
XO = Turner syndrome female

16. Klinefelter’s syndrome
XXY male
one in every 2000 live births
have male sex organs, but are sterile
feminine characteristics
some breast development
lack of facial hair
tall
normal intelligence

17. Klinefelter’s syndrome
How many Barr bodies would you expect?

18. Jacob’s syndrome male XYY Males 1 in 1000 live male births
extra Y chromosome
slightly taller than average
more active
normal intelligence, slight learning disabilities
delayed emotional maturity
normal sexual development

19. Trisomy X XXX 1 in every 2000 live births produces healthy females
Why?
Barr bodies
all but one X chromosome is inactivated
How many Barr bodies would you expect?

20. Turner syndrome Monosomy X or X0 1 in every 5000 births
varied degree of effects
webbed neck
short stature
sterile
How many Barr bodies would you expect?

21. Changes in chromosome structure
deletion
loss of a chromosomal segment
duplication
repeat a segment
inversion
reverses a segment
translocation
move segment from one chromosome to another
error of replication
error of crossing over

22. Recessive diseases
The diseases are recessive because the allele codes for either a malfunctioning protein or no protein at all
Heterozygotes (Aa)
carriers
have a normal phenotype because one “normal” allele produces enough of the required protein

23. Heterozygote crosses Aa x Aa A a Aa A a AA Aa AA Aa A a A a Aa Aa aa
Heterozygotes as carriers of recessive alleles
Aa x Aa A a Aa A a
male / sperm AA Aa AA Aa A a
female / eggs
carrier A a Aa Aa aa Aa aa
carrier
disease

24. Cystic fibrosis (recessive)
Primarily whites of European descent
strikes 1 in 2500 births
1 in 25 whites is a carrier (Aa)
normal allele codes for a membrane protein that transports Cl- across cell membrane
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
normal lung tissue
Cystic fibrosis is an inherited disease that is relatively common in the U.S. Cystic fibrosis affects multiple parts of the body including the pancreas, the sweat glands, and the lungs. When someone has cystic fibrosis, they often have lots of lung problems. The cause of their lung problems is directly related to basic problems with diffusion and osmosis in the large airways of the lungs.
People without cystic fibrosis have a small layer of salt water in the large airways of their lungs. This layer of salt water is under the mucus layer which lines the airways. The mucus layer in the airways helps to clear dust and other inhaled particles from the lungs.

25. bacteria & mucus build up mucus secreting glands
Chloride channel
transports salt through protein channel out of cell
Osmosis: H2O follows Cl–
Effect on Lungs
normal lungs
airway
Cl–
Cl– channel
H2O
cells lining lungs
cystic fibrosis
Cl–
In people without cystic fibrosis, working cystic fibrosis proteins allow salt (chloride) to enter the air space and water follows by osmosis. The mucus layer is dilute and not very sticky.
In people with cystic fibrosis, non-working cystic fibrosis proteins mean no salt (chloride) enters the air space and water doesn't either. The mucus layer is concentrated and very sticky.
People with cystic fibrosis have lung problems because:
Proteins for diffusion of salt into the airways don't work. (less diffusion)
Less salt in the airways means less water in the airways. (less osmosis)
Less water in the airways means mucus layer is very sticky (viscous).
Sticky mucus cannot be easily moved to clear particles from the lungs.
Sticky mucus traps bacteria and causes more lung infections.
Therefore, because of less diffusion of salt and less osmosis of water, people with cystic fibrosis have too much sticky mucus in the airways of their lungs and get lots of lung infections. Thus, they are sick a lot.
H2O
bacteria & mucus build up
thickened mucus hard to secrete
mucus secreting glands

26. delta F508
loss of one amino acid

27. Tay-Sachs (recessive)
Primarily Jews of eastern European (Ashkenazi) descent & Cajuns (Louisiana)
strikes 1 in 3600 births
100 times greater than incidence among non-Jews
non-functional enzyme fails to breakdown lipids in brain cells
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

28. 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
deforms red blood cells into sickle shape
sickling creates pleiotropic effects = cascade of other symptoms

29. hydrophilic amino acid hydrophobic amino acid
Sickle cell anemia
Substitution of one amino acid in polypeptide chain
hydrophilic amino acid
hydrophobic amino acid

30. Doctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems.

31. 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
exercise

32. Malaria

33. Prevalence of Malaria
Prevalence of Sickle Cell Anemia

34. 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

35. Heterozygote advantage
Sickle cell frequency
high frequency of heterozygotes is unusual for allele with severe detrimental effects in homozygotes
1 out of 400 African Americans
Suggests some selective advantage of being heterozygous
sickle cell: resistance to malaria?
cystic fibrosis: resistance to cholera?
Sickle Cell:
In tropical Africa, where malaria is common, the sickle-cell allele is both an advantage & disadvantage. Reduces infection by malaria parasite.
Cystic fibrosis:
Cystic fibrosis carriers are thought to be more resistant to cholera:
1:25, or 4% of caucasians are carriers Cc

36. Huntington’s chorea (dominant)
1872
Dominant inheritance
repeated mutation on end of chromosome 4
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
memory loss
muscle tremors, jerky movements
“chorea”
starts at age 30-50
early death
10-20 years after start
Testing… Would you want to know?

37. 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
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

38. A hidden disease reveals itselfAa x
AA x Aa A a
male / sperm A
male / sperm AA AA Aa Aa AA AA A a
female / eggs A a
female / eggs Aa Aa aa aa Aa Aa
• increase carriers in population • hidden disease is revealed

39. Don’t hide… Ask Questions!!