1. M.B.Ch.B, MSC, PhD, DCH (UK), MRCPCH
Genetics
Lec.3
Dr. Mohammed Hussein
M.B.Ch.B, MSC, PhD, DCH (UK), MRCPCH

2. Important principles that can characterize single-gene diseases
Variable expression
Incomplete penetrance
Pleiotropy
Locus heterogeneity
New mutations
Delayed age of onset
Anticipation
Imprinting
Uniparental disomy

3. Variable Expression
Most genetic diseases vary in the degree of phenotypic expression: Some individuals may be severely affected, whereas others are more mildly affected.
This can be the result of several factors:
Environmental Influences
Allelic Heterogeneity
Heteroplasmy
Modifier Loci

4. Incomplete Penetrance

5. Pleiotropy
Pleiotropy exists when a single disease-causing mutation affects multiple organ systems.
Pleiotropy is a common feature of genetic diseases.
Marfan syndrome provides a good example of the principle of pleiotropy

6. Marfan syndrome
Yao Ming

7. Locus Heterogeneity
Locus heterogeneity exists when the same disease phenotype can be caused by mutations in different loci.
For example, retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins.

8. New Mutations
In many genetic diseases, a large proportion of cases are caused by a new mutation transmitted from an unaffected parent to an affected offspring.
There is thus no family history of the disease

9. Delayed Age of Onset
Many individuals who carry a disease-causing mutation do not manifest the phenotype until later in life.
This can complicate the interpretation of a pedigree because it may be difficult to distinguish genetically normal individuals from those who have inherited the mutation but have not yet displayed the phenotype.
Example: Familial breast cancer

10. Genetic Anticipation
Anticipation refers to a pattern of inheritance in which individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generations.
For a number of genetic diseases, this phenomenon can be attributed to the gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene.

11. Huntigton
Disease

12. Imprinting
Imprinting refers to the fact that a small number of genes are transcriptionally active only when transmitted by one of the two sexes.
The homologous locus in the other parent is rendered transcriptionally inactive.
Thus, for imprinted loci, it is normal to have only the maternal (for some loci) active, or only the paternal (for other loci) active.

14. On rare occasion, the transcriptionally active gene may be deleted from the chromosome during gametogenesis.
This leaves the offspring with no active gene at that locus.
The gene from one parent is inactivated due to normal imprinting, and the gene from the other parent deleted by a mutation.
This situation may result in a genetic disease.

15. Prader-Willi Syndrome and Angelman Syndrome

16. Prader-Willi Syndrome

17. Angelman Syndrome

18. Uniparental Disomy
Uniparental disomy is a rare condition in which both copies of a particular chromosome are contributed by one parent.

20. Population Genetics

21. Definition
Population genetics is the study of genetic variation in populations.
Allow us to understand how and why the prevalence of various genetic diseases differs among populations.

22. Hardy-Weinberg Equilibrium
Hardy: British Mathematician
Weinberg: German Physician

23. Hardy-Weinberg Equilibrium

24. Hardy-Weinberg Equilibrium
If a population is large and if individuals mate at random with respect to their genotypes at a locus, the population should be in H-W equilibrium.

25. pp pq qq p q p p p p q q p q q q pp + pq + pq + qq = 1 p2 + 2pq + q2 =
1/4
1/4
1/4
1/4 pp + pq + pq + qq = 1 p p p p q p2 +
2pq + q2 = 1 q p q q q
Heterozygous carrier (Normal) pp pq qq
Homozygous Dominant
(Normal)
Homozygous Recessive
(Affected)
Heterozygous carrier (Normal)

26. P2 + 2pq + q2 = 1 p = frequency the normal allele (most common)
q = frequency the disease-producing allele (minor)
p2 = frequency of homozygous normal
q2= frequency of homozygous affected (diseased)
2pq = frequency of heterozygous carrier

