Patterns of Inheritance

Question 1

What are the rules of pedigree drawings?

Answer 1

Males are squares
Females are circles
Partners have a line between them
Siblings have a line above them
Line down for children
Affected people are shaded
Carriers have dots in
A person whose sex is unknown is a diamond
Twins have a pyramid shaped line connecting them /\ (identical= /-)
A triangle is an abortion
Double line joins union of consanguineous couple

Question 2

What is meant by autosomal dominant inheritance?

Answer 2

Manifest in HETEROZYGOUS form
Most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance).
Both sexes affected
Male to female & female to male transmission
Most will have an affected parent
50% risk to offspring

Question 3

What is penetrance? Can you give an example?

Answer 3

Penetrance- percentage of individuals who carry the mutation AND develop symptoms of the disorder- many dominant disorders show age-dependent penetrance
Examples of reduced penetrance scenarios are Huntington’s which occurs later in life or BRACA1 which increases chances of breast cancer but doesn’t guarantee breast cancer

Question 4

What are the features of autosomal dominant inheritance?

Answer 4

Variable Expressivity: variation in severity/symptoms of disorder between individuals with same mutn
New mutation rate: de novo mutation rate varies considerably between AD conditions
Somatic mosaicism: new mutn arising at early stage in embryogenesis
- Present in only some tissues/cells e.g. only 10% of cells, or a specific type of cells
Germ-line mosaicism (gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis
- mutn present in variable proportion of gametes; can be transmitted to offspring makes the chance of passing impossible to predict
Anticipation: worsening of disease severity in successive generations
- characteristically occurs in triplet repeat disorders

Question 5

What is meant by autosomal recessive inheritance?

Answer 5

Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
Carriers (heterozygote) not affected
Both sexes affected
Male to female and female to male transmission
Usually one generation affected
May be consanguinity e.g. cousin marriages

Question 6

What’s the difference between compound heterozygote and a compound homozygote?

Answer 6

Compound het

- 2 mutns in same gene
- Mutns are different

Cystic fibrosis

- ∆F508
- G542X

Homozygote

- 2 mutns in same gene
- Identical mutns

Cystic fibrosis
- ∆F508
- ∆F508
May suggest consanguinity

Question 7

What are the features of autosomal recessive inheritance?

Answer 7

Trait often found in clusters of siblings but not in parents & offspring.
Recurrence risk = 1/4 for each sibling of affected person.
Carrier probability =2/3 for unaffected siblings of affected person.
All offspring of affected person are obligate carriers.

Question 8

On what basis does X-linked inheritance work?

Answer 8

Women have two X chromosomes
	- Two copies of X-linked genes
	- Can be homozygous or heterozygous
Men have one X and a Y 
	- Only a single copy of X-linked genes
	- Hemizygous

Question 9

Is X-linked inheritance dominant or recessive?

Answer 9

X-linked inheritance can
be:
Recessive
	- Women are carriers + unaffected
	- No male to male transmission
Dominant
	- Women are affected
	- Males more severely affected/lethal

Question 10

What are some of the aspects of x-linked recessive inheritance?

Answer 10

X-linked genes never passed from father to son.
All daughters of affected males are obligate carriers.
Children of carrier females have a 50% chance of inheriting mutant allele.

Skewed X-inactivation: generally random but ~10% of women have uneven or skewed X-inactivation.
Manifesting carriers: some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD.

Question 11

What is Y-linked inheritance?

Answer 11

Always and only passed from fathers to sons

Question 12

What are the different types of mutations?

Answer 12

Mutations
Types:
	- Substitutions (point mutations)
	- Deletions 
	- Insertions
Found in:
	- Coding DNA
	- Non-coding DNA (such as promoters and introns)

Question 13

What is meant by a synonymous mutation?

Answer 13

A change in nucleotide that results in the same amino acid being produced therefore nothing changes

Question 14

What is meant by a missense point mutation?

Answer 14

Where you get a change in the codon producing a different amino acid
This may produce a malfunctioning protein although most of the time it still doesn’t cause many problems depending on where it occurs

Question 15

What is the impact of amino acid substitution?

Answer 15

Physicochemical similarity between the two amino acids
Functional role of the specific domain of the protein
Phylogenetic conservation of original amino acid amongst diverse species

Question 16

What is meant by a nonsense point mutation?

Answer 16

This results in a premature stop codon being incorporated causing the shortening of protein
If it’s close to the end of a protein it might not have much of an effect but if its half way through it may produce a malfunctioning or inactive protein

Question 17

What happens when the mutation results in the insertion or deletion of a base?

Answer 17

Can be in-frame (multiple of three) or frameshift (not multiple of three)
Frameshift is much more likely to be damaging as it completely changes the following sequence of amino acids

In-frame (multiple of three) or frameshift (not multiple of three)
The same goes for deletion as for insertion