Fig. 3.2.
Along the chromosome, each gene—each recipe, if you will—is a sequence of DNA letters that tells a cell how to make a particular protein. The proteins, in turn, make up much of the structure of a cell and, hence, the body, and carry out cellular functions. Thus, the genome consists of genes—sequences of DNA bases along the chromosomes—each of which codes for the assembly of a particular protein. Depending on the information in the genes, the proteins build an ant, a pine tree, or a human—with brown eyes or blue.
We humans are estimated to have about twenty-two thousand genes sprinkled among our chromosomes—that's only about 5 percent of the total DNA.4 The other 95 percent, sometimes called “junk DNA,” has long been thought of as sitting around twiddling its molecular thumbs doing nothing in particular. However, researchers are discovering that some junk DNA is intricately involved in the regulation of which genes are turned on or off in which tissues. This in turn ultimately determines an organism's phenotype—how an organism appears. Thus, although genes are still of paramount importance, there is a whole additional layer of complexity involving control of those genes—a sort of “index”—that we are just barely beginning to understand. What makes us special among primates may not so much be the genetic recipes themselves but when and where the regulatory sequences turn the genes on and off.
Even more interesting are recent findings based on how often genes repeat themselves—“copy number variants.”5 Perhaps 10 percent of genes, it seems, are in regions that can easily find themselves doubled, tripled, quadrupled, deleted, or scrambled. These different numbers and types of genetic copies can make dramatic differences in the genetic makeup between different population groups, as well as between more closely related individuals—perhaps even between siblings. The number of copies of different genes has already been linked with a variety of medical conditions, including Alzheimer's, kidney disease, and HIV. The expectation is that these copy number variants may become very significant in personality disorder research as well.
Differing versions of a gene that can fill a slot on a chromosome are called alleles. Alleles are simply variants of genes—kind of like a recipe variant where egg whites are substituted for egg yolks when baking a cake. But alleles can also be thought of as competitive versions of a gene. A different, “new and improved” version of an allele, for example, might help build a better molecule for ferrying oxygen around or might help grow sturdier bones.
But how do different alleles for a gene arise? Primarily through mutation. One of the bases—A, C, T, or G—might be miscopied when reproduction is taking place. Alternatively, sometimes genes stutter when they are copied, repeating certain parts of themselves, or, like dropping a stitch, losing a section. Either way, a slightly different allele is created that is passed down to future generations. Incidentally, about 25 percent of all human genes have alternate versions available. The lowest average number of alternate versions is found in the populations of New Guinea and Australia, while the dazzlingly highest number of alternate versions is found in the Middle East, western Asia, and southern, central, and eastern Europe.6
Yet even one simple change of a nucleotide at a single location can lead to problems—as if a cook used a teaspoon of salt instead of yeast in a recipe for bread. Such a change in a gene (making a new allele, or “flavor” of that gene) causes a change in the protein it builds. This often means that the protein doesn't function normally. Just such single mutations are responsible, not only for cystic fibrosis but for dozens of other devastating conditions such as hemophilia and sickle-cell anemia. Diseases such as Alzheimer's or schizophrenia, on the other hand, often involve more complicated confluences of unlucky alleles. The illustration below shows a few of the common and unusual illnesses that have so far been found to be associated with genes just on chromosome 17.
Our genotype is the actual information contained on the long strands of DNA molecules in the nucleus of our cells—we can determine our genotype only by using molecular methods. Our phenotype, on the other hand, relates to our appearance, which is determined by the output of the genotype and sometimes by environment as well.
Now we're ready to return to the subject of evolution. As we have seen, traits are controlled by a mix of genes—various alleles that affect characteristics such as skin color, disease resistance, memory, and even novelty seeking. If an allele helps produce a trait that confers an advantage, individuals who bear that allele will leave more offspring. That trait and that allele will occur in a greater proportion of individuals in the next generation, and the next generation as a whole will be better adapted to the environment. Sometimes, especially in small populations, chance events can also alter the mix of alleles in the next generation, a phenomenon called genetic drift. These incremental shifts in the frequency of alleles in the population—changes in the population's “gene pool”—constitute evolution. Specifically, they constitute a small-scale process termed microevolution. Larger-scale evolutionary change, such as the origin of new species or the founding of orders and classes, is called macroevolution.
