It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  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.

  Three Reasons Why Genes Might Make Us Sick

  The upshot of all this is that there are basically three ways that genetic variation can influence disease susceptibility. These are called the rare alleles, common variant, and small effect models. I will briefly describe each and then in the next section present a unified framework that iterates throughout the remaining chapters.

  The simplest model is that a disease can be traced to one badly disrupted gene. This is pretty much the case for cystic fibrosis, and for thousands of other rare conditions. Around 1 in 100 of us carries a mutated version of the CFTR gene without any ill effects, but if two carriers marry, their children have a 1 in 4 chance of getting both bad copies and consequently having cystic fibrosis. The incidence in the general population is only about 1 in 10,000, most of which is due to a few mutations that have been around for centuries, but actually hundreds of other mutations can be found in the gene as well. Whether the disease is so severe that it claims the life of an infant, or mild enough that a person can live to adulthood and maybe receive a life-saving lung transplant, is in part a function of which mutations they have, in part of the rest of their genome, and in part their upbringing.

  Single genes can also cause diseases in other ways. Muscular dystrophy is often due to a gene, dystrophin, that is so big that it picks up mutations often enough that most new cases arise in the individual who has the disease. Another small set of genes has an odd feature that makes them mutate at an unusually high rate, leading to the paralysis or ataxia observed in Fragile X syndrome and Huntington’s disease. For the most part, though, single gene diseases are rare.

  Large-effect mutations also do not generally explain common diseases, those seen in five percent to ten percent or more of people. Really the only
way they could is if there were hundreds of genes that cause a syndrome that we choose to think of as a single disease. Schizophrenia might be in this class, as might the wide spectrum of cardiovascular conditions that lead to heart attacks and stroke. It is possible that these rare mutations interact with one another, so that a person needs two or three of them in any condition to be predisposed to the disease. Unfortunately geneticists have not yet devised a systematic way to discover such mutations.

  Currently the most popular model is called the common disease-common variant, or CD-CV, hypothesis. It is the idea that if there are diseases found in ten percent of the population, then there ought to be alleles at about the same frequency that are found in these people, but not in “normal” people. This sounds reasonable enough, so millions and millions of dollars are being spent in pursuit of these alleles, each of which contributes about five percent to ten percent of the risk of illness. So far, Crohn’s disease, an inflammatory bowel syndrome, is the poster child success story, except that it is not actually a common disease. However, ten or so genes have been discovered that contribute to Crohn’s, each with correspondingly common risk alleles. Diabetes and prostate cancer also show signs of following the CD-CV model, but the jury is out on whether this will really be a common explanation for disease.

  The third possibility is that hundreds if not thousands of different genes—each with rare or common alleles that have small, barely detectable effects—contribute to each common disease. To some extent this is the default model when all other models fail, but it is beginning to look like it is going to be the predominant explanation. The trouble is that this model doesn’t really explain why diseases are discrete. Height, degree of extraversion, memory performance, and probably most human attributes are thought to be influenced by hundreds of genes, but they show a continuous gradation from short to tall, shy to outrageous, and forgetful to prolific. So why should there be people with disease and people without disease, if hundreds of genes are involved?

  A somewhat technical explanation for this is that there is a threshold of liability—in other words, a tipping point from health to sickness whenever you have a little more of something than is normally tolerated. Most people are pretty similar genetically, having average levels of whatever it is. They have some genes that increase the attribute and some that decrease it, but generally not an excess of either. However, inevitably a few outliers will have considerably more of the increasing or decreasing alleles, enough to send them beyond the threshold into the valley of illness.

  A Unified Theory of Complex Disease

  An added quirk is that there likely are mechanisms that ensure that as few individuals as possible exceed the threshold, even when they have more than their fair share of the risky alleles. This phenomenon is known as canalization. It says that not only do species evolve so that most individuals resemble one another, but they have also evolved buffering that ensures that everyone is “normal” despite the slings and arrows of outrageous fortune that life throws at them.

  Next time you trap a mouse, count the number of whiskers: Almost certainly there will be 17 or 18 on each side of the snout. Actually, my dogs also have this number of whiskers, but that may just be coincidence. This number of whiskers is very stable, unless the mouse happens to have a Tabby mutation, in which case on average it will only have a dozen or so whiskers. The catch is that the “or so” can be as few as 7 and as many as 20. Observations such as this are often seen when developmental circumstances are perturbed. Not only does the average appearance change, but it also becomes much more variable.

  It seems than that normal buffering mechanisms fall apart when the genetic system is pushed too far away from the optimum. Translated into the realm of disease, the idea is that the modern environment that humans have constructed has taken us out of the buffering zone, and left us more susceptible to perturbations that result in disease. It is, however, much easier to describe what canalization is than the mechanisms that produce it. This is partly because we don’t really understand the mechanisms, and partly because they are usually addressed in mathematical and statistical equations.