27. P2 + 2pq + q2 = 1 1 + 2q + q2 = 1 Simplification
Generally p, the normal allele frequency in the population, is very close to 1 (e.g., most of the alleles of this gene are normal).
In this case, we may assume that p ~ 1, and the equation simplifies to:
P2 + 2pq + q2 = 1
1 + 2q + q2 = 1

28. Summary
In summary, there are three major terms one usually works with in the Hardy Weinberg equation applied to AR conditions:
q, the frequency of the disease-causing allele
2q, the carrier frequency
q2, the disease prevalence

29. A Practical Application of the H-W Principle
A 20-year-old female has an AR genetic disease called Phenylketonuria (PKU). She asks you 2 questions:
What is the chance that she had to marry a man with the disease-producing allele.
What is the probability that she will have a child with PKU?
Note: the prevalence of PKU in the population is 1/10,000.

30. Answer Disease prevalence = 1/10,000 (given) So q2 = 1/10,000
q = disease-causing allele
2q = carrier frequency
q2 = disease prevalence
Disease prevalence = 1/10,000 (given)
So q2 = 1/10,000
So q = square root of 1/10,000, which is 1/100. This is the frequency of the disease producing allele
Carrier frequency = 2q = 2 x 1/100 = 1/50
The chance that she had to marry a man with the disease-producing allele is 1/50

31. 2. What is the probability that she will have a child with PKU?
The answer to the second question is based on the joint occurrence of 4 events:
The probability that the female carry the abnormal allele
The probability that the she will pass her abnormal allele to the child
The probability that the male carry the abnormal allele
The probability that the he will pass his abnormal allele to the child
1 * 2 * 3 * 4 = the risk of having a child with the disease

32. The answer to the second question is based on the joint occurrence of 4 events:
The probability that the female carry the abnormal allele (1) as she is known affected
The probability that the she will pass her abnormal allele to the child (1) as the disease is AR
The probability that the male carry the abnormal allele (1/50) as calculated before
The probability that the he will pass his abnormal allele to the child (1/2)
1 * 1 * 1/50*1/2 = 1/100

33. Example
A couple come for genetic counseling about the risk that their child will have cystic fibrosis.
The husband's sister has the disease, but he is not affected and there is no history in the wife's family of the disease.
Note: the prevalence of CF is 4/10000.

34. Answer 1/25 * 1/2 * 2/3 * 1/2 * = 1/150 Prevalence = 4/10000 = q2
q = disease-causing allele
2q = carrier frequency
q2 = disease prevalence
Prevalence = 4/10000 = q2
So q = 2/100
So 2q = 4/100 = 1/25 (carrier risk of CF in population) which is the risk for the wife .
Regarding the husband, as his sister is affected, so both parents must be carriers. Since he is not affected therefore there is a 2/3 chance that he is a carrier.
1/25 *
1/2 *
2/3 *
1/2 *
= 1/150

35. H-W Equilibrium for Dominant Diseases
In AD diseases the homozygous and the heterozygous are the affected
The heterozygous affected are the most common, so the prevalence is equal to the heterozygous (2q)
While the homozygous affected (q2 ) are less common but have more sever symptoms pp pq qq

36. q = allele frequency
2q = heterozygous affected = prevalence of the disease
q2 = homozygous affected (sever disease)

37. Example
q = disease-causing allele
2q = heterozygous affected (disease prevalence)
q2 = homozygous affected (sever disease)
The prevalence of hyperlipidemia (AD disease) in USA is 1/500, calculate the homozygous affected.
As the disease is AD, so the
Prevalence = 2q, so q= 1/1000
q2 = 1/ = 1/106 = homozygous affected (severely affected).

38. H-W Equilibrium for X-Linked recessive Diseases
Most cases occur in hemizygous males (xY).
So, q = disease-producing allele frequency also equals the prevalence of affected males.
q2= prevalence of disease in females. (very rare)
2q = prevalence of female carriers.