Fig. 3.3.
MACHIAVELLIAN GENES
A complex array of varying genes underlies the many different outward manifestations—phenotypes—of many different personality disorders. A person with an unlucky shake of the genetic dice can actually end up with full-blown versions of those disorders right out of the chute—these unfortunates often show their dysfunctional characteristics in early childhood, despite a loving and stress-free environment.
However, a person with a lighter dose of the genetics for a personality disorder is not necessarily predestined to descend into a full-blown, clinical version. There are two routes such a person can follow. With a relatively stress-free environment, the person may simply grow into someone who is “normal” but who can sometimes be difficult to deal with emotionally. The other route involves succumbing to all-out traits of a personality disorder.
How might this happen?
The key, it appears, is often stress. When a person experiences bodily stress, for example, physical exercise, it can turn certain genes on or off—perhaps through the regulatory function of the junk DNA. In the case of exercise, this stress can turn on genes that cause muscle growth—you see the result in the form of bulging biceps. But a body can experience stress in other ways—for example, by being beaten by a parent, working for a bullying boss, or drinking too much alcohol. All of these activities, amazingly, can switch different sections of one's genetic code from quiescence to an all-too-active state—or vice versa.7 The resultant proteins, which have different properties from the nonstressed versions, can, in turn, affect our personalities. Depending on the stress and our genetic predisposition, we can be pushed toward depression, eating disorders, drug abuse, or cancer.8 If a person already has a mild form of a personality disorder, he or she can be pushed into a full-blown version.
Intermediate Phenotype
Intermediate phenotype is a concept used by researchers who are wrestling with the relationship between genes and phenotype. To understand “intermediate phenotype,” it's helpful to remember that there is often an intermediate case between a full-blown manifestation of a disease and a less harmful variant. In personality disorders, intermediate phenotypes, sometimes called endophenotypes, are used to describe people with subclinical symptoms of diseases like schizophrenia or borderline personality disorder. The stipulation for an intermediate phenotype is that it be found in mildly ill but not “certifiable” siblings and other relatives, and that it even be found in some psychiatrically well relatives. This establishes that the phenotypes are related to risk for an illness and are not the illness itself.
So far, the concept of intermediate phenotypes has been most powerfully developed and used by Dr. Michael Egan and his colleagues at the National Institute of Mental Health for their research on schizophrenia. Schizophrenia, like borderline personality disorder, is a complex disease that results from many causes, including a multitude
of genes and environmental factors such as drug abuse, head injury, infections, and even a person's conscious thinking processes—all of which can influence each other.
Egan's work clarified the relationship between a particular allele related to cognitive function that had previously been weakly and inconsistently associated with schizophrenia. When Egan's group applied the concepts of intermediate phenotype by studying brain function and comparing genotypes in a wide variety of people—including patients with schizophrenia, their healthy siblings, and controls—the suspect allele suddenly popped out as a strong predictor of abnormal prefrontal brain function. This happened in every person sampled, whether or not the person had schizophrenia. Egan's study was one of the first times that a correlation of an intermediate phenotype with a gene was shown to clarify how a gene related to a complex clinical diagnosis.9
“What's so surprising,” marvels Daniel Weinberger, Egan's colleague at the National Institute of Mental Health, “is that it works.”10 It appears that the next step beyond imaging genetics may relate to the synergistic use of genotyping, neuroimaging, and intermediate phenotypes. It will be exciting to see what future studies reveal when these techniques are applied to antisocial personality disorder, other related syndromes, and their subclinical “intermediate phenotypes.”
