Impact of Mutation and Polymorphism

Although it will be self-evident to students of human genetics that new deleterious mutations or rare variants in the population may have clinical consequences, it may appear less obvious that common polymorphic variants can be medically relevant. For the proportion of polymorphic variation that occurs in the genes themselves, such loci can be studied by examining variation in the proteins encoded by the different alleles. It has long been estimated that any one individual is likely to carry two distinct alleles determining structurally differing polypeptides at approximately 20% of all protein-coding loci; when individuals from different geographic or ethnic groups are compared, an even greater fraction of proteins has been found to exhibit detectable polymorphism. In addition, even when the gene product is identical, the levels of expression of that product may be very different among different individuals, determined by a combination of genetic and epigenetic variation, as we saw in Chapter 3.

Thus a striking degree of biochemical individuality exists within the human species in its makeup of enzymes and other gene products. Furthermore, because the products of many of the encoded biochemical and regulatory pathways interact in functional and physiological networks, one may plausibly conclude that each individual, regardless of his or her state of health, has a unique, genetically determined chemical makeup and thus responds in a unique manner to environmental, dietary, and pharmacological influences. This concept of chemical individuality, first put forward over a century ago by Garrod, the remarkably prescient British physician introduced in Chapter 1, remains true today. The broad question of what is normal—an essential concept in human biology and in clinical medicine—remains very much an open one when it comes to the human genome.

The following chapters will explore this concept in detail, first in the context of genome and chromosome mutations (Chapters 5 and 6) and then in terms of gene mutations and polymorphisms that determine the inheritance of genetic disease (Chapter 7) and influence its likelihood in families and populations (Chapters 8 and 9).