Finding human disease Flashcards
Why is gene discovery important?
- Insight into normal, healthy and disease biology
- Prevention and early diagnosis of disease
- Developing new effective treatments
A genetic variant with a large phenotypic effect is analogous to a highly targeted drug
- Rare alleles with large effect can identify genes and pathways that can be manipulated for health benefit
- Indicate direction and magnitude of effects that can be achieved through modulating the target
- Useful proxies for adverse effects of pharmacologic inhibitors of a target
High throughput sequencing
high throughput sequencing (HTS) technologies are capable of sequencing multiple DNA molecules in parallel, enabling hundreds of millions of DNA molecules to be sequenced at a time
positional cloning
a laboratory technique used to locate the position of a disease-associated gene along the chromosome
Independent assortment
the alleles of two (or more) different genes get sorted into gametes independently of one another
linkage disequilibrium
non-random association of alleles at two or more loci in a general population
What does linnkage disequillibrium depend on?
how far the genes are from each other and how recently they have been introduced in the populaiton
What if you don’t know where the disease is and you want to use linkage to find it?
Map the entire genome of the family, innheritence of each segment of each chromosome is compared to the inheritance of the disease trait in the family, the regions that one or a few genetic markers “co-segregate” with disease are identified
How to find genes for recessive diseases
Because affected individuals that have disease due to consanguinity are homozygous for the disease-causing mutation and flanking genomic segments, we just map the genome of a few affected individuals and determining which region of the genome is consistently homozygous
How do you identify the disease gene?
Key criteria
* Independent variants that co-segregate with disease in different families
* Rare variants not seen in the general population
* Similar variants don’t cause a different disease
Supporting:
Variants affect the function of the gene
Gene makes sense from the point of view of known pathophysiology of disease
How do we find the genes underlying common traits?
Test affected and unaffected individuals for one million polymorphic markers (SNPs) spanning the genome
Search for SNP alleles that have a higher frequency in affected people than in unaffected controls
Association can be detected if:
One of these SNP alleles, itself, causes disease
One of the SNP alleles is in “linkage disequilibrium” with some unknown variant that is causing disease (next slide)
Haplotype
Series of SNPs or other variants lying close together on the same chromosome.
Where do Genome-wide association studies fail?
in cases where many rare variants, in aggregate, cause a common disease
Where do Genome-wide association studies thrive?
in disorders where genetic architecture is “common variant leads to common disease
Whenn do we use Genome-scale sequencing to find disease genes?
For finding genes with large or moderate effect where there are no large or inbred pedigrees (basically when pedigrees are useless). Such as:
etreme unexplained phenotypes
de novo mutations in sporadic cases
recessive mutations in small, outbred families
traits caused by somatic mutations
