Genetics 2 Flashcards
Prevalence of multifactorial diseases
60% of the population
Prevalence of single gene disorders
2% of the population
Prevalence of chromosomal and genomic disorders
0.38% of the population
Quantitative trait is defined as
Something that can be measured
Quantitative trait - usually determined by
many genes
Alleles can be contributing or noncontributing to the trait
In multifactorial diseases, the quantitative trait is
Liability or disease
The liability to the disorder is what you are measuring
Multifactorial diseases are described by what model
The threshold model
Many genes and environmental factors are involved
Threshold of liability
Everyone has liability - might be different for M and F
The lower the threshold, the more affected by the disease you are
If a multifactorial disease is more common in M it means what about their threshold
It is lower (so they have more liability/disease)
Implications of the threshold model - each birth of an affected child does what
Each birth of an affected child changes the risk analysis
Means that between the parents there are enough contributing alleles to cause disease
Birth of another affected child seems more likely
Implications of the threshold model - Birth of a child of the less affected sex does what
Increased the risk even more
Between the parents there are enough contributing alleles to cross a higher threshold of liability
Implications of the threshold model - in own words
If parents have one affected child, they now belong to a different population - when a child with a disorder is born, the curve is shifted so the chances of having another affected child increase (threshold decreases)
Pyloric stenosis - more common in who
boys
Pyloric stenosis - Threshold for parents with an affected boy vs. threshold for parents with an affected girl
Threshold for the parents with the affected boy is lower (so liability is larger)
Pyloric stenosis - Risk for parents with an affected boy vs. an affected girl
Risk with an affected girl is higher because there are more alleles between parents because the threshold was higher
Pyloric stenosis - what are the scenarios
Higher risk
Lower risk
Higher threshold
Lower threshold
Pyloric stenosis - Recurrence risk for a family with an affected girl
Always lower than having a boy because girls have a higher threshold
Pyloric stenosis - males need fewer contributing alleles to express the disease than females (their threshold is lower) so a family with an affected female proband
has more contributing alleles than a family with an affected male proband
What is an example of a multifactorial disease that is more common in girls
Hip dysplasia - so if you have a boy with hip dysplasia, the risk is much higher for the next generation
Multifactorial diseases - environmenral and genetic contributions
All multifactorial diseases have environmental and genetic components
How do we dissect or quantify the environmental vs. genetic contributions
Observe concordance and discordance with twin and adoption studies
Dissecting environmental and genetic contributions - concordance
The pair has the same trait
Dissecting environmental and genetic contributions - discordance
the pair is different from one another
Dissecting environmental and genetic contributions - twin studies
Compare concordance in pairs of monozygotic and dizygotic twins
Dissecting environmental and genetic contributions - adoption studies
Compare adopted children to their biological and adopted parents
Twin studies - monozygotic twins vs. dizygotic twins
Mono - genetically identical
Dizygotic - share 50% of their genes
Twin studies - what is the assumption that is made with MZ and DZ twins
They grow up under similar circumstances
Twin studies - if concordance in MZ is higher than in DZ, then the trait has what
Higher genetic component
Heritability can be estimated as (H^2) =
(concordance MZ - concordance DZ) x 2
The higher the heritability, the higher the
genetic component
Mapping of complex traits - what is it
Model free linkage analysis through association studies
Analyze whole genome for polymorphisms (sequence deviations) in affected families
Looking for polymorphisms that are associated with disease
Mapping of complex traits - what is the goal
Trying to find a polymorphism in a pedigree that correlates with a disorder
Tracking inheritance of polymorphism and trying to correlate it with inheritance of the disease
Polymorphism is what
You don’t know what gene it is or what it does but if the nucleotide of the polymorphism is associated with a disease, the gene that causes the disease should be close by because it tends to transmit together with the polymorphism
Genome wide association studies
Compare SNPs in patients and controls
Calculate odds ration for each SNP
Find SNPs that are strongly associated with the disease
Genome wide association studies - examble
Measured trait of circulation in skin and mapped polymorphism to circulation in skin
Then look to see at what locust you see a strong correlation with a phenotype and polymorphism
Risk analysis - relative risk ratio is what
a way to describe multifactorial diseases
What does a relative risk ratio of 1.5 for siblings mean
Siblings of affected individuals are 1.5 times as likely to develop the disease than the general population
Disease association of allele - in multifactorial diseases
there is a correlation between a particular allele and disease
Relative risk is a way to describe the disease association of an allele
Relative risk describes what
how much more likely a carrier of an allel is to develop the disease than a non carrier