Faced with the overwhelming variety of phenotypes that can arise from this mixture of genes and environment, it's hard to know where to even begin looking at a person's genome to determine which alleles might be key in motivating behavioral traits. But a fascinating new discipline, imaging genetics, has recently arisen that provides precisely the necessary tool. Imaging genetics uses medical imaging techniques to figure out a person's phenotype—the word phenotype meaning, in this case, the size and shape of organs such as the amygdala and cingulate cortex—and then evaluating the same person's genes to see how they compare. The value of using medical imaging for the comparison with genetics, instead of old-fashioned questionnaires and interviews, is that genes act much more directly on neural components like the amygdala than they do on a person's ultimate behavior—and they don't lie. You might think of the old research as being the equivalent of trying to figure out how a racing car works by comparing its blueprints (genome) with its performance statistics (behavior)—a dry and thankless exercise at best. Today's imaging genetics allow you to open the car's hood and look around with sophisticated measurement tools on hand. This, in turn, allows you to make comparisons between blueprints and performance even while the engine is running, so you can figure out what's really going on.
But, you might ask, are we seeing the cause of certain thinking patterns? Or the effect? Clearly for some organic brain diseases, such as schizophrenia, we are seeing the effect. But for other conditions, it's often not clear. After all, use of antidepressants can alleviate depression by changing brain chemistry—these changes can be clearly seen with imaging techniques.11 But the same changes in neural chemistry can be seen after a patient has used cognitive therapy techniques to change her thinking patterns!12
If you ever want to know whether your tax dollars are being used for a good purpose, go take a look at the extraordinary work that the National Institute of Mental Health and other National Institutes of Health are doing in digging out the genetic bases of psychiatric illnesses. Dr. Weinberger, quoted above, also happens to be the director of the National Institute of Mental Health's Genes, Cognition, and Psychosis program. He is one of the leading researchers in this area, as indicated by the number of key papers related to the genetics of personality disorders that bear his name. When I spoke with him about this book, he reiterated his feelings that genes are about risk—not fate—and that no single gene by itself can predict personality.13
Most especially, we know that there is no single gene known to create a psychopath, or to cause someone to suffer from antisocial personality disorder, or to generate more sinisterly successful variants of either one of these disorders. But there are a number of genes and gene complexes that have been found to affect brain function—most importantly, for our purposes, regarding traits such as impulsivity, mood, and anxiety. Through the use of such sophisticated new techniques and concepts as imaging genetics and intermediate phenotypes, researchers are discovering how alleles of particular genes can help underpin the dysfunctional behavior that can lead to a problematic personality or full-blown clinical pathology. In a sense, you might call these evil genes.b. Let's focus on a few of them.
Serotonin Receptors and Behavior
A variety of different studies have converged on serotonin as being a key communication molecule—“neurotransmitter”—behind the generation and control of emotions. Neurotransmitters are like little flares that carry information across the gaps—synapses—between sending and receiving neurons (see the picture on the next page). It turns out that the serotonin flares can interact with about fifteen different types of receiving cell landing sites, called “receptors.” Once serotonin lands on a particular type of receptor, it sets in motion a whole Rube Goldberg–style chain of events. If serotonin hits one receptor, for example, it's metabolically akin to flipping a switch to start a ball bearing rolling down a ramp to bash against your toaster handle and start your morning toast. On the other hand, if it hits another kind of receptor, it's a sort of physiological equivalent of pushing a button that launches the ball bearing out a bedroom window, allowing it to bounce against a plate on a tree and back in the kitchen window below, thus tapping a coffeepot's ON switch and starting your morning cup of cellular java.
Why are there so many different kinds of serotonin receptors? Researchers speculate that serotonin has apparently been used as a communication molecule dating back even to very primitive organisms. This common molecule is found, after all, in pretty much anything with a backbone, as well as in spineless creatures such as flatworms, nematodes, and leeches. For all of these creatures, serotonin assists with sensing, motion-related, as well as cardiovascular functions. Basically, serotonin is a handy molecule for many different purposes.14 Different receptors on different receiving cells each respond to the little serotonin molecules by kicking their own pathways into gear. Serotonin receptors are each created according to templates set out by specific sets of genes, with each gene often having two, three, or even more different versions—that is, alleles. Obviously, all these different possibilities can make for a dizzying variety of potential genes related to serotonin receptors alone.
