Population Genetics and Gene Mapping Lecture Oct 7 Flashcards
What is the ratio of variance?
It’s the proportion of the total variance (withing a population for a particular measurement) that is attributabel to the variation in the total genetic value.
What does heritability depend on?
the population
and the frequencies of the alleles in the population
What does alph1-antitrypsin do? Why are the different alpha antitrypsin genotypes of clinical interest?
alpha-antitrypsin is a major serum protein that inhibits proteolytic enzymes
a major target of the proteyolytic enzymes is leukocyte elastase, which can damage lung tissue if not down-regulated.
THere are 5 major alleles (M1, M2, Ms, S and Z) with the ZZ phenotype being the worst of - they only make 15% of the normal amount of alpha-antitrypsin
This means they don’t have enough alph antitrypsin to downregulate the leukocyte elastase prosteolytic enzyme, so it builds up and makes them more susceptible to emphysema and othe rlug diseases.
Who has the highest frequency of the alpha antitrypsin allele?
caucasians - especially Danes
Why is the alpha-antitrypsin gene an example of ecogenetics?
What are some other examples of ecogenetics?
It’s an example of ecogenetics because the genetic variation is susceptible to environment agents
this is evident because ZZ individuals who do not smoke are much better off than ZZ individuals who DO smoke.
other examples of ecogenetics: lactase deficiency and milk, fair complexion and UV light, ADH deficiency and alcohol, G6PD deficiency and fava beans, and many others
Why does heritability vary by population?
Because the frequencies of polymorphic alleles and disease associated alleles will vary by population
NO POPULATION IS WILD TYPE!! We are all susceptible to something.
What is the main example of a deleterious allele being maintained in a population due to heterozygous advantage?
THe beta globin S allele in africa - conferred heterozygous advantage against malaria
What is allele frequency and what is genotype frequency? WHich one is easy to figure out?
The allele frequency is the percentage of a particular allele in a population gene pool.
THe genotype frequency is the proportion of individuals in a population that have a certain genoypte.
Allele frequency is easier - you just count the alleles.
What do we need to use to fine genotype frequency?
The Hardy Weinberg Law
What are the 3 assumptions underlying the hardy-weinberg equation?
- population is large
- matings are randome
- allele freqnecy remains constant - not mutations, no negative selection, no genetic flux (immigration)
In terms of medical genetics, are we more interested if something is in Hardy-Weinberg equilibrium or dysequilibrium?
Dysequilibrium.
If alleles at a locus are NOT in HW equilibrium, this can indicate that a particular allele is associated with a disease
- that the aa genotype is selected against in an overall population
or
- the aa genotype is commonly found at a higher frequency in an affected population
What are the 4 different classifications of a function protein changes causing disease from a genetic mutation?
- loss of fucntion
- gain of function
- novel properties
- spatial and/or temporal dysregulation
Describe a loss of fucntion mutation. Example?
This is the largest category of disease causing mutation
they can occur in coding and non-coding gene regions
they can arise from a variety of mutations such as point mutations ,deletios and insertions
Examples include the beta-gloibn mutations (thalassemias), PAH in phenylketouria, and the p53 enzyme in cancer
Describe a gain of function mutation. Examples?
These can arise from two things: 1 increased gene dosage or 2. increased protein function
Down’s syndrome is an example that is probalby due to increased gene dosage
Achrondroplasia is an example of increased function - a point mutation results in overactivation of fibroblast growth factor receptor
What is an example of a disease arises from a mutation causing a novel property in th eprotein?
sickle cell disease - the sickel Hb chains aggregated when deosygenates leading to sickling of RBCs
What term describes the situation when different alleles of the same gene cause varying disease severity? Example?
Allelic heterogeniety
PAH in PKU is an example
WHat term describes the situation when mutations in different genes can yield clinical phenotypes? Examples?
locus heterogeneity
An example is the alterations in 5 different genes that can cause hyperphenylalaninemia
How can two siblings who inherit the exact same mutation end up having drastically different phenotypes (not reduced penetrance)
modifier genes
What is the classic example of a modifier gene?
ApoE
If you carry one or two (even worse!) alleles of the ApoE4 version, you are more susceptible to neurological disorders like Alxzheimer
ApoE is NOT the causative gene…it’s a modifier that can make it worse
WHat is the genetic mutation in Tay Sachs disease and what is the result?
It’s a mutation in the hexA gene
hexA is ubiquitously expressed, but the mutant phenotype will only result in the brain
you lose the enzyme needed to breakdown the Gm1 ganglioside sphingolipids so they buildup and cause neurological symptoms and death in early childhood.
More common in Ashkenazi - 1/27 carry the allele
What causes I-cell disease?
It’s caused by a defect in protein trafficking - the acid hydrolases that are required for lysosomes are not properly modified with the mannose 6 phosphate glycoprotein tag, so they get sent ou fot eh cell instead of into the lysosomes and you get a lysosomal storage disease
What is the incidence and carrier frequency of cystic fibrosis?
1/2500 in caucasians with 1/25 being carriers
What is the most common mutation in cystic fibrosis?
a deletion of a phenylalanin at 508
What is an example of a genetic disease caused by defects in structural proteins?
Muscular Dystrophy
Describe DUchennes Muscular Dystrophy
it’s an x-linked recessive disease
it is a mutation in the dystrophin gene
WIthout dystrophin, you can’t maintain muscle-membrane integrity because it’s needed to link actin skeleton to the ECM
THis means you get progressive muscle deterioration, leading to death by late teens
Why do 1/3 of DMD arise from new mutations in the sperm germline?
