Discovery of Human Disease Genes Flashcards
Definition of monogenic disease
Mutation in 1 gene that is both necessary and sufficient to produce the clinical phenotype
Definition of positional cloning
Used to locate the position of a disease associated gene on the chromosome
Definition of cosegregation
Transmission of 2 or more linked genes on a chromosome to the same daughter cell leading to the inheritance by the offspring of these genes together
Definition of recombination
2 chromosomes of a homologous pair exchange segments
Definition of genetic linkage
DNA regions that are in close proximity are more likely to be coinherited
Definition of non penetrance
Have the genotype associated with the disease but is not present in the phenotype
Definition of phenocopies
Have the phenotype associated with the disease but do not have the genotype normally associated with the disease
Definition of genetic heterogeneity
Mutations at 2+ loci that produce same/similar phenotypes
Describe the spectrum of genetic disease
Most disease states and traits result from a combination of genetic and environmental factors
What are the 2 key properties of monogenetic diseases
Mutation in 1 gene
-necessary and sufficient to produce clinical phenotype
Transmission seen in pedigrees (recessive/dominant)
Why identify disease causing genes
5 reasons
- Molecular confirmation of clinical diagnosis
- Accurate carrier testing for individuals/couples
- Presymptomatic testing for adult onset conditions (HD)
- Prenatal diagnosis for pregnancies at high risk of a severe disorder
- Understand pathological mechanisms
What is positional cloning
What are the 3 steps involved in this
Used to locate the position of a disease associated gene on the chromosome
Identification of multigenerational affected pedigree
Systematic evaluation of inheritance patterns across the genome
Mutational search within genomic areas cosegregating with disease
Name the 3 monogenic inheritance patterns
Autosomal dominant
Autosomal recessive
X linked recessive
What are the main properties of autosomal dominant diseases
- how many alleles are affected
- mode of transmission
- male to female ratios
- is transmission of disease from an unaffected individual possible
- Mutation in 1 allele => disease
- Vertical transmission
- Male : Female ratio affected is equal
- Male => male transmission possible
- Unaffected individuals => unaffected offspring unless mutation is spontaneous
What are the main properties of autosomal recessive diseases
- how many alleles are affected
- male to female ratio
- Mutations in both alleles => disease
- Parents are carriers
- Male : Female ratio affected is equal
- Consanguinity may be present
What are the main properties of X linked recessive
diseases
- how many mutated alleles are needed to be shown in the phenotype in both genders
- male to female ratio
- male => male transmission
- Mutation in 1 allele => diseased male
- Mutation in both alleles => diseased female
- Mutation in 1 allele in females => carrier
- Male : Female ratio is higher
- No male => male transmission
What is recombination
What is genetic linkage
2 chromosomes of a homologous pair exchange segments
Recombination can occur at any location along the chromosome
DNA regions that are in close proximity are more likely to be coinherited
How would you map genes with linkage relationships
Consider a series of variable loci across the genome and see if they are linked to the mutation locus
The higher the frequency of 2 alleles inherited together, the closer they are to each other
How would you calculate the statistical likelihood for linkage
What can the LOD score tell you
LOD10 = log10 L(linkage)/L(no linkage)
LOD score >3 => linkage
LOD score linkage excluded
How would you use the info found in linkage relationships
3 ways
- Identify genes within linkage intervals
- Assess genes as potential candidates based on biological functions
- Sequence genes in affected to identify causative mutations
What are the 3 confounders in linkage analysis
Non penetrance
-Have genotype associated with disease but not present in phenotype
Phenocopies
-Have the phenotype associated with disease but don’t have the genotype normally associated with the disease
If the no of people in a pedigree is too small, LOD scores from many pedigrees can be added together but can lead to confounders due to genetic heterogeneity
What can you do when the no people in a pedigree is too small in a linkage analysis
LOD scores from many pedigrees can be added together
What are the uses of DNA and exome sequencing
Why is this possible
Both are more affordable
-leads to personalised care and identification of disease causing genes
What are the 2 main uses of exomes
Causative mutations in monogenetic diseases found in exomes
Can catalogue all protein altering variation in an individual
How would you use exomes to compare unrelated individuals to identify variants that cause disease
Take a small no of unrelated individuals with the same disease
Find the no of genes that they have in common
Eventually will isolate the 1 true mutation
How would you analyse the true mutation from exome sequencing
The region containing the true mutation is sequenced, can identify what part => disease
What are the pros and cons of exome sequencing in monogenetic diseases
Pros
-not reliant on ascertainmnet of large pedigrees
Cons
-major confounder = genetic heterogeneity
