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42 Cards in this Set
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- Back
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Forward Genetics |
Observing the PHENOTYPE and then deducing what gene is responsible. Phenotype is known and we are trying to find the gene |
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Reverse Genetics |
Determining what phenotypes are the result of gene changes. Genotype is known and we are trying to define resulting phenotypes |
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Neurobehavioral Genetics - definition |
the use of forward and reverse genetics to determine the genes and molecular pathophysiology (the disordered physiological processes associated with disease or injury) of neurobehavioral traits and complex disorders. |
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Why are complex disorder difficult to figure out on the genetic level? |
Complex disorders are difficult to define because they do not follow traditional mendelian modes of inheritance - they are affected by variability, pleiotropy and penetrance |
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Pleiotropy |
a single mutation in a gene leads to multiple observable phenotypes that are seemingly unrelated - e.g. a disease that affects cognitive performance but is also associated with kidney function |
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How does the polygenic phenomenon complicate deciphering genes responsible for a certain phenotype? |
Polygenic means many (poly-) genes potentially have slight mutations that end up with a drastic effect. |
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Why do psychiatric disorders make genetic analysis more difficult exactly? |
It is difficult to quantify and therefore standardize phenotypes - there are still problems even diagnosing marginally effected individuals. |
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What do we use as genetic 'mile markers'? |
Polymorphisms |
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What is a micro satellite region? What do we call them? |
Short, repeated sequence found at many places throughout the genome. These are unique to individuals (the exact number of repeats varies) and can be used in DNA fingerprinting! |
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What are Copy Number Variations? How might they affect expression? |
Differences in the NUMBER of copies of large DNA sequences (bigger than 1000bp). These can include deletions and duplications. They can encompass several genes or sections of genes that can alter the position of other genes. |
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What are Single Nucleotide Polymorphisms? Where do we usually find them? |
A difference in a single base pair, usually not having any affect on gene function. They are often found in the non-coding regions or introns. They is about 1 SNP for every 100 bp - 'Tag SNPs' are SNPs that are found together as they often stay in groups. |
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What is a 'Set of Alleles'? What relevance does recombination of different alleles have on genetic mapping? |
They are 'versions' of a gene. 1 set is inherited together but recombination may alter which alleles are present on a chromosome. Recombination happens less frequently to alleles/polymorphisms that are PHYSICALLY closer together and can be used for GENETIC MAPPING |
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How is the Recombination Frequency related to Linkage and Association Studies? |
Both of these types of studies rely on the fraction of progeny that have recombined DNA to estimate how a close a genetic marker(s) is to a locus thought to be causal with the observable trait. |
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What is the Recombination Frequency? (theta) |
# of recombinant progeny/total # of progeny |
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How do you calculate the Likelihood of Pedigree (L) |
(1-theta)^NR*(theta)^R = L |
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What is the Null Hypothesis of a Likelihood Ration Test (LRT?) |
We assume that genes A and B are NOT linked i.e. theta = 0.5 |
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How do we calculate the LOD score? What is the LOD score you must beat to be considered linked? |
LOD = log[{(1-theta)^NR*(theta)^R}/(0.5)^(NR+R)] for us to consider two genes to be linked they must have a LOD score greater than 3 |
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When calculating the LOD score, what values do we use as theta? |
Theta represents the percent recombination and is therefore usually used to make a LOD table with values from 0.05 to 0.5. |
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What controls the perceived legitimacy of a Linkage Analysis? |
The most important factors for the power (what is the strength of the significance?) of a linkage analysis are the pedigree's size and structure. Humans don't have a lot of progeny -> small sample size. Secondary reasons include marker informativeness (some are more useful than others), distance of the gene from its disease locus, the phenocopy rate, genetic heterogeneity and the magnitude of the genetic effect. |
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What is a phenocopy? |
A variation in phenotype which is caused by environmental conditions such that the organism's phenotype matches a phenotype which is determined by genetic factors. It is not a type of mutation and is non-heridity |
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What are the assumptions do we make for linkage analysis? |
We assume: the system is at a linkage and HW-E, that there is random mating, no chiasma interference (physical structure of chromosome affecting recombination) and that there is no epistasis (interactions b/w alleles at different loci. |
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What are some advantages of linkage analysis? Some disadvantages? |