If the relative risk for allele X is 1.5 this means you tell your pt that
If we find that you are a carrier of allele X, your risk is 1.5 times the risk of a non carrier
Relative risk ratio vs. Relative risk
Ratio - no genetics, all family hx and pedigree
RR - molecular genetics
Characteristic inheritance of multifactorial diseases - what do they follow
NOT mendelian
They are determined by the threshold model
Characteristic inheritance of multifactorial diseases - Multifactorial diseases show ____ ____
Familial aggregation - it does run in families
Characteristic inheritance of multifactorial diseases - multifactorial diseases frequently show what kind of penetrance
Incomplete penetrance
Because it has an environmental component that can be modified
Characteristic inheritance of multifactorial diseases - disease is much more common among who
close relatives of proband than it is among less closely related persons
Characteristic inheritance of multifactorial diseases - Recurrence vs. Occurence
Threshold model explains why they recurrence risk is higher than the occurrence risk
The more affected children that are born to a couple, the higher the assumed number of contributing alleles in the parent generation - every time an affected child is born into a family, the recurrence risk has to be corrected upwards
HLA Haplotypes and Diabetes - HLA haplotypes are associated with what
Autoimmune disorders
HLA Haplotypes are inherited how
as blocks
they are codominant
HLA haplotypes - variation in the HLA region accounts for what percent of genetic risk for T1D
40%
HLA haplotype - which genetic variation affects risk for T1D
DR-DQ haplotypes
HLA haplotype - susceptibility alleles
The DR-DQ haplotypes hat increase the risk for T1D
HLA haplotype - protective alleles
The DR-DQ haplotypes that decrease the risk for T1D
Population genetics - Polymorphic means what
an allele present in more than 1% of the population is called polymorphic
Population genetics - polymorphisms - which genes have a high degree of polymorphism
HLA haplotypes
Population genetics - polymorphisms - which genes are non polymorphic
Histones
Population genetics - polymorphisms - Positive thing about HLA haplotypes (with high degree of polymorphism)
Good because everyone has a different resistance
Population genetics - non polymorphic like the histones - how do they become non polymorphic
Streamlined so much that any mutation in the gene will compromise the function and be incompatible with life
The hardy-weinberg principle
Hardy and Weinberg developed a simple model for the distribution of alleles in a population
The HW principles - The model makes what four assumptions
The population in large
All genotypes have the same fitness
Mating is random
No influx or efflux of alleles from the gene pool
HW principles - The model predicts that allele frequencies __ change over time
WILL NOT change over time
A rare allele right now will still be a rare allele 100 years from now
The HW principle - the equations allow to calculate what
Allele and carrier frequencies - make connections between the gene pool and the population
The reality - Genetic drift
Populations can be small and rare alleles can be lost by chance
The reality - Selection
Selection selects against mutant alleles
Homozygoud mutant have reduced fitness, so then alleles disappear from the population
The reality - Assortative mating
People who are genetically similar mate (homozygous) - and then you still have the same number of mutant alleles in the pool, but the distribution has changed and
Assorative mating increases the amount of homozygosity in a population
The reality - Bottleneck and Recovery
Bottleneck event where some catastrophic event wipes out most of the population - often heterozygotes are the ones that survive - and then the population that recovers has the allele frequency reflecting the survivor pool and not the initial population
The reality - Bottleneck leads to
the amplification of rare alleles that give carriers a selective advantage
The reality - bottleneck and recovery will do what to the allele frequency in the pool
Change it
Selection and genetic drift will do what do the allele frequency in the pool
Change it
Assortative mating will do what do the allele frequency in the pool
NOT change it! It will just change the fraction of homozygous individuals
The effects of selection - selection ___ the frequency of alleles that ___ fitness
Reduces the frequences of alleles that reduce fitness
The effects of selection - Dominant mutant alleles
Disappear quickly if not constantly regenerated by new mutations
New mutations make up for the disappearance of old mutations due to fitness
Positive selection - who has the advantage
Heterozygotes often have an advantage - wider spectrum of enzyme activity
Positive selection - Some alleles provide advantage only in what state
Heterozygous
and will cause disease when homozygous
Positive selection - it is hypothesized that what event selects positively for heterozygotes
Typhoid fever may select for CFTR mutations - people with mutation of CFTR have less severe typhoid fever
Malaria may select for B hemoglobin mutations
Founder Effect - what was the in class example
Ellis van Crefeld Syndrome (EVS)
Many members of community are descendants of the founder - marriages became consanguineous - no influx of new alleles and so can’t avoid consanguinity
Polymorphisms and disease - Polymorphisms may be at the root of many susceptibilities - what was example in class
Vit D receptor is a polymorphic gene
This polymorphism is correlated with increased risk of diseases like cancer and diabetes
