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- Autosomal Recessive
- "Mendellian" (not really)
- allelic heterogeneity / compound heterozygotes
- clinical heterogeneity
- locus heterogeneity
- treatment / screening
- Continuous phenotype
- e.g. blood pressure, height, etc
Binary - have phenotype or not
Goverened by more than one gene
- Multiple genes
- Environmental effects
Encompasses quantitative, polygenic, multifactorial, and everything else
Larger n -> normal distribution, where n is number of genes adding to phenotype
e.g. diabetes: you have it if you reach a certain blood/glucose level
Family aggregation studies
Compare ratio of blood relatives to general population
1st degree relatives
- 50% common genes
- e.g. siblings, parents
2nd degree relatives
- 25% common genes
- e.g. grandparents, aunts, uncles
3rd degree relatives
12.5% common genes
- (prevalence of siblings) / (prevalence in general population)
- If lambda > 1, then genetic
- Big drop between primary and secondary
Case control studies
Compare your freq with someone's similar to you (e.g. spouse)
- Look at adopted child vs. biol parents
- Look at adopted child vs. adopted parents
- e.g. Schiophrenia determined to be biological
- Monozygotic: approx 100% identical
- Concordance: % shared betweeen identical twins
- Compare to dizygotic twins
- If significant difference, genetic effect
Why monozygotic twins aren't 100% identical
- Somatic mutations
- 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
- (var in dizygotic - var in monozygotic) / (var in dizygotic)
- 2 (Concordance_monozygotic - Concordance_dizygotic)
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
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
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
What is the common variant hypothesis?
The hypothesis that variants that cause common disorders are common throughout the population
What is an example of a "simple" multifactorial disorder?
Digenic retinits pigmentosa
What is an example of a "complex" multifactorial disorder?
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
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
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
Single Nucleotide Polymorphisms (SNPs)
- 1/300 base pairs
- More common than other markers
- Made more useful with DNA chips
- Most changes probably benign
Restriction Fragment Length Polymorphisms (RFLPs)
- First DNA markers
- Technique that detects difference in size between samples of homologous DNA molecules
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.
- Nucleotides that have been duplicated in or deleted from the genome
- Very common
- Typically outside of genes
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
Comparative genome hybridization
- Compare patient and control DNA on an array.
- Spots corresponding to sequences that are increased in patient give a different color
DNA Fingerprinting (mini-satellites)
- 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
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
Base Pair Substitution
- Mutation where one base is substituted for another
- Probably occurs during DNA replication
- Found in humans from Human Genome Project
- e.g. Huntington's
- Mechanism unknown
- Usually increase in number
- Typically lose A or G
- Lose ~5000/day/cell
- Usually repaired
- 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
- Different mutagenic processes are overrepresented among single base pair substitutions.
- Methyllation of cytosine blocks repair at "CG" doublets resulting in transitions
- Most replication errors are repaired during "proofreading"
- 10^(-10) per base pair per cell division
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
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
alleles with frequencies less than 1%
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
Gain of function dominant mutations
- Enhances normal function of a protein
- e.g. Huntington's disease (triplet repeat)
- 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
- 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
Assumptions of Hardy-Weinberg Law
- Large populations with random matings
- Allele frequencies are constant
- p^2 + 2pq + q^2 = 1
- p^2 =freq(AA)
- The population genotype frequencies will remain constant if the allele frequencies remain constant
How are primers and PCR used to detect a deletion?
If the deletion contains the primer, then amplication will not occur.
What is "stratification"?
Within a large population, subgroups are more likely to mate within their own subgroup.
What is positive/negative assorted mating?
Chosing a mate with similar/different phenotype.
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.
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
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.
Inbreeding leads to an increase in _____ genotypes for all loci in the genome.
First cousin marriages range from ____ in some human popluations.
1% to 5-10%
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
The probability of a child of first cousin parents becoming ____ from a grandparent is ___ which is also the ____.
- homozygous by descent
- inbreeding coefficient
P(aa) = ____ in first cousin matings vs. q^2 for unrelated parents
15/16q^2 + 1/16q = q^2 + 1/16pq
Union of individuals related to each other as close as or closer than second cousins.
As the frequency of a decreases, the ratio of aa offspring from related parents to unrelated parents ____.
Calculating fitness (W)
Divide the mean number of offspring produced by a genotype by the mean number produced by the most prolific genotype
Selection coefficient (s)
- The relative intensity of selection against a genotype
- e.g. tay-sachs - no reproduction: s=1
Calculating the selection coefficient
s = 1 - W
Genotypic frequency: f(AA)
f(AA) = (number of AA individuals)/N
Allele frequency: p = f(A)
f(A) = (2nAA + nAa)/(2N)
Calculate allelic frequencies from individual frequencies
p = f(A) = f(AA) + (1/2)f(Aa)
Calculate allelic frequencies at X-linked loci
p = f(XA) = (2nXAXA + nXAXa + nXAY)/(2nfemales + nmales)
Calculate allelic freq's at X-linked loci from individual frequencies
p = f(XA) = f(XAXA) + (1/2)f(XAXa) + f(XAY)
When a population is in Hardy-Weinberg equilibrium, the genotypic frequencies are determined by ...
the allelic frequencies
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
Autosomal dominant alleles with decreased fitness tend to ___ in frequency until it reaches ___.
- an equilibrium
- mutation rate (u)/s, a->A
Selection against autosomal recessive alleles is ___.
- q = sqrt(u/s)
- q = sqrt(u) if s = 1, i.e. fitness of AA and Aa genotypes are 1.0.
For an autosomal recessive allele, if s=1, the change in frequency is q_n =
For X-linked Recessive, q = ___.
In X-linked recessive alleles, ___ of the X chromosomes belong to women, so ___ of the X-linked alleles do also.
So, u = ___
In X-linked recessive alleles that are lethal, ___ of affected males care new mutations
- Less fit
- Selected against
- removed from population
- More fit
- Becomes more common
- e.g. lactase persistence
- Heterozygous individuals have an advantage
- e.g. sickle cell and malarial resistence; sickle cell allele is kept relatively high in the population
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
What is genetic drift?
- Change in allele frequency due to chance.
- Small populations generally more prone to effects
- 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