Describe the characteristics of the autosomal dominant inheritance pattern
- most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance)
- males and females are equally likely to inherit the allele and be affected
- the risk for each child of an affected parent is 1/2
- if an unaffected individual’s siblings/children are not affected, and they do not carry the mutation, then they cannot pass it on to their own offspring
What is penetrance?
The percentage of individuals who carry the mutation AND develop symptoms of the disorder, many dominant disorders show age-dependent penetrance
List and describe some features of autosomal dominant inheritance patterns
VARIABLE EXPRESSIVITY: It is the variation in the severity/symptoms of the disorder between individuals with the same mutation.
NEW MUTATION RATE: the de novo mutation rate varies considerably between AD conditions
SOMATIC MOSAICISM: new mutations arising at an early stage in embryogenesis - present in only some tissues/cells
GERM-LINE MOSAICISM (gonadal mosaicism): new mutation arises during oogenesis or spermatogenesis - mutation must be present in a variable proportion of gametes; can be transmitted to offspring
ANTICIPATION: the worsening of disease severity in successive generations - characteristically occurs in triplet repeat disorders
Describe the characteristics of autosomal recessive inheritance
- manifest in homozygous/compound heterozygous form
- carriers (heterozygous) not affected
- both sexes affected
- male to female and female to male transmission
- usually, one generation affected
- may be consanguinity (eg. cousin marriages)
What is the difference between compound heteroygote and homozygote?
Compound Heterozygote:
- two mutations are in the same gene
- the mutations are different
Compound Homozygote:
- two mutations are in the same gene
- they are identical mutations
- (may suggest consanguinity)
List some features of autosomal recessive inheritance
- the traits are often found in clusters of siblings, but not in parents and offspring
- the recurrence risk is 1/4 for each sibling of an unaffected person
- the carrier probability is 2/3 for unaffected siblings of the affected person
- all offspring of the affected person are obligate carriers
Describe how the difference in sex chromosomes affects X-linked inheritance
Women have 2 X chromosomes.
- thus, they have two copies of X-linked genes, giving slight protection
- they can be homozygous or heterozygous for these disorders
Men have one X and one Y chromosome.
- thus, they only have a single copy of X-linked genes
- they are said to be hemizygous
How is X-linked inheritance either recessive or dominant?
RECESSIVE:
- women are carriers + unaffected
- no male to male transmission
DOMINANT:
- women are affected
- males more severely affected/lethal
Describe the characteristics of X-linked recessive inheritance
- X-linked genes are never passed from father to son
- all daughters of affected males are obligate carriers
- children of carrier females have a 50% chance of inheriting the mutant allele
Skewed X-Inactivation: normally, the majority of genes on one of a woman’s X-chromosomes are inactivated (it’s generally random, but ~10% of women have uneven or skewed X-inactivation)
Manifesting Carriers: some women have some symptoms in X-linked recessive conditions (eg. cardiomyopathy in DMD)
List the types of mutations and where they are found
Types of mutations:
- substitutions (point mutations)
- deletions
- insertions
Found in:
- coding DNA
- non-coding DNA (such as promoters and introns)
What is a silent substitution?
When there is a nucleotide change that does not change the amino acid made
How do we determine the impact of an amino acid substitution?
- physicochemical similarity between the two amino acids
- functional role of the specific domain of the protein
- phylogenetic conservation of the original amino acid amongst a diverse species
