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Phenylketonuria (PKU)
- Autosomal Recessive
- "Mendellian" (not really)
- allelic heterogeneity / compound heterozygotes
- clinical heterogeneity
- locus heterogeneity
- treatment / screening
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Quantitative
- Continuous phenotype
- e.g. blood pressure, height, etc
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Qualitative
Binary - have phenotype or not
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Polygenic
Goverened by more than one gene
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Multifactorial
- Multiple genes
- Environmental effects
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Complex
Encompasses quantitative, polygenic, multifactorial, and everything else
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Additive inheritance
Larger n -> normal distribution, where n is number of genes adding to phenotype
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Threshold model
e.g. diabetes: you have it if you reach a certain blood/glucose level
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Family aggregation studies
Compare ratio of blood relatives to general population
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1st degree relatives
- 50% common genes
- e.g. siblings, parents
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2nd degree relatives
- 25% common genes
- e.g. grandparents, aunts, uncles
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3rd degree relatives
12.5% common genes
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lambda_siblings
- (prevalence of siblings) / (prevalence in general population)
- If lambda > 1, then genetic
- Big drop between primary and secondary
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Case control studies
Compare your freq with someone's similar to you (e.g. spouse)
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Adoption studies
- Look at adopted child vs. biol parents
- Look at adopted child vs. adopted parents
- e.g. Schiophrenia determined to be biological
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Twin studies
Concordance
Discordance
- Monozygotic: approx 100% identical
- Concordance: % shared betweeen identical twins
- Compare to dizygotic twins
- If significant difference, genetic effect
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Why monozygotic twins aren't 100% identical
- Somatic mutations
- X-inactivation
- epigenetics
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Heritability
- Proportion of phenotypic varion due to genetic causes
- Typically from 0 to 1 (but can be >1)
- Difficult to measure in humans, but twin studies help
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Heritability calculations
- (var in dizygotic - var in monozygotic) / (var in dizygotic)
- 2 (Concordance_monozygotic - Concordance_dizygotic)
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What is an association study used for?
- Finding a correlation between a genetic variation and the condition being studied
- Look at whole genome for SNP variation within affected group and compare with control group to identify variants
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What is a rare variant with respect to association studies?
- All variants found in a study do not usually account for total genetic variability
- Rare alleles/variants do not usually show up in these studies
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How do copy number variants affect association studies?
- Copy number variants (CNVs) are larger repeats that can't be found with association studies.
- Another reason why association studies don't account for total genetic variability
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What is the common variant hypothesis?
The hypothesis that variants that cause common disorders are common throughout the population
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What is an example of a "simple" multifactorial disorder?
Digenic retinits pigmentosa
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What is an example of a "complex" multifactorial disorder?
Alzheimer disease
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Why are DNA markers useful?
They are a way to look at a variation without looking at the protein that is encoded by the gene
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Describe minisatellites (VNTRs)
- 10-50bp repeats
- Can be heterozygous for number of repeats, n
- n varies due to crossing over/recombination
- Found near telomeres
- Can be found in more that one locus
- Function not known
- Once used in fingerprinting, but probabilities of alleles unknown, so not ideal
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Describe microsatellites (or Short Tandem Repeats -STRs)
- 1 to 4bp repeats
- n can vary, but usually less than 100
- Used in mapping human genome
- Easily scored by PCR by size
- Used in forensics typically looking at 13 loci
- Probabilities can be estimated because alleles are known
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Single Nucleotide Polymorphisms (SNPs)
- 1/300 base pairs
- More common than other markers
- Made more useful with DNA chips
- Most changes probably benign
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Restriction Fragment Length Polymorphisms (RFLPs)
- First DNA markers
- Technique that detects difference in size between samples of homologous DNA molecules
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Polymorphism (population genetics)
- Two or more alleles where at least all appear in more than 1% of the population
- By setting the cutoff at 1%, it excludes spontaneous mutations that may have occurred in — and spread through the descendants of — a single family.
