How Genes Work and Why They Come in Different Flavors
Even if you haven’t asked yourself why it is that genes makes us sick, perhaps you have wondered why it is that your sister has legs up to her ears and piercing blue eyes that haven’t been seen in the family since Great-Aunt Bessie, while you seem to have inherited a horrible mix of dad’s stockiness and mom’s frumpiness? And what’s up with your brother’s moroseness: Where did that come from?
It is not much of an explanation, but the straight answer is that genetics is a lot more complex than the idea that there’s a gene for every trait. Most traits, or attributes, are regulated by many genes, not just one. Furthermore, while it is a nice abstraction to suppose that genes come in normal, or good, versions and mutant, or bad, ones, the reality is that there are always multiple different flavors of normal. The gradation from the most common allele to various types of normal alleles to abnormality is continuous. Just having certain alleles is insufficient to predict whether a person will get a disease.
Crucially, too, the environment has a pervasive effect on the way our genes function. “Environment” means much more than the temperature outside or the nutritional content of the food we eat. It also includes influences as diverse as a mother’s health during pregnancy and the pressure that peers and society put on us to behave in certain ways. As we shall see, in many cases environmental interventions are likely to have a much greater impact on public health than pharmaceutical ones. Unfortunately, most of us find it easier to pop a pill than to buck a social trend, so drugs are likely to have an ever-increasing role in disease control.
Without going into any mechanistic details, it is helpful to recognize that genes function on two levels, the biochemical and the biological. The biochemical is hidden to most observers, and therefore typically excluded from general conversation. The biological is what we actually see.
Each of the 23,000 or so genes scattered along our chromosomes encodes the information to perform a specific biochemical function. Less than a third of these genes function in every cell in your body to provide the basic building blocks and to generate energy—they are the bricks and mortar, if you like. Another third of our genes makes every one of the hundreds of different cell types in your body different. Neurons need proteins that process electrical signals, muscle cells are full of actin and myosin that make them stretch and contract, and white blood cells carry around the components of your immune system. These are the doors and windows and furniture and appliances. The final third of our genes is responsible for regulating which genes are used when and where and in what amount. Turning on hair keratin in your pancreas wouldn’t be good, and light receptors have no place in your heart, so development and physiology are highly regulated processes. These genes are the architects, foremen, and designers.
We hear and read about genes for cancer and for autism, or are given to believe that there is an aggression gene or a blonde hair gene. The reality is that these attributes are many steps removed from the molecular functions that the genes perform. If a gene contributes to cancer, it is because it normally performs a role in making sure that the right number of cells are produced at the right time and place. The reason there may be a genetic contribution to spirituality is not because some genes function to ensure that we have a belief in God, but rather because there are genes that affect how the neurons are wired together and the strength of signaling across synapses.
Fly geneticists like to name genes after the way flies look when the gene is mutated. Antennapedia flies have legs on their heads, technical knock out ones fall over when you bump their heads, and shaven baby embryos don’t have any hairs. It is an amusing, but unfortunate habit, because it reinforces the notion that there are genes for traits. Time after time it turns out that the same gene does completely different things in different contexts. A favorite example of mine is staufen, which is required both for sperm development and for memory. It is not that male flies think with their penises, but rather that both of these attributes turn out to depend on a biochemical process called intracellular RNA localization, which staufen is involved in. Almost without exception the biological functions of genes are not written in the DNA, but rather emerge from the network of biochemical interactions within cells, and in turn the manner in which cells work together to build tissues and organs.
It follows that the reason we are all a little different from one another is because these interactions occur between ever so slightly different copies of the genes. Each gene comes in multiple different flavors—I mean, alleles—that have cropped up during the evolution of the species. These different alleles have their origin in the process of mutation, which is basically what happens to genes when you leave them out in the sun or exposed to poisons.
Mutations are ultimately the source of all things good, but for the most part are harmful, tending to break genes. Every one of us has a few mutations that neither of our parents had, simply because mistakes are made every time the genome is copied. (But don’t get too upset about this: The error rate is only about one in a billion letters in the DNA. Most of us would be thrilled to make a mistake only once in every hundred times we do something.) Mutations are also so plentiful that we all carry several of them that would kill us if we got the same one from both parents.
Mutations are so plentiful in fact that there is no way that natural selection can possibly purge them all. Obviously alleles that would tend to kill a person will not generally last long in the gene pool, and similarly ones that would tend to make us sick should not fare well either. But all new mutations are extremely rare when they appear, and nature has bigger fish to fry. It is more concerned with common alleles that affect the fitness of a large percentage of the population, so the fate of new mutations is largely governed by chance. Consequently, some mutations manage to drift around for a while and can even become reasonably common before they start having a noticeable effect on public health. The process is called mutation-selection-drift balance, which is a fancy way of saying that a lot of bad things happen to genomes, and evolution deals with them, but it is so busy that some of the bad things hang around for a while.
Some mutations are also good for you. Maybe they offer protection from diabetes; maybe they make a person more fertile. These tend to be favored by natural selection, but before they become the standard allele, they necessarily share real estate in the genome with the original allele. Typically it takes thousands of generations for one allele to replace another, so in the meantime you have variation. Sometimes the new allele will be better under some conditions, while the ancestral one is better under others. Maybe they have different effects in men and women, or in rural and urban settings. In such cases, geneticists speak of balanced polymorphisms, the classic case being sickle cell anemia, which is bad under some circumstances but protects a person from malaria in others.
You will also see it argued that many of the bad effects are actually offset by some absolute good that they do. Perhaps at a different stage of life they are sufficiently beneficial that natural selection overlooks their contribution to disease. Or perhaps at some earlier phase of human evolution they were the right gene in the right place at the right time. It is easy to get carried away with devising clever stories along these lines. Some, particularly in the domain of psychology, are even tempted to postulate that promoting disease is in itself advantageous to the selfish genes, but it really stretches credulity to suppose that there is some benefit to having genes that make us suicidal. We won’t go down that road. Rarely is it necessary anyway.
It turns out that as species go, humans are actually among the least variable, at least at the level of their DNA. Nevertheless, the average person has a few million differences between the copy of his genome received from his mother and the copy received from his father. Somewhere among all those differences are the genetic variants that are responsible for all genetic diseases, but no more than a couple dozen have a big enough impact on any particular disease for us to have any hope of finding them. Finding a few dozen out of a few million is a genuine needle-in-a-haystack problem.