39. q = allele frequency = prevalence of affected males 2q = heterozygous female carriers q2 = homozygous affected females

40. Example
q = disease-causing allele (disease prevalence in male)
2q = heterozygous female carrier
q2 = homozygous affected female (sever disease)
The prevalence of hemophilia in males is 1/10,000, calculate the prevalence of female carriers and the females affected.
The prevalence of the disease = q = 1/10,000
2q is the female carriers = 2/10,000.
q2 is the affected females = 1/ = 1/108

41. Summary AR diseases: AD diseases: X-L diseases: q = allele frequency
2q = heterozygous carriers
q2 = homozygous affected = prevalence of the disease
AD diseases:
2q = heterozygous affected = prevalence of the disease
q2 = homozygous affected (sever disease)
X-L diseases:
q = allele frequency = prevalence of affected males
2q = heterozygous female carriers
q2 = homozygous affected females

42. Factors responsible for genetic variation in populations
Although human populations are typically in H-W equilibrium for most loci, deviations from equilibrium can be produced by:
Mutation
Natural Selection
Genetic Drift
Gene Flow
Consanguinity

43. Mutation
Mutation is ultimately the source of all new genetic variation in populations.
Founder effect

44. Natural Selection

45. Natural Selection
Natural selection acts upon genetic variation, increasing the frequencies of alleles that promote survival or fertility (referred to as fitness) and decreasing the frequencies of alleles that reduce fitness.
Cystic fibrosis (heterozygote resistance to typhoid fever)
Hemochromatosis (heterozygote advantage in iron-poor environments)
Glucose-6-phosphate dehydrogenase deficiency (heterozygote resistance to malaria)

46. Genetic Drift
Mutation rates do not vary significantly from population to population, although they can result in significant differences in allele frequencies when they occur in small populations

47. Gene Flow Gene flow refers to the exchange of genes among populations.
Because of gene flow, populations located close to one another often tend to have similar gene frequencies

48. Consanguinity and its Health Consequences
Consanguinity refers to the mating of individuals who are related to one another (typically, a union is considered to be consanguineous if it occurs between individuals related at the second-cousin level or closer).
Consequently, there is an increased risk of genetic disease in the offspring of consanguineous matings

49. Revision

50. Determining type of inheritance in a pedigree
Ask yourself the following questions
Dose an affected individual have an affected parent?
Yes: Dominant disease
No: Recessive disease
If it is Recessive, then ask: Dose all affected are males?
Yes: X-linked recessive disease
No: Autosomal recessive disease
If it is Dominant, then ask: Is there male-male transmission?
Yes: autosomal dominant disease
No: may be an X-linked dominant
Are all daughters of an affected male also affected?
Yes: X-linked dominant
No: autosomal dominant disease

51. Autosomal Dominant  YES YES Autosomal Dominant Autosomal Recessive
X-Linked Dominant
X-Linked Recessive 
1. Dose an affected individual have an affected parent?
YES
2. Is there male-male transmission?
YES

52. Autosomal Recessive  NO NO Autosomal Dominant Autosomal Recessive
X-Linked Dominant
X-Linked Recessive 
1. Dose an affected individual have an affected parent? NO
2. Dose all (or almost all) affected are males? NO

53. X-Linked Recessive  NO YES Autosomal Dominant Autosomal Recessive
X-Linked Dominant
X-Linked Recessive 
1. Dose an affected individual have an affected parent? NO
2. Dose all (or almost all) affected are males?
YES

54. Autosomal Dominant ?  ? YES NO YES Autosomal Dominant
Autosomal Recessive
X-Linked Dominant
X-Linked Recessive ?  ?
1. Dose an affected individual have an affected parent?
YES
2. Is there male-male transmission? NO
3. Are all daughters of an affected male also affected?
YES

55. Typical pedigrees for mitochondrial diseases
Transmission of the disease is only from a female.
All offspring of an affected female are affected.
None of the offspring of an affected male is affected.

56. M.B.Ch.B, MSC, PhD, DCH (UK), MRCPCH
Dr. Mohammed Hussein
M.B.Ch.B, MSC, PhD, DCH (UK), MRCPCH