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Indels
- "Insertions/Deletions"
- Nucleotides that have been duplicated in or deleted from the genome
- Very common
- Typically outside of genes
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Copy Number Variants (CNVs)
- Large sequence variants
- Some are apparently harmless
- Usually tandem repeats
- Seen in schizophrenia
- Also exist as inversions
- Not visible with light microscope
- Differences in "normal" people and certain diseases
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Comparative genome hybridization
- Compare patient and control DNA on an array.
- Spots corresponding to sequences that are increased in patient give a different color
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DNA Fingerprinting (mini-satellites)
- Outdated
- Diagram does not show locus - just comparing patterns
- Don't know probabilities
- Still useful for paternity testing
- Used when suspect was tested for a reason, e.g. pitchfork murder case
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Microsatellite Profiling: CODIS (Standard)
- 13 Loci
- PCR gives size due to number of repeats
- Probabilities can be estimated because allelic frequencies are known
- Used in cold cases
- Used in Sykes family analysis
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Base Pair Substitution
- Mutation where one base is substituted for another
- Probably occurs during DNA replication
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Triplet Repeats
- Found in humans from Human Genome Project
- e.g. Huntington's
- Mechanism unknown
- Usually increase in number
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Depurination
- Typically lose A or G
- Lose ~5000/day/cell
- Usually repaired
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Deamination
- Lose amino group from base/cytosine
- About 100/day/cell
- Typically replaced by Oxygen (C->U)
- Usually repaired, but can be blocked by methyl groups
- Can lead to transition: GC->AT
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Mutational Hotspot
- Different mutagenic processes are overrepresented among single base pair substitutions.
- Methyllation of cytosine blocks repair at "CG" doublets resulting in transitions
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Replication errors
- Most replication errors are repaired during "proofreading"
- 10^(-10) per base pair per cell division
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Estimating Germline Mutation Rates in Humans
- Number of new muttions per locus per generation
- Measure incidence of new autosomal dominant or X-linked disease that is fully penentrant at birth
- e.g. Achondroplasia: 7 out of 242,257
- i.e. 7 mutations out of 2*242,257 alleles
- Typically range from 10^-4 to 10^-7
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Sex Differences in Mutation Rates
- More rounds of replication in spermatogenesis over the lifetime, leads to more mutations in highly penetrant dominant diseases.
- However, other diseases may have specific biological origins that lead to greater incidence in female gametogenesis
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Rare variants
alleles with frequencies less than 1%
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Loss of Function recessive mutations
- Loss of protein function is common
- e.g. Phenylketonuria (PKU)
- Can cause damage in brain due to lack of enzyme to break down phenylalanine
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Gain of function dominant mutations
- Enhances normal function of a protein
- e.g. Huntington's disease (triplet repeat)
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Haploinsufficiency dominant
- Diploid organism has only single working copy of gene, but needs both for wildtype expression
- e.g. Waardenburg syndrome, deafness caused by one defection copy of gene
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Dominant-negative mutations
- Mutations that act in opposition to normal gene function.
- e.g. osteogenesis imperfecta, where mutant disrupts normal expression of two types of proteins
- In this case, would be better to have a mutation that has no gene product
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Assumptions of Hardy-Weinberg Law
- Large populations with random matings
- Allele frequencies are constant
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Hardy-Weinberg Law
p=freq(A)
q=freq(a)
- p^2 + 2pq + q^2 = 1
- p^2 =freq(AA)
- q^2=freq(aa)
- 2pq=freq(Aa)
- The population genotype frequencies will remain constant if the allele frequencies remain constant
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How are primers and PCR used to detect a deletion?
If the deletion contains the primer, then amplication will not occur.
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What is "stratification"?
Within a large population, subgroups are more likely to mate within their own subgroup.
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What is positive/negative assorted mating?
Chosing a mate with similar/different phenotype.
