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The Usual Suspects

It’s after midnight. The investigators hunker over a desk loaded with papers, coffee mugs, and stacks of manila folders. Their eyes, red and stinging from the room’s fluorescent lights and the lateness of the hour, pore over the contents of a folder labelled “7-repeat,” a member of the prominent DRD4 family with a nasty reputation. It’s a repeat offender, convicted on charges of aggravated ADHD and second-degree substance dependence. One of the investigators points to a line in the report. The other jots down the info in a notepad. Their efforts haven’t been in vain. They can pin the suspect to 18 victims in their sample alone.

They parse the data, make sure there isn’t some variable skulking behind the scenes, setting 7-repeat up as a fall guy. Nothing turns up. The case looks promising. With a satisfied nod, the investigators write up a warrant for further scrutiny. The charge: aiding and abetting the development of depression in susceptible children. A serious offence.

The human genome is a vast and labyrinthine network of codependent variables, dozens of which can be responsible for a single, seemingly simple trait. Nevertheless, researchers studying the effects of gene-by-environment interactions on childhood development seem to come across the same few subjects over and over again. These “usual suspects” are not the sole focus of this book — we will discuss other genes as well, along with studies that don’t focus on any one gene in particular — but their names will be mentioned frequently over the following chapters, so it is perhaps worth getting to know them. However, before we do that, we should first take a moment to discuss what exactly a gene is.

What Is a Gene?

It is outside the scope of this book to chronicle every gene responsible for moderating a person’s susceptibility to adverse conditions. Such a list would be far too extensive for our purposes, nor could its contents be truly exhaustive. The human genome contains a complex interplay of genetic and epigenetic variables (more on epigenetics in a later chapter), and our understanding of how it works is still far from comprehensive. The common notion that one gene is responsible for one trait is at best overly simplistic, and at worst completely false. Even the most simplistic traits are determined by multiple genes, and a single gene can be responsible for multiple traits.[7]

Perhaps part of the problem stems from the word gene itself. Despite the fact that just about everyone has heard of them, few people could accurately tell you exactly what genes are. This confusion extends into the scientific community, where the precise definition of the word gene remains fluid, as new discoveries continue to roil the already murky waters of our understanding. You might be wondering how this could be. We’ve cloned cats and sheep. We’ve made great strides in the field of genetic therapy. We’ve mapped the human genome. How could we have done all that without even knowing what a gene is?

The reason is that genes are more of a theoretical construction than a physical thing. They are a method of categorizing data in a manner satisfying to the human mind. But they do not, strictly speaking, exist.

When we discuss DNA, the molecules that make up the abstract concepts we refer to as genes, we are on firmer ground. The essential buildings blocks of genetics are nucleotides, tiny molecules comprised of a sugar, a phosphate, and a nucleobase. The bases determine the character of the nucleotide. They come in four varieties: adenine, thymine, cytosine, and guanine. Nucleotides are commonly referred to by whatever base they possess or, when documented in sequence, by each base’s first initial (A, T, C, and G, respectively).

The sugar of one nucleotide bonds readily with the phosphate of another, allowing nucleotides to form chains millions of units long called polymers. Each polymer links up with a sympathetic partner running parallel, and together the two molecules entwine, forming the iconic double helix as depicted on the front of biology textbooks the world over. Unlike the sugar–phosphate bonds of each individual polymer, which can occur regardless of which bases the adjacent nucleotides possess, the bonds between the two polymers are highly specific. Each nucleotide has only one compatible molecule: adenine links with thymine, and cytosine with guanine. As a result, each polymer forms a perfect template for its partner — by observing the nucleotide sequence of one strand, one could assemble a flawless replica of the other. This attribute is the backbone of genetic inheritance.

Nucleotides are the letters with which the sweeping epic of the human genome is written, and their alphabet, at a mere four characters, is mercifully small. However, just as an Anglophone could not pick up a book written in Swedish and read it simply by identifying the consonants and vowels, understanding the alphabet of DNA means little without an adequate grasp of its lexicon and grammar.

