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

If you examine Fig. 19.1 as a whole and consider the DNA sequence shown as your personal genome, the situation looks pretty grim. You might be led to believe that genes dictate everything, and that biology is destiny. But if you focus on the lower levels of regulation in Fig. 19.1, a different picture emerges. The picture is different because much of the regulation that occurs after transcription (regulation of mRNA stability, regulation of translation, posttranslational modifications) is determined by the physiological state of your cells, which in turn is strongly influenced by your lifestyle choices. For example, your cells can synthesize 12 of the amino acids in proteins, but if any of these is present in sufficient amounts in your diet, it is absorbed during digestion and not synthesized. The amino acid you ingest blocks the synthetic pathway through feedback effects.

The effect of an intervention—genetic or environmental—at any given level can affect regulatory processes at both higher and lower levels. This cascade of regulatory effects in both directions can occur because the expression of any gene is regulated at multiple levels, and because there is much feedback and signaling back and forth between nucleus and cytoplasm. It is because of these feedback and signaling mechanisms that the effects of lifestyle choices can be propagated up the regulatory hierarchy. For example, it has been shown that dietary intake of fats and cholesterol affects not only the activity of enzymes directly involved in the metabolism of fats and cholesterol, but also the levels of transcription of the genes encoding these enzymes by affecting the activity of their regulatory transcription factors. Similarly, lifestyles that combine balanced diets with exercise and stress relief have been shown to increase transcription of genes whose products prevent cellular dysfunction and decrease transcription of genes whose products promote disease.

So far, we have been talking primarily about complex traits of the type discussed in Chapter 18, which are affected by multiple genes and by multiple environmental factors as well as by genotype-by-environment interaction. For example, there are both genetic and environmental risk factors for breast and ovarian cancers, as we have seen. Simple Mendelian traits caused by mutations in single genes, such as cystic fibrosis and alpha-1 antitrypsin (α-1AT) deficiency (Chapter 17), are less responsive to lifestyle choices. But even in these cases, lifestyle matters. For example, people with α-1AT deficiency should not smoke tobacco and should avoid environments with low air quality.