L56, L57: Pedigree And Gene Linkage, Genetic Basis Of Single Gene Defect

Question 1

Single gene / Mendelian disease

Answer 1

1. Autosomal dominant
2. Autosomal recessive
3. X-linked dominant
4. X-linked recessive

Question 2

Autosomal dominant disease

Answer 2

• Huntington’s disease: CAG repeats (multiple glutamine) —> toxic to neurones —> unsteady gait, involuntary movement
• Familial Alzheimer’s Disease (FAD)

1. Both sexes (not sex chromosome related)
2. 50% offspring affected if parent affected
3. 0% offspring affected if parent unaffected
4. Vertical inheritance
5. Late onset
6. Variability in severity (homozygotes more severe)

Question 3

Autosomal recessive disease

Answer 3

• Cystic fibrosis: CFTR mutation (defective chloride ion channel) —> diarrhoea, respiratory infections, pancreatic insufficiency
• mainly inborn errors of metabolism
• sickle cell anaemia, Thalassaemia, phenylketonuria

1. Both sexes
2. 25% affected if both parents normal
3. Horizontal inheritance (skip generation)
4. Early onset
5. More common in certain ethnic group
6. Consanguinity more likely

Question 4

X-linked recessive diseases

Answer 4

• Haemophilia A —> blood does not clot properly —> heavy bleeding and bruising
• G6PD

1. Mostly males (since males are hemizygous XY)
2. No male-to-male transmission (since male only pass X to daughter, male inherited from mum)

Question 5

X-linked dominant disease

Answer 5

1. Females + Male
2. No male-to-male transmission
3. All daughters affected if father affected (differentiate from Autosomal Dominant)
4. Female:Male = 2:1 due to high lethality in male

Question 6

Summary of Autosomal dominant, Autosomal recessive, X-linked dominant, X-linked recessive disease

Answer 6

1. Autosomal dominant:
   - Huntington’s disease
   - Familial Alzheimer’s Disease (FAD)
2. Autosomal recessive:
   - Cystic fibrosis
   - Sickle cell anaemia
   - Thalassaemia
   - Phenylketonuria
3. X-linked dominant:
4. X-linked recessive:
   - Haemophilia A
   - G6PD

Question 7

Mitochondrial inheritance

Answer 7

1. Exclusive maternal inheritance
2. Male and female
3. Multiple generations
4. All children affected from affected mum; Children unaffected from affected father

Question 8

Interpretation of pedigree

Answer 8

Steps

1. Male-to-male transmission? Yes: autosomal, No: X-linked
2. Female? Yes: X-linked dominant, No: X-linked recessive

Autosomal dominant: at least one parent affected, every generation, both sexes
Autosomal recessive: parents not affected but children affected
X-linked recessive: mostly males
X-linked dominant: no male-to-male, both sexes

Question 9

What is segregation ratio

Answer 9

Ratio of affected to normal

Autosomal dominant: 1:1
Autosomal recessive: 1:3
X-linked recessive (normal father x carrier mum): 1:1 (in sons)
X-linked dominant (normal father x affected mum): 1:1

Question 11

Identical-by-descent vs Identical-by-state

Answer 11

Identical-by-state: same nucleotide sequence in 2 individuals
Identical-by-descent: same nucleotide sequence in 2 individuals due to inheritance from common ancestor

Question 12

Mendel’s law of inheritance

Answer 12

1. Law of segregation
2. Law of independent assortment
3. Law of dominance

Question 13

Shortcomings of Mendel’s law of inheritance

Answer 13

1. Crossing-over (against law of independent assortment)
2. Incomplete dominance / co-dominance (against law of dominance)
3. Multiple alleles
4. Multiple gene / polygenic trait

Question 14

What is crossing over

Answer 14

Recombination / exchange of genes in a pair of homologous chromosome after chromosome have duplicated (2 pairs of chromatids)

Question 15

Recombination fraction

Answer 15

• No. of recombinant / (recombinant + parental) x 100
• used to determine distance between 2 genes —> Disease Gene Mapping
• far apart: 50% (independent assortment)
• close together: 0% (2 genes segregate together —> no recombinants / more parental types)
• <50%: two genes are in linkage
• 1% = 1 cM (centimorgan) = 1 million bp

If a person has marker gene and he is diseased —> see if marker gene follow diseased person —> calculate recombinant fraction —> find out disease gene location

Question 16

Genetic marker

Answer 16

• must have known location in genome
• sufficient variability between individuals

1. Microsatellites
2. SNP

Question 17

Limitations of gene linkage studies

Answer 17

1. Long generation time
2. Uncontrolled mating
3. Uncontrolled study participation
4. Uncontrolled environmental factors
5. Small family size

Question 18

Hardy-Weinberg law

Answer 18

Frequencies of each genotype is stable over successive generations, GIVEN THAT large population + random mating

Random mating: Allele are assigned independently

Genotypic ratio: p^2: 2pq: q^2
(Genotype frequency: Allele frequency x Allele frequency)

For gene frequency <99%, the gene is said to have polymorphism (having other versions of the gene)

Phenotype frequency: frequency of observable traits