Finding Disease Genes (Dr. Spritz L1) Flashcards
Why is our ability to make accurate predictions on the role of genes in most diseases actually pretty low?
With a few exceptions, it is usually the case that genes do not confer the same risk of disease to all individuals.
Many genes interact (along with environment) to result in disease
We calculate an odds ration to assist in predicting risk
What is the rationale for finding disease genes?
- provide clues to pathogenic mechanisms
- new approaches to treatment
- inference of environmental risk factors
- disease prevention
In order for personalized medicine to work, what do geneticists have to discover first?
- risk genes for common diseases
- specific risk variants
- high-risk gene combinations
Once genetic the genetic risk of an individual is known, what is the next step in the application of personalized medicine?
once a person’s genes are known, an accurate DNA-based predictive diagnostic process based on their individual genetic risk can be conducted.
Once a diagnosis based on an individual’s genetic risk is made, what is the next step in personalized medicine?
Use the genetic diagnosis of disease susceptibilities and pharmacogenetic analysis of optimized drugs (optimal efficacy and specificity) to design an individual treatment and/or preventative.
What do Odds Ratios contribute to the landscape of personalized medicine?
Since the odds ratios of “most” genes are low, accurate prediction of genetic risk, once an individual’s genome is known, is actually pretty low.
What is Odds Ratio (OR)?
OR = (risk of disease with a gene variant) / (risk of disease without a gene variant)
Describe positional cloning a bit more.
First, PC is the way genes are really mapped today.
Positional cloning is a way to map a gene by focusing your attention on a specific region of the genome. You carry out a systematic analysis of all the genes in the suspected (disease causing) area and look for mutations and/or variants that contribute directly to a disease. (p. 208, blue box)
Explain the difference between Functional Cloning (FC) and Positional Cloning (PC) and what are they used for?
FC and PC are different pathways for finding a disease gene within the genome.
FC: Disease –> Function –> Gene –> Map
basically, you investigate genes that you already know (Dr. Spritz investigated hemoglobin and thalassemia)
PC: Disease –> Map –> Gene –> Function
basically, you now have to look for the gene and deduce its function because you don’t necessarily know the function up front.
What is a polymorphic DNA marker?
A marker can be a SNP or a CNV (of which microsatellites are a subset) at a known genomic position which we can “score”.
In Positional Cloning, polymorphic markers are used as surrogates for disease mutations (which are harder to pinpoint). Due to linkage disequlibrium, knowing which markers a person carries implies which disease genes they are carrying. Sort of a 2-for-1 deal
What is a microsatellite?
stretches of DNA containing units of 2, 3 or 4 nucleotides repeating
- are multi-allelic
- the number of repeats of the unit will vary from person to person allowing for DNA fingerprinting.
occur 1 / 30,000 bp’s roughly
What is a VNTR?
variable number tandem repeats = MINI-satellite
is a stretch of 100 to 1000 bps that then repeats in tandem along the dna
also varies person-to-person in the number of repeats of the 100-1000bp unit.
What is a SNP?
bi-allelic
1/50-300 bp
used for association
The occurence / allele frequencies differ in different ethnic groups / populations
Due to linkage, it is likely that a particular haplotype will be passed on to the next generation unchanged. So is useful for identifying if people are related (through many generations) vs. not related
What is a haplotype?
A combination of alleles (DNA sequence) at adjacent locations on a chromosome that are inherited together.
Can be one locus, several loci or an entire chromosome depending on the number of recombination events that have occurred between a given set of loci.
What did / does the 1000 Genome project do?
Sequenced 1000 genomes from different ethnic groups
catalog human genetic variations based on SNP’s
useful for analyzing sequence-based RARE VARIANTS that may be causal for common diseases