The Gene: An Intimate History - Siddhartha Mukherjee Page 0,49

is an organism’s genetic composition. It can refer to one gene, a configuration of genes, or even an entire genome. A phenotype, in contrast, refers to an organism’s physical or biological attributes and characteristics—the color of an eye, the shape of a wing, or resistance to hot or cold temperatures.

Dobzhansky could now restate the essential truth of Mendel’s discovery—a gene determines a physical feature—by generalizing that idea across multiple genes and multiple features:

a genotype determines a phenotype

But two important modifications to this rule were necessary to complete the scheme. First, Dobzhansky noted, genotypes were not the sole determinants of phenotypes. Obviously, the environment or the milieu that surrounds an organism contributes to its physical attributes. The shape of a boxer’s nose is not just the consequence of his genetic heritage; it is determined by the nature of his chosen profession, and the number of physical assaults on its cartilage. If Dobzhansky had capriciously trimmed the wings of all the flies in one box, he would have affected their phenotypes—the shape of their wings—without ever touching their genes. In other words:

genotype + environment = phenotype

And second, some genes are activated by external triggers or by random chance. In flies, for instance, a gene that determines the size of a vestigial wing depends on temperature: you cannot predict the shape of the wing based on the fly’s genes or on the environment alone; you need to combine the two pieces of information. For such genes, neither the genotype nor the environment is the sole predictor of outcome: it is the intersection of genes, environment, and chance.

In humans, a mutant BRCA1 gene increases the risk for breast cancer—but not all women carrying the BRCA1 mutation develop cancer. Such trigger-dependent or chance-dependent genes are described as having partial or incomplete “penetrance”—i.e., even if the gene is inherited, its capacity to penetrate into an actual attribute is not absolute. Or a gene may have variable “expressivity”—i.e., even if the gene is inherited, its capacity to become expressed as an actual attribute varies from one individual to another. One woman with the BRCA1 mutation might develop an aggressive, metastatic variant of breast cancer at age thirty. Another woman with the same mutation might develop an indolent variant; and yet another might not develop breast cancer at all.

We still do not know what causes the difference of outcomes between these three women—but it is some combination of age, exposures, other genes, and bad luck. You cannot use just the genotype—BRCA1 mutation—to predict the final outcome with certainty.

So the final modification might be read as:

genotype + environment + triggers + chance = phenotype

Succinct, yet magisterial, this formula captured the essence of the interactions between heredity, chance, environment, variation, and evolution in determining the form and fate of an organism. In the natural world, variations in genotype exist in wild populations. These variations intersect with different environments, triggers, and chance to determine the attributes of an organism (a fly with greater or lesser resistance to temperature). When a severe selection pressure is applied—a rise in temperature or a sharp restriction of nutrients—organisms with the “fittest” phenotype are selected. The selective survival of such a fly results in its ability to produce more larvae, which inherit part of the genotype of the parent fly, resulting in a fly that is more adapted to that selective pressure. The process of selection, notably, acts on a physical or biological attribute—and the underlying genes are selected passively as a result. A misshapen nose might be the result of a particularly bad day in the ring—i.e., it may have nothing to do with genes—but if a mating contest is judged only by the symmetry of noses, then the bearer of the wrong kind of nose will be eliminated. Even if that bearer possesses multiple other genes that are salubrious in the long run—a gene for tenacity or for withstanding excruciating pain—the entire gamut of these genes will be damned to extinction during the mating contest, all because of that damned nose.

Phenotype, in short, drags genotypes behind it, like a cart pulling a horse. It is the perennial conundrum of natural selection that it seeks one thing (fitness) and accidentally finds another (genes that produce fitness). Genes that produce fitness become gradually overrepresented in populations through the selection of phenotypes, thereby allowing organisms to become more and more adapted to their environments. There is no such thing as perfection, only the relentless, thirsty matching of an organism to its environment. That is the engine that