The gene is the biggest in the human genome, so there is lots of space for something to go wrong
Mothers who are carriers for the DMD mutation will display what sign?
No clinical manifestations, but will often show elevated creatine kinase levels
In what tissues are mitochondrial diseases most often found?
tissues with high energy demands: CNS and muscle
What are four characteristics of the inheritance of complex diseases?
- There is no simple Mendelian pattern of inheritance
- Familial aggregation- relatives are more likely to be affected as well
- Environmental factors play an important role
- Complex diseases are more common agmon close relatives of the proband with the greatest concordance between monozygotic twins
What are the two general approaches to identify a gene underlying a complex disease?
- you can test a candicate gene for variance in a disease population
of
- You can map a gene in a family that has a history of the disease
In terms of mapping disease genes, what does physical mapping entail?
It’s figuring out the actual sequence and physical location on a chromosome
Note that this is synonymous with structure but not usually function
The physical map is now complete with the human genome project, we just need the genetic map now.
In terms of mapping disease genes, what does GENETIC mapping entail (as opposed to physical mapping)?
This is the mapping based on the phenotypic traits within families
this does NOT require actual knowledge of the genes or the sequence
It indicates the relative position of genes (as defined by function)
What is the underlying prinicple behind linkage analysis?`
It uses statistics to determine whether two genes (the loci or markers they are based one) are likely to lie near on another based on the frequency that they are transmitted together as an intact unit during meiosis
the closer two things are on the chromosomes, the less likelyt they’ll be separated during recombination
What does it mean to say that 2 genetic loci are linked?
They are linked if they are transmitted together from parent to offspring more often than you would expect under independent inheritace
What is the recombination frequency?
WHat does an Rf > than 50% mean?
What does an Rf < 50% mean?
THe Recombination frequency is the likelihood of separation.
An RF equal or freater than 50% means the two genes (or markers) are NOT linked
An RT of less than 50% means they are linked
How can the recombination frequency be used to determine how far away two genes are from one antoher?
Rf pf 1% - 1 centimorgan (cM) unit of genetic disease (this corresponds to about 2 MB of sequence)
Once a gene is genetically mapped, how can it be ultimately identified?
It can be positionally cloned using the physical map as a guide
What does “determining the phase” mean?
You need to figure out whihc of two marker alleles is linked to the disease for any polymorphic marker within ANY ONE FAMILY because it can vary.
Specific alleles and markers on a chromosomes are considered “in phase” if they are coinherited from the same parent, meaning they were present together on a single transmitted gamete from that parent
HOw many generations are needed to determine the phase?
at least 3
Describe linkage equilibrium/dysequilibrium.
Equilibrium is when the frequencies of marker alleles and the frequencies of disease alleles correspond.
So if A = .7 and a - .3
then the disease alleles whould be linked to A in 70% of affected families and linked to a in 30% of affected families
If the frequencies vary, then they are indisequilibrium, which can mean the specific allele marker is VERY close to the disease gene
In other words, linkage dysequilibrium occurs when 2 genetic loci are found on the same haplotype more often than would be expected through random association
How is the liklihook of loci being linked expressed statistically?
Through LOD scores
it’s the liklihood that the data is true if the loci are linked
Statistically it asks if the RF is significantly different than 0.5.
Postivie LOD scores incidate the loci are likely linked (the greater the LOC, the higher the liklihood of linkage)
Negative LOD scores indicate the two loci are NOT linked.
How does association anlysis differ from linkage analysis?
One starts with a candidate gene in which one suspects a defect or polymorphism responsible for the disease
you then look within families and populations to determine if people with the disease are more likely to carry that particular mutation or polymorphism in the candidate gene
GWAS are a version of this on mass scale
Between linkage and associated, which is more commonly used in single-gene diseases? complex diseases?
Linkage analysis is used more often in single-gene diseases while association analysis is used more often in complex gene diseases.
Which has higher resolution, linkaeg or association analysis?
association analysis - as low as 10 to 50 kB
What markers are most often used today in association analysis? Because remember, we don’t need to know the actual gene to do this.
SNPs and SNP haplotypes
What did the GWAS use to identify SNPs associated with complex gene disease susceptibility?
SNP chips
Overall, the genetic variance accounted for by the different gene varients identified through GWAS is much lower than anticipated.
WHere is the rest of the genetic variability coming from them?
- exceptionally rare variants that were not detected on the SNP chips likely account for a significant portion
- copy number variation
- transposable elements
- gene switches in non-coding regions may be mutated
- transgenerational epigenetic effects
Ultimately, it’s just more complicated than we expected.
How does SIb-pair analysis work?
You use small families and ask whether affected siblings share specific gene aleles at a frequency higher than expected by random chance.
Can also ask whether an affected offspring and unaffected siblings share or do not share parental alleles.
In SIb-pair analysis, what does “identical by state” and “identical by descent’ mean?
Which one is more important for sib pair analysis?
Identical by state means that the alleles shared by the siblings are the same in what they are. So they both have the A allale or they both have the a allele, etc.
Identical by descent means that the alleles shared by the siblings were inherited from the same parent- either mom or dad.
For sib pair analysis, we’re concerned about identical by descent because we want alleles that were inherited with the disease alleles - and they’re have to be on the same gamete to mean anything to us.
