Genetic diversity and disease: opportunities and challenge.

Abstract

Historically, the investigation of nature's mistakes in the form of so-called inborn errors of metabolism has attracted wide and justifiable interest (1). Some of these errors, such as phenylketonuria, are important in their own right; although rare, they are treatable and thus are of considerable public health interest (2). Others, although less common and less treatable, such as the inborn errors that affect cobalamin (or Vitamin B12) metabolism are important because they give an insight into the role of an enzyme or biochemical pathway in the maintenance of normal function and health (3). It is obvious, however, that these historical examples do not include a whole side of genetic variation and disease that remain largely uninvestigated. Epidemiological studies indicate that there is a very significant familial component to virtually all chronic diseases such as cardiovascular disease, colorectal cancer, or common birth defects, such as spina bifida and other neural tube defects (NTDs; ref. 4). As the human genome is sequenced scientists find that certain sequences are highly conserved. Yet even within the conserved sequences there are some genetic variations. Infrequently there are insertions or deletions of sections of the gene (5). Frequently there are single nucleotide changes (polymorphisms). The alteration of a base in the sequence could result in a variety of outcomes. If the nucleotide is in the 85% of the gene that makes up the intronic regions, it would have no effect unless it is at a splice site with an exon. If it is in the regulatory region, it might affect the binding of a regulator of gene expression. If it is within one of the exons, the base change might lead to a new triplet code that encodes for the same amino acid, resulting in no change in the protein. Finally, a change might lead to a different amino acid being encoded. To what degree, if any, this amino acid change would affect function could be highly variable and very difficult to predict. Because proteins are folded into a three-dimensional structure, it is impossible to say with certainty which amino acids are involved in essential functions. Even if one knows, through x-ray crystallography or site-directed mutagenesis, which amino acids are involved in the catalytic site or in regulatory sites, it could not be assumed that a change in the amino acid sequence distant for these regions would be unimportant. Such a change might alter the stability of the protein or how a protein interacts with other proteins or membranes. In fact, the changes in genotype that are now attracting the most interest are the ones in which small changes in sequence result in an outcome (phenotype) that is subtly different from the normal and difficult to detect. If the altered genotype resulted in a dramatically altered phenotype, it probably would not have survived during evolution. If it did survive, it would be very rare, and if recognized it would fall into the category of an inborn error in metabolism. The mapping of the human genome has now presented the opportunity to identify, within a very short period, all the common genetic polymorphisms. The challenge will be to determine whether they result in an altered phenotype and whether this alteration in phenotype results in the increased risk of a particular disease. As discussed, we know that these genotype changes are common, and we can anticipate that the resultant phenotype change will range from none to something quite subtle (they will not be similar to inborn errors of metabolism). We can also predict that multiple genotypes will be studied for associations with multiple diseases. Such multiple testing will result inevitably in a number of purely chance associations between an altered genotype and the risk of a particular disease. Knowing whether the genotype results in an altered phenotype will then be crucial in sorting out real from chance associations. The anticipated phenotype alteration will be small at best, and our current ability to detect small changes in function is poor in most areas. In this issue of PNAS new research explores an important novel approach to determining the likelihood of how an altered genotype might result in an altered phenotype (6).