Final Flashcards
Law of addition
use when events are mutually exclusive. Adds to 1
Law of multiplication
use when events are independent
when is binomial distribution used?
to calculate when a particular distribution of events will occur in a sample (ex. 3 out of 5 affected)
variables in a binomial distribution
- P = probability of observing r incidences of type A events and n-r incidences of the other type(s)
- n = the total number of events
- r = the number of type A events of observed
- q = the probability of type A event occurring
- p = the probability of type A event not occurring (i.e. 1-q)
Hardy Weinburg Equilibrium
(p + q)^2 = p^2 + 2pq + q^2 = 1
which variable do we use for disease incidence in Hardy Weinburg?
q^2
AR: given q^2, what is the carrier frequency in a population?
2pq, and we can usually assume p is 1. (same applies for estimating carrier frequency in females for an x-linked disease given the number of affected males)
AD Hardy Weinburg
we assume homozygotes are rare, so p~1. So, frequency of the mutant gene is equal to 1⁄2 the incidence of the trait
Assumptions of Hardy Weinburg
Population in infinitely large, mating is random, allele frequencies are constant over time
Subtypes of nonrandom mating
consanguinity, stratification, assortative mating
reminder: be able to describe second cousins once removed, etc.
abc
Coefficient of relationship definition
R: Relates to a consanguineous couple and indicates the proportion of alleles that on average they would be expected to share by virtue of their relationship.
Coefficient of relationship calculation
(1/2)^ number of people between, multiplied by 2 if related through two people (ex, mom and dad).
Coefficient of inbreeding definition
F: Relates to the child of a consanguineous relationship and indicates the probability that, at a given locus, the child will receive two identical alleles derived from a common ancestor. I think it’s 1/2R.
autozygous
homozygous for an allele inherited from same ancestral source (used for consanguinity usually)
Coefficient of inbreeding calculation
F = 1⁄2 R
mutation rate of a gene (μ)
q (frequency of allele in a population) represents a balance between the mutation rate of the gene (μ) and the effects of selection (s) against the allele
μ=q x s
Fitness (f)
probability of transmitting one’s genes to the next generation compared to average probability for the population.
Coefficient of selection (s)
1 - f (a measure of the loss of fitness)
how does medical treatment affect f for AD and AR conditions
f is increased in AD, non affected very much in AR
In general, what is value of mu?
- μ = the mutation rate per gamete per generation
* ~10-5 to 10-6 per gene
what is risk for an AD condition in offspring on unaffected parents?
2μ (could arise in egg or sperm)
Prior probability that a female is a carrier of an X linked disorder is
4μ (many slides on this. Go through them)
directional selection
eliminates lethal dominant mutations, occasionally selects for a new mutation, pushes a population to homozygosity
Balancing selection
selection favoring heterozygotes, will maintain lethal recessive alleles, maintains/increases heterozygosity of population
Unstable selection
selection against heterozygotes, pushes population towards homozygosity, pushes populations to diverge
Genetic Drift
when the pool of gametes is formed for the next generation represents a random sample of alleles from the population (not representative of the population)
Founder Effect
when a small subpopulation breaks off from a larger population the allele frequencies may be different from those of the original population
Population Bottleneck
when a population is reduced to a very small number
LOF mutation
reduction or complete loss of protein function
GOF mutation
too much, too active, wrong time, wrong place, mutant protein gains a new function
Dominant negative mutation
nonfunctional mutant protein interferes with normal protein function
GOF associate with disease (homo/hetero)?
homogeneity
Which is more common- GOF or LOF?
LOF
Describe LOF in a recessive vs. dominant disease
In recessive, one LOF is fine because one working copy is enough. In dominant, LOF is not enough (haploinsufficiency)
Two hit hypothesis
dominant inheritance and recessive at cellular level
Mendelian condition
governed by single gene
Locus
A particular position on a chromosome
Allele
alternative variants of a DNA sequence
Polymorphism
the presence of two or more relatively common alleles in the population at a given locus
Haplotype
a given set of alleles at a particular locus (or cluster of loci) on a single chromosome
genotype
the set of alleles that make up a person’s genetic
constitution (collectively or at a single locus)
phenotype
the observable expression of a genotype as a trait
morphological, clinical, cellular, biochemical, behavioral….
Genetic heterogeneity
Allelic heterogeneity and Locus Heterogeneity
Locus Heterogeneity
where the same condition is caused by mutations at more than one loci (gene) *This can result in complementation in a recessive condition.
Allelic heterogeneity
different mutations (alleles) within a given gene cause the same condition. Common when the condition is caused by loss-of-function mutations. Variation in the severity of the mutations can be related to prognosis.
Phenotypic/clinical heterogeneity
different mutations in the same gene (different alleles) cause different conditions.