Advantages: no sensitive to across pedigree allelic heterogeneity nor pop history. No candidate genes to guess, well developed/used 400-800 bp markers that we KNOW (cheap & accurate), can detect a signal up to 20cM away, the P-value (LOD score) is accurate given the data and genome-wide level is significantly well defined. Disadvantages: Model based - you must change all if any of the assumptions change! analysis is only WITHIN pedigrees not across, not great with many loci for the same trait. |
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What increases computation time in Linkage Analysis? |
the number of people, number/type of markers used and any missing data (lost records, unknown relatives, etc) are all complicating factors |
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Contrast association and linkage studies. |
Association studies consider Identical by State (IBS) and looks over several pedigrees in a small region from ONE generation . Linkage attempts to determine linkage between multiple genes in one pedigree from lots of generations (IBD- identical by descent). |
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What are IBD and IBS? How are they related to pedigree analysis? |
IBD - identical by descent - two identical alleles from known, common predecessors IBS - identical by state - DNA segments which do not signify the sharing of a recent common ancestor and are therefore not IBD Linkage analysis looks at multiple generations in one pedigree by looking for polygenic traits in individuals IBD while Association studies look at at IBS individuals in a population. |
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What are the characteristics of Mendelian traits? |
Single gene affects the phenotype, only two or three distinct phenotypes and clear patterns of inheritance |
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What are the characteristics of Quantitative traits? |
Usually on a numeric scale, have complex patterns of inheritance, often are a result of multiple genes and many have environmental factors. |
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What are the types of Quantitative traits? |
There are four types of quantitative traits: continuous (bp, height, IQ), meristic - a count (# of follicles/#of toes), ordinal - a ranking (cancer staging, Brack neurodegeneration staging and categorical - eye color, type of cancer |
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How do we strengthen the evidence of linkage to a locus in traits that are quantitative? |
To get a more robust linkage we must look for the extreme phenotypes in the population - the closer you can get to distinguishing phenotypes the stronger the analysis |
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What are the roles of the mean, variance and the standard deviation in quantitative genetics? |
mean - finds the center of the distribution variance - estimates the spread of the distribution SD - is also an estimate of the spread |
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What is the variation in heritability (Vg)? |
proportion of phenotypic variation attributed to our genetic differences |
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What is Broad-Sense Heritability (H2)? |
a fraction of total phenotypic variation that is due to genetic differences in populations. H2 = Vg/Vt Vt = Vg +Ve |
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What is the Effect Size of a QTL? |
What percent of variability is due to a QTL? |
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Where/when are the best places to look for QTNs? What are QTNs? |
Quantitative trait nucleotides, often refers to the differences. We need to look for them in the right tissues at the right time of development and many are found in regulatory regions. Not all QTNs alter expression at all, look for them in protein expression genes, splicing factors, etc. We look for polymorphs b/w parental strains that may change those things. |
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How do we find QTLs between markers? |
Interval analysis is a method for estimating the probability of the presence of a QTL between markers. |
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What is Interval Analysis used for? |
Interval analysis depends on a regression model and can help us determine correlations using a regression co-efficient. |
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Does QTL analysis actually map the gene? |
No - methods that look at QTLs are telling us about how one gene's expression might effect the expression of another. i.e. if they are closely linked activating type genes they will have an additive effect and result in a more extreme phenotype however if they are contradictory (one is positive regulator one is neg for example) they might never been seen in this way |
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What is the overall process of gene analysis? |
1) ID the Qualitative Trait Nucleotides (QTNs) that actually affect expression 2) generate a list of potential candidate genes from online data bases 3) look for genes that are expressed in an appropriate tissue and are involved in a relevant pathway. 4)Sequence exons, intro-exon junctions, promoter regions and highly intron regions that are highly conserved across species 5) Look for polymorphisms between parental strains that may cause an amino acid change, gene splicing or others that change gene expression |
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Define Cloning |
Replication of a certain DNA sequence |
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What are characteristics of good cloning vectors? |
The always have lots of cloning sites. They always have the origin of replication, a selectable marker (tag) and a multiple cloning site. |
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What are some ways we isolate/amplify genes of interest? |
PCR is the first way but only clones the DNA itself. Most gene replication for use in experiments are made in bacteria models. |
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How is a mutation different than transgenic? |
A mutation is a change in sequence that is NOT common to the population. A mutant is an INDIVIDUAL in a population. A transgenetic organism has a foreign gene having been incorporated into its genome. |