  The essence of these equations is that stability arises through the deeply interconnected web of interactions among genes. If I were to give you 100 pieces of string and ask you to make a carrying bag, the simplest thing you could do would be to tie them all together at both ends, resulting in a sling. This would be fine for carrying around tennis balls, but somewhat disappointing if you tried to use it to carry your loose change. A slight improvement would be to divide the strings into two groups, and lay two slings perpendicular to one another. If you had time, you could weave the strings into a cross-hatching cloth, and by adding reinforcing strings at different angles you could make this web even stronger. Such a cloth would be able to hold heavy objects that distort it and to absorb breaks in a few of the strings.

  Genetic networks are similarly structured as interacting linkages that together form a tighter, more coherent whole than would be produced simply by adding together bits and pieces. But the whole inevitably has holes, particularly when stressed, and these holes lead to disease.

  Now think about some recipe you used to love to make as a child. Let’s say your favorite ham and cheese omelet, or if you were unusually adept in the kitchen, a soufflé. When you were a child, you probably stuck pretty close to the recipe, knowing that so long as you balanced the amount of ham and cheese you added, the omelet would turn out nicely. Then you went away to college and went through a phase of not eating breakfast or stopping for a McBiscuit on the way to work, and now you’ve forgotten the exact recipe. You think you have it right, but every other time you make one, the kids get a pained look on their faces and spit it out. There’s probably something wrong with the number of eggs you are using or the amount of milk. Or maybe it is because you are using an electric stove instead of gas, or the eggs where you live now are a different size than those where you grew up. It’s frustrating, but you just can’t recapture the magic of the old combination.

  In this metaphor for the origins of complex disease, the recipe stands for the genetic program for healthy development, growing up and changing the recipe stands for genetic evolution, and switching cooktops stands for environmental change. The key is that tens of millions of years of genetic evolution devised canalized systems for regulating the amount of glucose in our blood; the balance of immune response to bacteria, viruses, and parasites; and the way the chemicals signal in the brain. These systems were well able to absorb normal fluctuations, without exposing too many individuals to disease. But humans are an incredibly young and rapidly evolved species, and we have completely changed our environment in the past century. This pushes us—as well as many of our domesticated companion animals that get similar diseases—out of the buffered zone, exposing genetic variation that may never have had an effect in the past.

  So while it is convenient to assume that humans are close to some optimal design, we have not actually been around for long enough to allow the genome to make fine adjustments that ensure that most people are buffered from disease. Humans are without a doubt a long way from any such equilibrium. We shared a common ancestor with chimpanzees just five million years ago, and with Homo erectus cavemen just a million years ago. As a species, Homo sapiens has been in existence for just 140,000 years, somewhere around just 10,000 generations. The flies sitting on the fruit salad at your barbecue have likely been around as a species for 100 times as many generations.

  Perhaps it wouldn’t matter so much, except that we’re also a really, really different species in so many ways. We’re just beginning to explore our novel world. From the Arctic to the Antilles, and from Newfoundland to New York, humans are re-creating their niche, putting pressure on the gene pool to deal with all kinds of extremes. We live longer than our close ancestors, consume strange diets, walk upright with a funny pelvis, have babies with big heads, share our homes with a menagerie of animals, and cope with really complex
social settings. If you feel stressed at times, imagine things from the perspective of the genes that helped us get here.

  The point is that recent human evolution has required substantial changes in our genetic makeup, disrupting genetic relationships that had evolved over millions of years. These changes have left us exposed. Like an adolescent still growing up and trying to come to terms with a constantly changing world, we’re just a little uncomfortable with who we are. Presumably we’ll get to a more comfortable genetic place, but not for a few more hundred thousand generations.

  The Human Genome Project

  Let’s turn now to the issue of how geneticists study the origins of disease, beginning with something called the Human Genome Project. This is an effort to identify and describe the function of every one of the genes in the human genome, particularly those related to disease. Early on, there were some naïve expectations that just by sequencing a genome, the genes would be obvious and within a few years we would have cures for all the major maladies that afflict citizens of the developed world.

  It hasn’t turned out that way, for good reasons, but the technical accomplishments have exceeded expectations, and it is doubtful that anyone foresaw the direction that genome science would take. The first announcement of a draft human genome sequence was greeted by President Bill Clinton as a step toward a closer understanding of God’s design. Less spiritual observers saw it as a step toward diagnostics and interventions for hundreds of diseases. Cynics saw it as yet another example of scientists’ hubris in throwing hundreds of millions of dollars at a problem without solving anything. My sense is that, like man’s walking on the moon, it is an achievement that serves as an identifiable landmark in the emergence of a new domain of human endeavor, but will eventually be seen as just another small step along the human journey of self-perception.