Genetics Flashcards
1
Q
Single gene mutations: Base substitution (3)
A
Silent mutation: change in base pair, but same protein
Nonsense mutation: changes that result in a stop codon
Missense mutation: changes that affect amino acid produced by codon
2
Q
Single gene mutations:
Indels
A
- Frameshift mutation: Alters the reading frame significantly if deletions don’t occur in multiples of 3 –> results in a completely different sequence of amino acid which completely alters the protein or result in a downstream stop codon
- If indels occur in multiples of 3, then it will truncate the protein but might maintain some semblance to original protein
3
Q
Autosomal dominant pedigree
A
- Vertical transmission
- Passed from fathers and mothers to sons and daughters
- Male-to-male transmission (i.e. no X-linked features)
- If 1 parent has the disease, 50% chance offspring will have disease
4
Q
Autosomal dominant pedigree:
- Penetrance, expression, mosaicism, de novo
A
- Penetrance: black or white –> complete penetrance vs incomplete penetrance (= “skipped” generation); the ability of a known disease-causing genotype to exhibit the disease phenotype
- Expressivity: same genotype, but variable (always present) phenotype, differing severity of disease, complete penetrance
- Mosaicism: more than 1 genotype in different cells; suspect gonadal mosaicism if normal parent and 2 or more affected offspring
- De novo: spontaneous mutation
5
Q
Autosomal recessive pedigree
A
- Disease is seen in siblings in single generation
- Males and females equally affected
- Fathers and mothers can each transmit an abN allele
- Parents of affected person are usually carriers/unaffected
- Risk for 2 heterozygotes to have an affected child is 1/4, carrier risk for a sibling is 2/3, wildtype homozygous (i.e. normal child) 1/3
- Consanguinity increases the risk of AR conditions
6
Q
2/3 rule
A
- If there is an AFFECTED offspring, the risk of the sibling being a carrier is 2/3
- -> But beware, the 2/3 rule only applies to siblings of an affected individual.
- Therefore, the carrier risk of a person with WITHOUT an affected sibling will be 2/4 = 1/2
7
Q
How do you work out the incidence of a recessive condition?
A
Square the carrier frequency and multiply by 4
E.g. Friedrich ataxia has carrier frequency of 1/100
Incidence = (100x100)x4 = 1 in 40,000
8
Q
How do you work out carrier frequency in a recessive condition?
A
Opposite of incidence!
- Divide incidence by 4 and square root of that number
9
Q
X-linked inheritance
A
- X-linked recessive:
- -> 1/4 risk of an affected male child in each pregnancy from female carrier
- -> All daughters of a male with an X-linked dz = obligate carrier
- X-linked dominant:
- -> 1/2 risk of an affected male child in each pregnancy from female carrier
10
Q
X-inactivation
A
- Females have 2 X chromosomes and only 1 X is active in any one cell due to X-inactivation
- X-inactivation process is usually random –> 50:50 split between maternal and paternal inherited X-chrom being active in 1 cell
11
Q
Non-random X-inactivation
A
- Skewed X-inactivation: e.g. 90:10 instead of 50:50
- A female carrier would mainfest condition if X-inactivation is non-random and skewed towards abnormal X
- Can result in X-linked recessive disease and can protect from X-linked dominant disease
12
Q
Anticipation
A
- Seen in triplet repeat disorders
- Disease gets worse over successive generations due to increase in repeat numbers
13
Q
Mitochondrial inheritance
A
- Mitochondrial DNA is only maternally inherited
- Affected mother can pass down to both son and daughter
- An affected male will not pass down mutated mitochondrial gene to their offspring
- Heteroplasmy: some mitochondria have mutations and others don’t in a cell
14
Q
Mitochondrial bottleneck
A
- Not all mitochondria are replicated equally to daughter cells during oogenesis
- Mitochondrial load of each daughter cell dictates likelihood of dz (difficult to predict)
E.g. asymptomatic Mo can have profoundly dz child - Cannot use maternal mutant load to predict foetal mutant load
15
Q
Mitochondrial vs X-linked inheritance
A
- No male to male transmission
- X-linked: sons are affected, daughters are less severely affected
- Mitochondrial: sons and daughters are equally affected and descendants of affected male cannot have the dz
16
Q
Autosomal dominant: homozygote
A
- Usually heterozygote (AD dz are caused by mutation in only 1 copy of gene)
- Homozygote AD are usually genetically lethal
17
Q
How can a female offspring have the disease phenotype in an X-linked recessive inheritance?
A
- If father has the disease (Xa,Y) and mother is a carrier (Xa,x)
- Skewed X-inactivation
18
Q
Imprinting
A
- Parent of origin!!! is important
- Imprinting silences gene expression
–> Maternally imprinted gene = gene is inherited from mother is silent and the gene from father is expressed
and vice versa - Imprinting of an abnormal allele switches off the mutation –> no disease
- Imprinting is reset in each generation: methyl tags stripped during gametogenesis, imprinting pattern rewritten in ovaries/testes in before passing down to offspring
19
Q
Imprinting “pedigree” example explanation
- Remember: imprinting disorder and imprinting pedigrees are different things
- Imprinting disorder = abnormality in imprinting process
- Imprinting pedigree = normal imprinting process, but inheritance of mutated gene
A
Paternally imprinted gene example:
- Female offspring (K) has: Ai,a –> mutated allele imprinted so not expressed (from father)
- Imprinting is reset during gametogenesis: gamete has a chance of having A or a
- If K passes down A, this mutated gene will no longer be silenced because it is a PATERNALLY imprinted gene and it’s the mother (K) passing it down
- K’s offspring will have the disease phenotype
20
Q
Imprinting pedigree: maternally imprinted genes
A
Maternal imprinting:
- All affected persons inherit mutated gene from father (so there is half a chance that his offspring will have dz)
- No affected children from females
- Mothers with mutated genes silence it when they pass it on to offspring
- Half the children of a male will express the dz
- Imprinting is reset when passed onto next generation
