Patterns of inheritance Flashcards
What are the classic mendelian models of inheritance?
Autosomal Dominant
Autosomal Recessive
X-linked
Y-linked
Describe the autosomal dominant allele.
- Manifests in heterozygous form, meaning only one mutated allele needed to inherit condition
- Multiple generations affected
- Most will have affected parent (not all due to new mutations and incomplete penetrance)
- 50% risk of transmission to offspring
- if an affected individual’s siblings/children are not affected and they do not carry the mutation, they cannot pass it on to their offspring
give some features of autosomal dominant inheritance.
Penetrance Variable Expressivity New mutation rate Somatic (post-zygotic) mosaicism Germ-line (gonadal) mosaicism Anticipation
Define penetrance.
% of individuals who carry the mutation (genotype) AND develop symptoms of the disorder (phenotype)
-many dominant disorders show age-dependent penetrance, e.g. the older a person is, the more likely they are to develop the condition if carrying a susceptible genotype
Describe the autosomal recessive allele.
- manifested only in homozygous/compound heterozygous form (both mutated alleles have to be present to inherit the disorder)
- carriers not affected
- usually one generation affected
- may be consanguinity (e.g. cousin marriages)
- e..g. Cystic fibrosis (manifests in homozygous and compound heterozygous form)
Describe Reduced/Incomplete penetrance.
Not all individuals with a mutant genotype show the mutant phenotype
e.g. person with mutation does not develop symptoms of disorder
Give some features of autosomal recessive inheritance.
- trait found in clusters of siblings but not in parents and offspring
- recurrence risk= 25% for each sibling of affected person
- carrier probability= 2/3 for unaffected siblings of affected person
- all offspring of affected person are obligate carriers
Define variable expressivity.
Individuals with the same genotype may have different phenotypes
e.g. variation in the symptoms of disorder in individuals with the same mutation (neurofibromatosis 1)
What is X-linked inheritance?
A pattern of inheritance in which a recessive gene is carried on the X chromosome, so males are more likely to be affected because they are hemizygous (one X and Y chromosome)
Recessive X-linked:
- women are carriers + unaffected (unless skewed X inactivation)
- no male to male transmission
Dominant X-linked:
- women are affected
- males are more severely affected/lethal
Give some features of X-linked Recessive inheritance.
- X-linked genes never passed from father to son (sons get X from mother)
- All daughters of affected males are obligate carriers (daughters get one X from father)
- Children of carrier females have a 50% chance of inheritance mutant allele
Somatic (Post-zygotic) Mosaicism
new mutation arising at early stage in embryogenesis
- present in only some tissues/cells
- some cells will contain mutation, but majority don’t
e. g. Trisomy 21
Are women not affected by X-linked recessive disorders?
The EXPECTED is that women are not affected by X-linked recessive disorder, however this is not always the case due to skewed X-inactivation
What is Germ line (gonadal) Mosaicism?
new mutation arises during oogenesis or spermatogenesis
-mutation present in variable proportion of gametes and can be transmitted to offspring
What is Skewed X inactivation?
occurs when the inactivation of one X chromosome is favoured over the other, leading to an uneven number of cells with each chromosome inactivated
causes manifesting carriers, with symptoms of X-linked recessive conditions e.g. cardiomyopathy in DMD
What is meant by anticipation?
worsening of disease severity in successive generations
-occurs in triplet repeat disorders (e.g. Huntington’s Disease)
What is Y-linked inheritance?
- mutation is always and only passed from fathers to sons
- example is a form of hirsutism between fathers and sons (hairy ears)
What does a pathogenic mutation cause?
Alteration of the function of the gene product and can cause a disease phenotype
What are the different types of mutation?
substitution, deletion, insertion
Where can mutations be found?
Coding DNA
Non-coding DNA (e.g. promoters and introns)
What is a Silent/Synonymous Base Substitution
This is a mutation where a nucleotide changes without the amino acid changing due to the degenerate code
-silent mutations are caused by mismatch repair system not functioning properly
What is a Point Mutation- Missense/Non-synonymous?
A mis-sense mutation is when a base substitution causes for a change in amino acid
incorrect amino acid may produce malfunctioning protein (if amino acid very different then more likely to be pathogenic, but if very similar it might not have an impact on protein)
What is a Point Mutation- Nonsense/Non-synonymous?
A nonsense mutation is when there is a premature stop codon resulting in a truncated protein
Can cause removal of functional parts of protein and shortening of protein
However, mRNA strand can sometimes be degraded by nonsense mediated decay
What is a frameshift mutation?
mutation that involves the insertion or deletion of a nucleotide in the DNA sequence
Which mutations are most likely to be pathogenic?
Nonsense mutations and frameshift mutations
