Lecture 4: Mutations

Question 1

Types of mutations

Answer 1

Chromosomal disorders, single gene (monogenic) disorders, complex/multifactorial disorders

Question 2

Monogenic disorders

Answer 2

• caused by individual mutant genes, may be contained in mitochondrial or nuclear genomes
• exhibit obvious pedigree patterns (inheritance)
• i.e. substitution, deletion, insertion.

Question 3

Substitution mutations

Answer 3

Most common: Transition from purines or pyrimidines –> pyrimidines

Less common: Transversion from purine <–> pyrimidine

Trasnversions are theoretically 2x more likely common, but C>T is a hotspot.

Purine: A or G
Pyrimidine: C or T

Question 4

Pathogenic mutations occur in:

Answer 4

Protein coding regions (exons): about 90%
Disrupting RNA stability or RNA splicing (introns): 10%
Affecting gene regulation/dosage : 1%

Question 5

Frameshift mutations

Answer 5

Can occur in multiples of threes.

Exception: F508 mutation in cystic fibrosis. 1 copy = carrier with mild symptoms, survival advantage from cholera and typhoid fever. 2 copies = cystic fibrosis.

Question 6

Autosomal recessive inheritance

Answer 6

Genotype is homozygous recessive. Males and females are equally affected, recurrence risk for siblings is 1/4 if parents are carriers. Genetically rare, not clinically recognisable (asymptomatic).

i.e. cystic fibrosis.

Question 7

Autosomal dominant inheritance

Answer 7

Genotype of proband is homozygous dominant, phenotype appears in every generation. 50% risk of inheriting if parent is affected. Male to female ratio is equal.

i.e. Myotonic dystrophy

Question 8

X-linked inheritance

Answer 8

Incidence is much higher in males than females. Affected male passes diseases onto daughter, who will be carriers. Carriers/heterozygous have no/mild effect due to random X inactivation.

i.e. androgen insensitivity syndrome.

Question 9

X-linked dominant inheritance

Answer 9

Affected males with normal females will produce normal sons and affected daughters.

Both male and female offspring of a female carrier will have 50% risk of inheriting. Affected women have milder disease. i.e. Retinitis pigmentosa.

2 female: 1 male.

Question 10

Y-linked dominant

Answer 10

Only affects males, always affected father (unless sporadic mutation).

Question 11

Complex/multifactorial disorders

Answer 11

Lifestyle factors are modifiable factors leading to multifactorial disease.

Question 12

Endogenous mutations

Answer 12

due to spontaneous errors in DNA replication and repair. 99.9% will be repaired by proof-reading mechanisms

Question 13

Mutagens

Answer 13

Induce mutations. Most mutagens act directly by either damaging a particular nucleotide or being incorporated in the nucleic acid.

Question 14

Trisomy 13 - Patau syndrome

Answer 14

Extra/third chromosome in pair 13. Increased risk with ^maternal age
95% cases result in a miscarriage, live births rarely survive beyond 1 year.

Features: Holoprosencephaly (failure for forebrain to divide properly), heart defects, dysmorphology, seizures, intellectual defect.

Question 15

Structural abnormalities

Answer 15

Arise due to errors in cell division when chromsomes align - meiotic non-disjunction at meiosis 1 and 2.

Homologous recombination between areas of concentrated repeated sequences frequently create deletion and duplication mutations.

Duplications and deletions alter gene dosage due to copy number variations.

Question 16

Cri du chat syndrome aka 5p monosomy

Answer 16

Monosomy of a particular region of a chromosome. More severe phenotype if larger area was duplicated/lost.

Major identifying features: monotone, weak, cries like a cat, round face, intellectual disability, heart defects, etc.

Question 17

XO - turner’s syndrome

Answer 17

Chromsome loss

Question 18

Trisomy 21 - Down syndrome

Answer 18

Chromosome duplication