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Lecture 04 - Assessing your risk for genetic diseases...

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Unformatted text preview: Assessing your risk for genetic diseases... diseases... ...begins with pedigree analysis. Taxonomy for pedigree analysis: circle = female, square = male; shaded = affected, unshaded = unaffected; half-shaded = "carrier", when inferred. halfcarrier" inferred. Mom & dad are carriers. They produce daughters & sons, homo- & heterozygotes homo in exactly the predicted proportions for illustrative purposes only. Pedigree for an autosomal recessive disease, like Tay-Sachs. We infer that all Tayparents (I.1, I.2, I.3, I.4) MUST be carriers. A counselor's job is to compute the risk of counselor' II.2 & II.3 being carriers & hence the risk of the disease appearing in their children. Below are the possible offspring of I.1 & I.2. Since II.2 is not affected, she can only be one of two kinds of genotypes. Therefore, she has a 2/3 chance of being a carrier. 1 If II.2 & II.3 each have a 2/3 chance of being carriers, what are the chances that their children will have Tay-Sachs disease? Tay- In a mating between a pair of carriers (heterozygotes), 1/4 of the children are heterozygotes), expected to be affected. Since II.2 & II.3 each have a 2/3 chance of being a carrier, the genetic counselor tells the parents that the odds of having a child with Tay-Sachs are: Tay2/3 x 2/3 x 1/4 = 1/9 = 11.1% Inferring parental genotypes & predicting offspring genotypes is straightforward for the simple Mendelian diseases. Autosomal dominant diseases show up in every generation or go extinct, and have no bias with respect to sex (e.g., Huntington's). Huntington' X-linked recessive diseases (e.g., hemophilia) are often largely restricted to males. Who are carriers? Who are not? The Human Genome Project is shedding light on these noncommunicable diseases. Many of the mutant alleles that cause them have single amino acid substitutions due to single base-pair differences base("single-nucleotide polymorphisms") in singlepolymorphisms" their DNA sequences. "SNP's" can be assayed by "biochips". SNP' biochips" DNA chips start with single-stranded DNA singlebonded to a plate; strands are assembled with single nucleotide differences. 2 DNA to be sequenced is "denatured", broken denatured" into short pieces, and attached to a dye. Strands bond only if sequences match. DNA chips are vast "microarrays"; the dye microarrays" lights up under a laser and reveals the sequence. G C T C A A G A A T G C A T The more we look, the more we find. Most cystic fibrosis is due to a deletion of a phenylalanine in the CFTR chloride channel... but there are 100 other alleles! channel... But do insurance companies have a right to that genetic information? Even though they currently do not, insurers most certainly covet it: "Eighteen states have laws prohibiting discrimination on genetic grounds. There is federal legislation in the hopper. ... when the tests become perfectly predictive, predictive, managed care plans may also want to revisit the insurability issue." issue." - Matthew Y. Biscan, J.D., of Hall & Biscan, Evans, in Managed Care (Jan 1997) So, do we really want to know if we are doomed to get these diseases? Yes, if there is preventive maintenance. Yes, if you are an insurance company. The law & the doctors are on your side... States + federal legislation prohibit insurers from discriminating based on genetic information. The AMA Code of Ethics prohibits doctors from giving out genetic information: E-2.135 Insurance Companies and Genetic Information. Physicians should not participate in genetic testing by health insurance companies to predict a person's person' predisposition for disease. But this issue is not ready to go away yet. Insurance companies are content for now, because the simple Mendelian diseases are not major, expensive public health issues. The National Human Genome Research Institute supports privacy, too. Serious public health issues in the U.S. have gone from the usual sorts of diseases (bacterial) that still plague most of the world's population to manifestations of world' self-destructive overconsumption in just a selfhandful of generations. 3 How do you deal with a pedigree in which an individual only had a 30% chance of getting a disease? Or where many such genes played into the phenotype? Why do we have car insurance? Why do young males pay more for it? This is how most disease phenotypes work (cardiovascular, cancer, etc.). It poses technical challenges to insurers which work in our favor (low probabilities, several expensive tests to find all genes). The crux of this issue will be the ways in which genetic information differs from other personal information (like tickets). The U.K. Human Genetics Commission has prevented the use of genetic information: "The Commission is concerned that the insurance industry's principle of open disclosure and utmost good industry' faith by the parties seems to fall most heavily on the consumer. Few people are provided with information as to how their premiums are loaded." loaded." "If people feel that the taking of a genetic test may at some future stage seriously disadvantage them in some respect, then they may be reluctant to undergo genetic tests in a clinical context; this also threatens public participation in genetic research." research." Source for both quotes: http://www.hgc.gov.uk/ http://www.hgc.gov.uk/ 4 ...
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