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Stratification results in a ____ frequency of homozygotes for the whole population than what would be expected on the basis of HWE for the entire population.
higher
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Mating on the basis of difference in HLA status will result in ___ ____ genotypes than would be expected by HWE. This is an example of ___ assortive mating.
- more heterozygous
- negative
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Mating on the basis of height, IQ, skin color, etc., will result in ___ ____ genotypes than would be expected by HWE. These are examples of ___ assortive mating.
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Inbreeding leads to an increase in _____ genotypes for all loci in the genome.
homozygous
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First cousin marriages range from ____ in some human popluations.
1% to 5-10%
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Identity by Descent
- Two or more alleles are identical by descent (IBD) if they are identical copies of the same ancestral allele.
- Common in inbreeding
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The probability of a child of first cousin parents becoming ____ from a grandparent is ___ which is also the ____.
- homozygous by descent
- 1/16
- inbreeding coefficient
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P(aa) = ____ in first cousin matings vs. q^2 for unrelated parents
15/16q^2 + 1/16q = q^2 + 1/16pq
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Define consanguinity
Union of individuals related to each other as close as or closer than second cousins.
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As the frequency of a decreases, the ratio of aa offspring from related parents to unrelated parents ____.
increases
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Calculating fitness (W)
Divide the mean number of offspring produced by a genotype by the mean number produced by the most prolific genotype
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Selection coefficient (s)
- The relative intensity of selection against a genotype
- e.g. tay-sachs - no reproduction: s=1
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Calculating the selection coefficient
s = 1 - W
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Genotypic frequency: f(AA)
f(AA) = (number of AA individuals)/N
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Allele frequency: p = f(A)
f(A) = (2nAA + nAa)/(2N)
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Calculate allelic frequencies from individual frequencies
p = f(A) = f(AA) + (1/2)f(Aa)
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Calculate allelic frequencies at X-linked loci
p = f(XA) = (2nXAXA + nXAXa + nXAY)/(2nfemales + nmales)
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Calculate allelic freq's at X-linked loci from individual frequencies
p = f(XA) = f(XAXA) + (1/2)f(XAXa) + f(XAY)
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When a population is in Hardy-Weinberg equilibrium, the genotypic frequencies are determined by ...
the allelic frequencies
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Gene Flow / Migration
- Transfer of alleles/genes between populations
- e.g. african amerians due to slavery
- e.g. pku: common to celts - can follow "transmission" thruout the world
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Autosomal dominant alleles with decreased fitness tend to ___ in frequency until it reaches ___.
p=___
- decrease
- an equilibrium
- mutation rate (u)/s, a->A
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Selection against autosomal recessive alleles is ___.
- inefficient
- q = sqrt(u/s)
- q = sqrt(u) if s = 1, i.e. fitness of AA and Aa genotypes are 1.0.
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For an autosomal recessive allele, if s=1, the change in frequency is q_n =
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For X-linked Recessive, q = ___.
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In X-linked recessive alleles, ___ of the X chromosomes belong to women, so ___ of the X-linked alleles do also.
So, u = ___
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In X-linked recessive alleles that are lethal, ___ of affected males care new mutations
1/3
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Negative selection
- Less fit
- Selected against
- removed from population
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Positive selection
- More fit
- Becomes more common
- e.g. lactase persistence
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Stabilizing selection
- Heterozygous individuals have an advantage
- e.g. sickle cell and malarial resistence; sickle cell allele is kept relatively high in the population
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Positive selection - Amylase
- AMYI gene encodes for an enzyme used to digest starches
- High starch eaters contain on avg 7 copies of gene
- Low starch eaters contain on avg 2 copies of gene
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What is genetic drift?
- Change in allele frequency due to chance.
- Small populations generally more prone to effects
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Founder effect
- Founder population has allele frequency that differs from parent population; sometimes detected by haplotype analysis
- e.g. Amish of Lancaster County - Ellis van Creveld syndrome; Tay-sacks in Jewish population; Finland
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