W4 -Mapping Mendelian Disease Flashcards
What is the lymphatic system?
Part of the circulatory system. Functions include: fluid homeostasis, immune functions and fatty acid transport.
What is primary lymphedema?
Chronic condition - will not disappear.
Caused by:
- A developmental abnormality or a dysfunction of the lymphatic system
It is often progressive.
The phenotype varies: Age of onset, site, inheritance patterns, associated features, genetic causes
Lymphedema is: debilitating, embarrassing, stressful and recurrent infections.
Why is this research important?
There is no cure at the moment.
Compression garments, programmed exercises.
Intense bandaging helps with the compressions.
How do we study genetic disease?
Bench to beside
- Clinic: Patients, families
- Labs: Gene identification, Functional studies
- Clinics: Diagnostic tests, counselling and treatment.
How do we study genetic disease?
1) Gene identification by gene mapping: homozygosity mapping, linkage analysis, GWAS
2) Spotting disease-causing mutations: sequencing
3) Proof of causing disease: ____
What is linkage analysis?
What is happening when a cell undergoes meiosis - recombination, segregation. Determines if they are linked or unlinked.
- Gene mapping tool
- Observed loci to draw inferences about an unobserved locus
- Family based design (from few large families to many small nuclear or sib-pairs)
Goal: Find genomic regions linked to disease.
How can we use info about linked alleles to identify disease causing genes?
- Allele is linked to a disease locus, same allele will be inherited by 2 affected relatives more often than expected by chance.
What is Generelised Lymphatic dysplasia?
Hennekam syndrome (HS)
- Antenatal hydros with ascites and pleural effusions
- Oedematous at birth
- Intestinal lymphagie ____
What kind of tools do you use to observe alleles?
Use Genome-Wide Human SNP Array
A DNA sample is added to each GeneChip and you use a chip for each family member of your pedigree.
The DNA will bind to the SNP/allele specific probes on the chip and you can get readout for each sample.
How do you generate the file with your pedigree information plus the genotyping data from the SNP array?
The pedigree is translated into code.
Variant calls for each of the 100s of SNP markers on the linkage chip. There is a maternal and paternal allele.
How do you run your file in a linkage programme?
Merlin, PLINK
How is the data gathered presented?
Nonparametric linkage testing gives you a plot for each.
Inheritance pattern is not taken into consideration.
What is Parametric analysis?
Impose rules about inheritance and disease frequency.
Parametric region highlights:
- All affected in the pedigree are equal, but different to unaffected. ____
What are LOD score?
> 3.0 are taken as significant evidence for linkage.
-2 = inconclusive
Anything below = unlinked
LODmax = 2.1 in HS family.
What are the final steps of providing the mutations in the gene identified are disease causing?
Zebra fish full of fluid - same mutations found in human.
