human and viral genetics Flashcards
define characteristics of autosomal dominant disorders
1 copy of mutated allele is sufficient to cause an individual to be affected, WT is recessive
affected parents can transmit to any progeny (male or female equally likely) and at every generation
with autosomal dominant disorders why aren’t typical ratios seen in humans?
due to small progeny sizes
what is Huntington’s disease?
an autosomal dominant genetic disorder that results in cerebral atrophy and neuronal death (specifically the dopaminergic neurons of the striatum in the basal ganglia)
causes motor dysfunction and cognitive decline
what common pattern/repeat is seen in Huntington’s?
what is classed as normal?
polyglutamine repeat - CAG repeats (CAG codes for glutamine)
the normal number is 36, any higher is concerning, the more repeats the earlier onset the disease
why are later generations affected earlier with HD?
CAG repeats are unstable and therefore prone to expansion in cell replication
this means the repeat expands when a parent passes it on to a child
this is known as anticipation
what specifically does Huntington’s affect and how
mutation in the HTT gene causes the protein to misfold and aggregate (when misfolded proteins come together)
this has many downstream effects on mitochondria, transcription, axonal transport etc..
autosomal recessive disorder - why doesn’t the phenotype appear in every generation?
it’s recessive - both parents have to be carriers
what is cystic fibrosis and how common is it?
1 in 22 are carriers, 1 in 2000 are sufferers
it’s a build up of thick mucus in the airways that can result in organ damage, as a result of a mutation to the CFTR gene that encodes for a Cl- channel responsible for hydrating the airways
are all cases of cystic fibrosis the same? how does this effect treatment?
mutations can be missense (single base change changes amino acid), nonsense (premature stop codon/termination of protein) or frameshift
different mutations cause different molecular phenotypes so treatment often differs, if someone has heterozygous mutations then they might need a combination of treatments as they have more than one issue with the Cl- channel, whether that be in trafficking, not made at all, less effective, made less etc…
what is the most common mutation in CFTR?
a deletion in phenylalanine
what is an X-linked disorder and what does this mean for the likelihood of inheriting/passing it on?
typically recessive - the mutation is found on the X chromosome
inheriting -
males can inherit it when only the mother is a carrier as they have a Y chromosome - nothing to dominate
females require both parents to be carriers to suffer
passing on -
males are unlikely to have descendants showing the phenotype as their male children get the Y, and female will most likely only be carriers
female carriers have a 50% chance of passing it onto male progeny and 50% chance of female progeny being carriers
themselves
while female sufferers have a 100% chance of passing it on to male progeny and 100% chance female progeny will be at least carriers
what are some cystic fibrosis treatments?
class I mutations (nonsense mutations) need production correctors
class II mutations need drugs to improve the intracellular processing of CFTR
class III and IV need drugs to recover CFTR function
Duchenne muscular dystrophy -
what gene does it effect and why is this an issue?
how it is inherited?
mutation in dystrophin gene, this protein acts as a bridge between actin cytoskeletal filaments and ECM, when defective the result is weakening of the muscles
Effects skeletal and cardiac muscle
dystrophin is largest human gene of 79 exons long
X-linked disease, exclusively passed on by the mother
what mutation is most common in Duchenne muscular dystrophy?
60% of cases are due to deletions of one of the exons, with a hotspot between exons 40-54
why does Becker’s dystrophy have less severe symtpoms?
also cause by deletions, but in-frame deletions, so the protein is made it’s just a bit shorter
what is a method of treating Duchene muscular dystrophy?
Use of antisense oligonucleotides
The idea is to block splicing machinery, to keep premature stop codons out of the mRNA, to prevent nonsense mutations and get that shorter, partially functional protein from Becker’s dystrophy
what are the characteristics of complex disease?
quite common (66% lifetime risk)
they are polygenic - multiple genetic components contribute (though these risk alleles are usually only suggesting susceptibility and are not deterministic)
environmental factors can effect
not inherited in a mendelian pattern as more than one genetic component ( and environmental factors) is involved, but does run in families
what is the point in identifying the genetic components involved in complex disease?
helps with early diagnosis and treatment
knowing the specific issues/molecular basis may help develop therapeutics/treatments
environmental risks can be identified and lifestyle changes made
what are the three categories of complex disease?
1) Small number of dominant alleles = large risks, e.g. Parkinson’s
2) Common disease common variant model (CDV = many alleles each give a small risk, e.g. type II diabetes
3) Intermediate - one major dominant allele exerts large effect, with maybe a few smaller contributing alleles e.g. breast cancer
what is an SNP? major and minor allele?
a single nucleotide polymorphism
this is just when a single nucleotide is changed
they are found in coding and non-coding regions
when looking at populations there is a major allele - the one with the greatest frequency
the second most common allele in the population is known as the MAF - minor allele frequency
define rare and common SNPs
rare SNPs have an MAF of < 5%
common SNPs have an MAF of > 5%
explain what linkage analysis is
looks for linkage between mapping markers and occurrence of diseases in families
It attempts to locate a disease-causing gene/s by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest
what is GWAS?
genome-wide association studies
search for alleles in a population that occur more frequently in disease cases than matched controls
define phenotypic variation and heritability
phenotypic variation = genetic variation + environmental variation
Heritability = the degree of variation in a phenotype within a population that is due to the genetic variation
how are twin studies used to investigate heritability?
twin studies can help calculate relative genetic and environmental contributions of complex traits, how much of it is genetics?
you compare monozygotic twins who are 100% genetically identical, with dizygotic twins who share 50% of alleles
both sets of twins will share an environment that is assumed to have equal influence on both
probably won’t be asked, but in twin studies what do A, C and E stand for?
A = genetic variance (constant for identical, variable for not)
C = common environment (constant for both)
E = specific environmental (variable for both)
explain what is meant by continuous phenotypic variation and use an example
it’s the idea that in complex disease there can be a wide variety of severity and symptoms, many loci can contribute to a disease, and in different combinations they can give rise to different phenotypes
an example of this would be major depression - it has 44 significant risk loci, with all humans carrying a different combo of these alleles, resulting in different phenotypes
some complex diseases have a threshold hypothesis for susceptibility - what does this mean? us an example and explain how it effects relatives differently for male and female?
when you reach a number of mutations in risk alleles, you get the disease, its either you have it or you don’t (opposite of continuous phenotype?)
an example is pyloric stenosis (causes vomiting in infants and is more likely to affect males as allele is on X chromosome)
female carriers carry more of the risk alleles as they’re XX so their relatives have far greater risk than relatives of affected males