Fig. 3.4. The molecules of serotonin shown in this illustration are given off by the cell that is sending the message. The serotonin binds to “docks” (receptors) in the receiving cell and instructs that cell to either fire or stop firing, among other processes. The amount of serotonin in the gap known as the synapse, as well as the types of receptors (there are at least fifteen types), influences the cell's response. Two different types of sending cell molecules can reduce serotonin levels in synapses. Autoreceptors direct the cells to slow down serotonin production, while reuptake transporters absorb the neurotransmitter back into the sending cell to prepare for the next firing.
Different serotonin-related alleles have been found to be strongly associated with various aspects of personality and temperament, as well as mood disorders. But because these alleles interact and overlap, it's difficult to state definitively that any given allele is responsible for a given personality disorder. Sometimes an allele might help produce a disorder—but if that same allele is found with a constellation of other mitigating alleles, it might not produce the disorder at all. Indeed, the idea that groups of genes underlie personality types is an important one and has been given the name “QTL (Quantitative Trait Loci) Model” for behavioral traits.15
Our knowledge of how the different serotonin receptors relate to emotions is currently rather limited. We do know that one of those receptors, with the cryptic name 5-HT1B, plays a selective role in controlling offensive aggression.16 Other serotonin receptors have also been implicated in problematic behaviors. Certain a
lleles of the 5-HT2A receptor, for example, have been found to be associated with self-mutilation, anorexia, and a history of suicide attempts.17 The HT3A receptor, on the other hand, appears to have a critical influence on the amygdala (the “fight-or-flight” decision-making area of the brain), especially when a person is reacting to another's facial expressions. The HT3A receptor also affects how fast certain areas of the brain process information. Some versions of alleles related to this receptor appear to cause the extremes of neural activity seen in bipolar disorder.18 Overall, research about serotonin receptors and their associated alleles is just at the “tip of the iceberg” stage—enough to hint that there may be something going on related to precisely the sorts of emotions and behavior that are seen in various subclinical and clinical personality disorders.
On the other hand, if we switch our attention to serotonin transporters, as opposed to receptors, we will find that research is far more advanced.
The Long and the Short of It—Serotonin Transporters
Reflecting on the illustration a few pages back showing synapses and serotonin, we are reminded that serotonin receptors are equivalent to docking points that help trigger reactions in the next neuron. Once the reaction is triggered—the switch is flipped—the serotonin is then free to go back and float around in the space between the neurons. But if serotonin is already filling the space, how can a “sending” cell release new serotonin to trigger a new reaction? Somehow, the serotonin already in that space has to be pulled back into the original trigger neuron so that it can be used to trigger the next signal. One of the key molecules that helps do this is a special transporter molecule called SERT (for “serotonin transporter”). You can think of SERT as a cleverly designed protein conveyer belt that helps scoop excess serotonin out of the cleft between neurons and carry it back into the trigger neuron. Two different alleles have been found that help produce SERT—a short allele with fourteen tandem repeats, and a longer version with sixteen tandem repeats. (“Tandem repeats” is short for “repeated tandem base pairs,” such as GCGCGCGCGCGC. Sometimes the tandem repeats confuse the cell's DNA copying apparatus, so it's easier for these alleles to be miscopied and made shorter or longer.) The difference between the short and long SERT alleles doesn't lie in the information that codes for the transporter molecule itself but rather in the part of the gene that controls how often the transporter molecule gets produced. The short version of the allele doesn't allow for production of as many transporter molecules. You might think of it as a copy machine that puts out only half the copies you request. The resulting lack of transporter molecules allows serotonin to linger longer and appears to predispose people toward anxiety, impulsivity, suicidal thoughts, affective instability, bulimia, and binge drinking.19 People with two shorts (one from the mother and another from the father) have fewest transporters and seem to feel these effects most strongly.
Evil Genes Page 6
