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Flashcards in Finding Disease Related Genes Deck (24):

Define linkage disequilibrium

Genes that are non-randomly inherited


What causes linkage disequilibrium

Physical linkage of genes
Functional interactions (even on diff chroms)


Define haplotype

Regions of high linkage disequilibrium ie inherited together


What's the LOD score

The logarithm of the ratio of 2 loci of:
The odds they're Linked w a specified recombination fraction : the odds they're not linked


Describe ways cytogenetically can detect disease related genes

Bkpts of balanced rearrangements
Deletion/ duplication
Positional cloning
Chromosome walking
Chromosome jumping


How can balanced rearrangement cause disease

Submicroscopic del-/ dup
Disruption of gene at breakpoint
Position effect
X-autosomal translocation


What's positional cloning

Method to ID gene solely on approx chromosomal location
Linkage mapping
Chromosome abns
Linkage disequilibrium


Describe chromosome walking

Common method used it produce clones covering a RoI
Start with known makers @ each end of RoI
Use marker to probe genomic library to ID other clones that share sequence- ie tile RoI extending out until entire region is covered
Very slow method
Issues: high % rrpt sequences- non specific binding


Describe chromosome jumping

Restriction digest DNA - fragment ~80-130kb in size
Ligate to a marker and circulise DNA (now far DNA is near marker)
Digest with 2nd ER- cuts junction DNA
Ligate into a vector- use as probe in chromosome jumping to ID further positions of RoI

Genes within cloned genomic reign IDd using cDNA library
If probe hybridises to cDNA- can deduce sequence


How do you perform autozygosity mapping

ID family/cohort w. Homogeneous phenotype
Genotype large # SNPs/ microsatellite (genome)
ID regions of homozygosity in affected ppl
Use bioinformatics to for this (IBD Finder)
Fine map using polymorphic markers to differentiate homo from auto
ID candidate gene and sequence


Name four ways can find a disease related gene

Autozygosity mapping


What's the coefficient of inbreeding

The probability a child for a consanguineous family is homozygous for a specific gene from a common ancestor
F= 16 for 2nd cousins


What factors affect autozygosity mapping

informative affected and unaffected ppl in the cohort
Frequency of allele in population (Lower freq- more likely its autozygous).
Degree of relatedness (further away= small regions of IBD Therefore more significant if share IBD) (greater chance 2nd allele entered family resulting in homozygosity).
Phenotypic heterogeneity: essential phenotype are accuarte so looking for same diseas


What's linkage

The tendency for genes /markers to be inherited together as they're located nearby on the same chromosome


What's linkage based on

Because meiotic recombination is random the smaller distance between two loci the more chance they'll be inherited together
Use markers to track inheritance of an unidentified gene


What's parametric linkage

The probability a gene is linked to a marker when studied though their LOD scores
Need to know relationship between phenotype and genetic similarities


What's no parametric linkage

Studies the probability of an allele being IBD with itself
Not appropriate for finding genes involved in common diseases
Not a precise model


What LOD score means the loci are linked or not

+ score (>3) = linkage likely
- score (-2): unlikely


How do you carry out linkage mapping

Use markers across genome in families
Use computer programmes to ID regions with high LOD scores
Fine map candidate region with densely packed markers to find candidate genes
Sequence genes to look for mutations


If analysing affected siblings using linkage what would you be looking for

AD traits: affected sibs would share 1 haplotype for RoI
AR traits: affected sibs would share 2 haplotype a for RoI

Random inheritance sibs would share: 0,1,2 alleles (1/4, 1/4, 1/2)


If investigating an AR trait by WES who would you test

Affected siblings: shared variants/ compound heterogeneity


If investigating an X-linked recessive trait by WES who would you test

Two remotely related male family members


If investigating an dn AD trait by WES who would you test

Affected proband and unaffected mum and dad


What complex traits is WES being used to investigate

Autoimmune disorder: lupus