CASE 3 YOU, FROM A TO T: YOUR PERSONAL GENOME

SNPs result from point mutations, the most frequent type of mutation, which occurred in the past and then spread through the population. A point mutation is the substitution of one base pair for another in double-stranded DNA (Chapter 14). Each of us is genetically unique partly because of the abundance of SNPs in the human genome. There are approximately 3 million SNPs that distinguish any one human genome from any other. SNPs are abundant in the genomes of most species, and while many have no effect on the organism, some are thought to be the main source of evolutionary innovation and others are major contributors to inherited disease. Practically speaking, SNPs are important because they can be used to detect the presence of a genetic risk factor for a disease before the onset of the disease. For example, the ability to detect the β-globin SNPs shown in Fig. 15.1 allows prenatal identification of the β-globin genotype of a fetus.

While there is great interest in developing ultrafast DNA sequencing machines that can determine anyone’s personal genome quickly at relatively low cost, 99.9% of the nucleotides between any two genomes are identical. An alternative is to focus on genotyping just SNPs. As many as one million SNPs at different positions in the genome can be genotyped simultaneously, and the genotyping can be carried out on thousands or tens of thousands of individuals. Such massive genotyping allows any SNP associated with a disease to be identified, which is especially important for complex diseases affected by many different genetic risk factors (Chapter 18).

What does it mean to say that a given SNP is associated with a disease? It means that individuals carrying one of the alleles of that SNP are more likely to develop the disease than those carrying the other allele. The increased risk depends on the disease and can differ from one SNP to the next. Sickle-cell anemia affords an example at one extreme of the spectrum of effects. In this case, the T–A base pair in the S allele of the β-globin gene is the SNP that results in the amino acid replacement of glutamic acid with valine in the protein. Because SS individuals always have sickle-cell anemia, it would be fair to say that homozygous S “causes” sickle-cell anemia.

But except for inherited diseases that result from single mutant genes, which are usually rare, the vast majority of SNPs implicated in disease increase the risk only moderately as compared with individuals lacking the risk factor. We then say that the SNP is “associated” with the disease since the SNP alone does not cause the disease but only increases the risk. For heart disease, diabetes, and some other diseases, many SNPS at different places in the genome, as well as environmental risk factors, can be associated with the disease. Usually, genetic and environmental risk factors act cumulatively: the more you have, the greater the risk.

As emphasized in the case of Claudia Gilmore’s genome, certain SNPs in the BRCA1 and BRCA2 genes are associated with an increased risk of breast and ovarian cancers. Women who carry a mutation in either of these genes can minimize their risk by frequent mammograms and other tests that enable early treatment. Both genes are large—BRCA1 codes for a protein of 1863 amino acids and BRCA2 for one of 3418 amino acids—and many different mutations in these genes can predispose to breast or ovarian cancer. In certain high-risk populations, however, such as Ashkenazi Jews, only a few mutations predominate, and the SNPs associated with these mutations can be detected easily and efficiently.

318