Mapping mendelian disease Flashcards
What is mendelian disease?
disease that is caused by a single gene (monogenic), with little or no impact from the environment (e.g. PKD)
What is Non-mendelian Disease?
diseases or traits caused by the impact of many different genes (polygenic), each having only a small individual impact on the final condition (e.g. psoriasis)
What is multifactorial disease?
diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)
How is mendelian disease studied?
1) CLINIC
Ø seeing patients and families in the clinic
1) LABORATORY
Ø patients are studied via gene identification to find out the underlying defect causing the disease
Ø functional studies are carried out
2) CLINIC
Ø laboratory findings are then used in the clinic to run diagnostic tests
Ø patients given counselling
treatment
What is gen idendification?
Finding the gene underlying disease of a patient by gene mapping:
- homozygosity mapping
- linkage analysis
- GWAS
How do we find the exact gene-causing mutations?
When we find out where the gene defect is, sequencing is carried out to find the disease-causing mutations.
How do we prove that these genes cause the disease?
In silico experiments
In Vitro experiments (biopsy, cell culture techniques)
In Vivo experiments (animal models)
What is Genetic Linkage?
tendency for alleles of genes at neighbouring loci on the same chromosome to co-segregate at meiosis and be inherited together
What is a haplotype?
A group of alleles of different genes on a single chromosome at linked loci
What is crossing over?
Non-sister chromatids exchanging DNA segments during meiosis
more likely to occur between loci separated by some distance than closer together (if closer together they co-segregate and are linked)
What is the Aim of linkage analysis?
To find the genomic region(s) linked to the disease
How is linkage analysis used to identify disease causing genes?
DNA markers (observed locus) are used to draw inferences about a disease gene (unobserved locus) on a chromosome somewhere in the genome. If a marker is linked to a disease locus, the same marker alleles will be inherited by two affected relatives more often than expected by chance.
If markers from a specific region of the genome are always inherited together, it is very likely that the disease gene is in that region.
If the marker and the disease locus are unlinked, the affected individuals in a family are less likely to inherit the same marker alleles.
If the marker and the disease locus are linked, all the affected individuals in a family are more likely to inherit this haplotype block.
What are the Steps of Linkage Analysis?
1) Take a Pedigree
2) Blood samples taken from many family members
3) Genotype data used to generate a file with pedigree information plus the genotyping data from the microarray. File is put in a computer program
4) Run a linkage program on the computer
What is Non-Parametric Linkage Analysis?
NPL studies the probability of an allele being identical by descent with itself
-no rules imposed in NPL (no particular genetic model assumptions)
no peaks=no linkage
NPL highlights regions (with high LOD scores) where the variant calls for:
-all affected are equal/identical, but different to unaffected
Further analysis required to find the disease-causing gene
What Parametric linkage analysis?
studies probability that a disease-causing gene is linked to a genetic marker through the LOD score
-imposes rules about inheritance and disease frequency (genetic model assumptions)
highlights regions (with high LOD scores), where:
- all affected are equal/identical, but different to unaffected
- and the genotypes follow the imposed inheritance pattern
