(version 15 Apil 2008)
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Over the last ten years or so, a large number of DNA-based ``tests'' for disease risk have been developed. Here we discuss (i) how these are found, (ii) what they mean, and (iii) social implications.
Can score individuals as affected / unaffected. For example, you either have cancer or you don't
Alternatively, if known, the appropriate underlying physiological variable can be used as a quantitative character
e.g., Blood pressure vs. hypertension (affected / normal)
In most cases, don't know underlying biochemical variables.
QTLs (Quantitative Trait loci) -- those underlying quantitative traits
DS (Disease susceptibility) genes -- those influencing an individual's susceptibility to a particular disease (e.g., heart disease, Alzheimer's). Note that DS genes are simply QTLs that influence a disease.
One looks for associations between the trait and the average values for particular alleles at the candidate locus
Each copy of allele e4 found to increases cholesterol level by 5-10
Each copy of allele e2 decreases cholesterol level by 15-20
e4 e4 -- mean age of onset 68.4 years
e4 e- (heterozygote) mean age of onset 75.5 years
No e4 alleles -- mean age of onset 84.3 years
Individuals with long alleles higher in Novelty seeking
More exploratory, thrill-seeking, excitable
Individuals with no long alleles lower in Novelty seeking
More deliberate, rigid, and orderly
D4DR accounts for about 10% of all genetic variance in the trait novelty seeking
High amounts of polymorphism at the DNA level
Two random humans differ by on average 20 million base pairs
These differences provide genetic (molecular) markers for mapping genes
KEY : QTLs, DS genes can be detected by looking for marker-trait associations using these markers.
Here the idea is to compare the number of shared maternal and paternal marker alleles in pairs of affected sibs.
Affected sibs 1 & 3 share (1/2) their marker alleles
Both share paternal marker, but have different maternal marker
If the marker is unlinked to disease, we expect, on average, 50% of marker alleles shared
If significantly more than 50% of the marker alleles are shared, this indicates linkage to a QTL.
Using sib pairs nicely controls for shared environmental effects.
22 families with a total of 159 pairs of affected sibs were examined
57% of doubly-affected sib pairs shared the same allele from their parents at a microsatellite marker D18S56.
This is significantly different from 50%, suggesting this marker is linked to a DS gene influencing depression.
Hamer (1993) examined 32 pairs of gay bothers. 22 of these shared the same marker allele from their mother (an X-lined marker in region Xq28).
freq = 22/32 = 67%, which (for this sample size) is significantly different from 50%, indicating a QTL influencing male sexual preference linked to this maker.
No such association was found in 36 pairs of lesbian sisters
Most genes show linkage-disequilibrium between very tightly-linked markers
The usefulness of this observation is that we can use tightly-linked markers as indicators of whether a particular chromosome carries a disease allele.
How does this association arise?
Even after hundreds of generations, most chromosomes carrying the mutant allele also contain the tightly linked alleles on the original chromosome.
This feature has been exploited for very fine mapping of diseases genes, an approach called linkage-disequilibrium mapping
For many mutant alleles, there is a predominant haplotype (collection of very tightly-linked markers) with which it is associated, reflecting the haplotype of the original chromosome on which the mutant arose.
BRCA 1: Women who carry a mutation in the BRCA1 gene have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 years
BRCA 2: In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, prostate, and pancreatic cancers.
women with an altered BRCA1 or BRCA2 gene are 3 to 7 times more likely to develop breast cancer than women without alterations in those genes
Among individuals of Ashkenazi Jewish descent, researchers have found that about 2.3 percent (23 out of 1,000 persons) have an altered BRCA1 or BRCA2 gene. This frequency is about 5 times higher than that of the general population.