disequilibrium test, for example, if a given allele contributes to a given disease, then the probability that an affected person has inherited the allele from a heterozygous parent should vary from the expected Mendelian ratio of 50:50; association with a neutral polymorphism due to population admixture displays no such deviation in family data (Spielman et al., 1993).

A second pitfall is that testing of multiple hypotheses, aggravated by publication bias, can lead to fallacious conclusions concerning associations. Researchers who test a single genetic change (mutation) for its association with a single disorder base their statistical conclusions on a single hypothesis. Many researchers, however, seek associations using multiple genetic variants. Each test represents an independent hypothesis, but there is a tendency to publish only positive results. In fact, these may merely represent those cases expected to fall outside the 95 percent confidence limits in tests with multiple genetic variants. Statistical correction for multiple testing is possible, but such corrections result, in a loss of statistical power (Altshuler et al., 1998).

The types of DNA markers used in association studies include restriction fragment length polymorphisms, variable-number tandem repeats, microsatellites (short tandem repeats), and single nucleotide polymorphisms (Collins et al., 1997). These markers are listed roughly in the order in which they have been used historically. NCI is initiating a research program to identify all variations in the human genome (Richard Klausner, Director, National Cancer Institute, personal communication, 1998). The Human Genome Diversity Project is a follow-up to the Human Genome Project. When the goals of the Human Genome Project—mapping of all human genes and determination of the sequences of all DNA in those genes—are achieved, it will still be unknown how the genes and the DNA vary among the 6 billion or 7 billion or more people who will inhabit the Earth at that time. The functions of all those genes will also still be unknown, as will how variations in the structure of the DNA and genes relate to variations in function, including variations in susceptibility to common disorders, including cancers.

The Human Genome Diversity Project proposes to identify the range of DNA variation that can be the basis for studies of genetic factors in common disorders. In the pursuit of the Human Genome Diversity Project or any DNA-based studies with special populations, including ethnic minorities and medically underserved individuals, concerns about the risks of discrimination and stigmatization have been raised. The ethical, legal, and societal implications of the project have been addressed by Knoppers et al., (1996, 1998) and by the report of a committee of the National Research Council.

The newly organized DCCPS recognizes that epidemiology and genetics

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