Lecture 25: Beyond CSI I: Genetic Markers for diseases

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.

ApoE known to be involved in cholesterol metabolism

Each copy of allele e₄ found to increases cholesterol level by 5-10

Each copy of allele e₂ decreases cholesterol level by 15-20

ApoE e₄ also examined for role Alzheimer's

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

Variation in gene size due to length variation in Exon III of D4DR

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.



Family-based mapping: Affected sib pairs

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.



Example: Manic-depressive illness

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.



Example: Genetics of sexual orientation

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



Population-level approaches: Linkage-disequilibrium mapping

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.

Breast cancer

Risks

• North American women have the highest incidence of breast cancer in the world.
• Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer).
• Women in the U.S. have a 1 in 8 (12.5%) lifetime chance of developing invasive breast cancer and a 1 in 35 (3%) chance of breast cancer causing their death.
• In 2007, breast cancer was expected to cause 40,910 deaths in the U.S. (7% of cancer deaths; almost 2% of all deaths).
• Roughly 5-10% of these cases appear to be from hereditary form of the disease.

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.