Human Genetics Flashcards
Penetrance
frequency of disease phenotype if risk genotype is present
- complete penetrance: if risk genotype is present, 100% will have disease phenotype
Autosomal recessive
- 1/4 offspring affected
- affected offspring from unaffected parents
- ex: CF
Autosomal dominant
- 50% offspring affected (w complete penetrance)
- no skipped generation
- unaffected offspring from affected parents
- ex: Huntingtons
X linked recessive
- affects all males from female carriers
- ex: fragile X
Y linked
- only males
- not many examples bc leads to infertility
- Retinis pigmentosa
- usually de novo
Mitochondrial inheritance
- only inherited from the mother
- affected mother = all affected offspring (if complete penetrance)
- affected father = no offspring affected
- ex: MELAS
(if mother only has 75% penetrance, not all children will have phenotype)
Parent of origin effects
- depends on whether a variant is inherited from the mom or dads chromosome.
Maternal Parent of Origin - Dominant
only 1/2 of offspring of female carriers will be affected.
Inheritance pattern complexity
- reduced penetrance - not all with gt have pt
- phenocopy - pt without gt
- variable expressivity - risk gt gives different pt.
Recurrence risk
Auto dom: 50% siblings
Aut rec: 25% siblings
reduced: % pen x normal risk.
How to determine if a phenotype is genetic?
- Family studies
- Twin Studies
- adoption studies
- segregation analysis
- linkage analysis
Linkage Analysis
- look at recombination rate
- no linkage = 50%
- can be done using SNP chip.
Physical vs Genetic map
- Physical Map: based off of nucleotide seq and # nt from the p telomere
- Genetic Map: distance based off of likelihood of recombination bt 2 markers. in cM = % recomb rate
Linkage Equilibrium
- frequency of each haplotype at two SNP sites
- 4 possible combinations
- combination 1 x 2
0 LD
Linkage Disequilibrium
- happens when two genes are linked and have a LOWER chance of recombining.
- usually closer together = more LD
Perfect LD
- only two haplotypes
- LD = 1, r2 = 1
Complete LD
- three haplotypes
r2 < 1.
Association Analysis
Compare allele or genotype frequencies of variants bt 2 groups
- case controlled with affected pt and neg controls.
- risk allele: higher freq in disease
- protective allele: lower freq in disease
Population Stratefication
presence of a systematic difference in allele frequencies between subpopulations in a population, possibly due to different ancestry
- Caveat to population analysis
- may result in false positive
TDT X^2 Test
used during family-based association
x2= (b-c)^2 / (b+c)
Genotyping QC
might have a mendalian compatibility so u need to QC.
- might be differences due to primer variation
- check HWE!!
- make sure there is no missing data, check for poor clustering
- check samples for quality.
. You are reviewing a manuscript for a journal. The authors performed a genome-wide association with a microarray SNP chip with 1 million SNPs. They found a single SNP whose minor allele frequency was more common in cases with a disorder than in controls with a p value of 1 x 10-20 . They are reporting that this specific variant contributes substantially to risk for the disorder.
a. Provide a list of at least 3 reasons that in spite of the significant p value that the association may be a false positive. Explain ways of checking for the presence of these potential problems.
p value is 1 x 10^-20
- Population Stratification. Check to see if the control matches the population
- Check for missing data. Samples with high missing rate may have problems with quality or concentration. Can also check clustering. Is this missingness informative?
- Check for Mendalian incompatibility rate. There is now software that uses algorithms to check. Can also use any pedigree data.
b. You went through the paper and felt that the reasons for a false positive association had been excluded, based on your list above and therefore agree that they have a true positive association. Explain why this may not be the specific variant that is contributing to risk for the disorder. A drawing may be useful.
- variant could either be contributing to disease OR just high in LD.
- the biological importance of the variant needs to be investigated. Can be used to ID a gene. Then resequence the gene in the more expt and control groups to determine the functional form.
- then the putative function of the protein encoded by the gene needs to be established.
- need to go from statistical significance -> biological relevance.
A new human disorder has been identified. Pedigree analysis does not reveal a classical monogenic pattern. This is a relatively common disorder (1% of the population) that contributes to early death. If one sibling has the disorder, there is a 40% chance that the other sibling will also have the disorder. What is the relative sibling recurrence risk?
% sibling recurrence risk / % population = 0.4/0.01 = 40-fold increase risk.
Is it familial or environmental? Can look at twin studies. Segregation analysis. Pedigree analysis. Adoption studies. Confirm it is genetic.
A variant within this region is genotyped within 1000 trios consisting of an affected child and two parents. Heterozygous parents transmit allele A fifty times and transmit allele B 150 times. Calculate the Transmission Disequilibrium Test (TDT) statistic – show your work. You will not need a calculator.
DTD X2 = (b-c)2/(b + c)
(150- 50)2 / 200
1000 / 200 = 5
If the TDT is highly significant, does that confirm that the variant is the specific variant contributing to susceptibility. Explain why it does or does not.
No. Could be normal pattern of variance, perfect LD. Look for a mutation or loss of function mutation. What is AROUND the LD?
is relative risk genetic?
mz»_space; dz = sib
How can u get a more precise location of a deletion on 2q11?
- get the exact nt sequence
- is there more detailed banding info available?
2 methods to see if the person you are studying has the deletion?
- FISH: metaphase vs interphase
2. SNP-chip: look for deletion in known markers in that region