Homozygote
An individual with a pair of identical alleles at a nuclear locus
Heterozygote
An individual with two different alleles at a nuclear locus (usually one mutant/variant and one wildtype/reference, these individuals are often referred to as “carriers”)
Compound heterozygote
An individual with two different mutant/variant/non-reference alleles of the same gene
hemizygous
They only have one allele at a particular locus e.g. sex chromosomes in a male, deletion of one copy of a locus, Turner syndrome
Law of segregation
When an individual produces gametes, the two copies (alleles) of a gene separate so that each gamete receives only one allele
Law of independent assortment
The segregation of the alleles of one gene is independent of the segregation of the alleles of another gene (Note: this is only true if the genes are on different chromosomes or far apart on the same chromosome)
Penetrance
The proportion of individuals with a particular genotype who manifest that genotype in their phenotype. The probability that a genotype will have ANY phenotypic expression.
Expressivity
the degree to which a particular genotype is expressed in the phenotype
True dominant
Heterozygote is indistinguishable from homozygote. (Rare/nonexistent? amongst human disorders. )
Incomplete (semi) dominance
Homozygous individual has more severe phenotype than heterozygous individual.
Co-dominance
Heterozygotes show phenotypic effects of both alleles equally e.g. AB blood group
Can genes and alleles be dominant/recessive?
No, just phenotypes and inheritance patterns
How does consanguinity complicate x-linked conditions?
can make it look like there is male to male transmission, can produce homozygous females
anticipation
the tendency of a condition to become more severe (or have earlier onset) in successive generations
Pleiotropy
when one gene influences two seemingly unrelated traits
qualitative traits
dichotomous. discrete. Have it or don’t
quantitative traits
variable. Can be measured
sex-specific thresholds
If condition is less common in females, but a female has it, her relatives are MORE at risk than if she were a male with the condition
How do you measure familial aggregation?
relative risk ratio of prevalence of disease in relatives to prevalence in general population
Phenocopy
a mimic of a phenotype that is usually determined by a particular genotype produced instead by the interaction of environmental factors with a normal genotype e.g. breast cancer in a BRCA1/2 negative relative
Genocopy
a genotype that causes a phenotype similar to that determined by a different genotype
concordant
A pair of relatives who both have a certain trait are
heritability definition
How much of the variation in phenotype between individuals in a population is caused by genetic differences. Heritability is not a fixed property of a trait. If environmental factors change, heritability may increase or decrease
heritability calculation
Variance of a phenotype (VP) is determined by the sum of the individual causes of variation VP= VE+ VG.
Heritability is the proportion of total variance that is genetic h2=VG/VP
when does homologous recombination occur?
prophase of meiosis I
Do males or females have more crossover recombination?
females
syntenic
loci are on same chromosome
how many chromatids are involved in a crossover?
2, but can be several crossover events between different combinations of the chromatids
Theta of 0 means
loci are so close we don’t see recombination between them
Theta of 0.5 or 50% means
loci far enough away to assort independently or on different chromosomes
Linkage
tendency for alleles close together on the same chromosome to be transmitted together
Is linkage allele specific?
No, location specific
Linkage equilibrium
The combinations of alleles are seen with the frequencies that you would predict from the individual allele frequencies in the population (multiply each allele frequency together to get expected genotype frequency)
Reasons for linkage disequilibrium
allele entered population recently, loci are close together, loci relative to recombination hotspots, selection
linkage analysis
Try to determine if gene of interest (location unknown) is is linked to particular marker with known location
For an informative meiosis, one parent must be
heterozygous at both loci
Positive LOD score
likely to be linked
Negative LOD score
not likely to be linked
LOD (Z) score between -2 and 3
inconclusive
Association studies
population wide studies of alleles/haplotypes associated with phenotypes
cohort studies
pick a population and divide by presence/absence of allele. See who develops condition
case control studies
pick a group with condition, then pick matched controls. See you has allele/haplotype
Risk (or incidence)
number of people who develop condition over total number of people (people in numerator also included in denominator)
Odds
people who develop outcome over people who don’t (no one is in both numerator and denominator)
What measure do we use in cohort studies?
relative risk (expresses probability)- risk of disease in those with a particular allele
what measure do we use in case control studies?
odds ratio- odds of disease occurring in individuals with a particular allele over odds of disease occurring in individuals without the allele. “Having the allele give X times the odds of…” Compare to 1
when does OD approximate RR?
When disease is rare, odds ratio approximates relative risk
causes of association
causation, linkage disequilibrium, indirect effect, population stratification, type I error
Bonferroni correction
adjusts threshold for total number of questions asked to maintain low false positive
Interference
one crossover event reduces chance of another crossover event near by
Yield of microarray for ID/DD/ASD/MCA
~15-30%