The nucleotide letters form “words” called codons, which in the language of DNA are all three letters long. Each codon represents an amino acid. When placed in sequence, they instruct the cells they inhabit to construct a series of amino acids called a polypeptide chain. The beginning and end of each chain is determined by special “start” and “stop” codons. These codons do not represent an amino acid. They are not words, but punctuation. With them, codon sequences form the genetic equivalent of sentences.

The common definition of a gene is a unit of inheritance that codes for a protein. If a gene is a group of nucleotides that codes for a protein, and a protein is a series of polypeptides linked together into a single unique shape, then, for the purposes of our metaphor, a gene is a set of one or more codon sequences, or a genetic paragraph. On the surface, the analogy seems apt. However, this straightforward definition has, in recent years, come up against significant scientific scrutiny. Unlike actual text, genes are not grouped neatly along a unidirectional, linear sequence, wherein the parameters between one gene and the next can clearly be set. Rather, a single gene sprawls across a great swath of DNA, and the sequences that code for a protein (called exons) are interspersed with long stretches called introns that code for nothing at all. Deemed “junk DNA” due to their apparent lack of function, introns must be transcribed into RNA and removed before the exons can be spliced together and sent outside the nucleus to be translated into amino acids. In literary terms, this would be the equivalent of garbage text banana judge effervescing creamsicles breaking up an otherwise philosophy the grandeur at sideways intelligible sentence. It is not, to our eyes, the most efficient way of doing things.[8]

Complicating matters further, a phenomenon called alternative splicing allows a single gene to code for more than one protein. During the splicing stage of gene transcription, where the selected passage of DNA has been transcribed into RNA and the introns are being removed, portions of the exon are occasionally omitted, creating an RNA sequence that will only code for some of the amino acids prescribed by the gene. This will change the character of the polypeptide chain and, ultimately, the protein. Though it may seem like an error in the transcription process, alternative splicing is a normal part of gene expression. In humans, approximately 95 percent of genes with more than one exon sequence are alternatively spliced, greatly increasing the amount of polypeptide chains for which the human genome can code.

As if things weren’t ill-defined enough, genes cannot even be read without the intervention of other genes. Proteins bond to groups of nucleotides called promoter sequences, which, true to their name, promote the transcription of the gene with which they are affiliated. Often, promoter sequences are found adjacent to the gene they promote, but recent research has shown this is not necessarily the case. Promoters can occur hundreds of thousands of base pairs away from the target gene, or even on a different chromosome altogether. What’s more, genes themselves can be cobbled together from the exons of other genes, some of which may come from two or more different chromosomes.

So, with all this in mind, what exactly is a gene? The term “unit of heredity,” though falling out of favour in some circles, is still fairly accurate. But unlike other units of measure — inches, litres, grams, and so forth — genes are not tied to any sort of physical constant. They can be dozens or hundreds or thousands of base pairs long. They can exist across great stretches of DNA, or even across chromosomes. They can reconfigure to different lengths and code for different end products through alternate splicing. They are defined, in short, not by any precise physical characteristic beyond their approximate molecular makeup (all contain sugars, phosphates, and nucleotides), but by what they do: code for an RNA chain.[9]

The genes we will discuss over the course of this book have each been labelled “the gene” for a plethora of adverse conditions, from alcoholism to heart disease to adultery. These hyperbolic claims are usually the result of errors in translation between scientists and the public, not a deliberate misrepresentation of the facts. “Gene for cheating found” simply makes for a better headline than “scientists discover three-way causal relationship between gene, environmental influences, and an increased predisposition toward adultery.” In truth, the genes accused of causing these conditions aren’t “causing” anything. They are, at most, permitting them to happen. How? That’s not an easy question to answer, in part because we don’t yet know precisely how these genes influence our behavioural development. However, on a purely chemical level, we have a good understanding of their purpose.

The Science of Feeling Good

The name Dopamine Receptor D4 (or DRD4) refers to both a gene and the protein-based product for which it codes,[10] called a receptor. A receptor is a protein product that facilitates communication between cells. A multitude of receptors exist within the human body, each attuned to one specific molecule. In this case, the dopamine receptor binds with — as one might suspect — dopamine. Along with serotonin (which we will get to shortly), dopamine is a neurotransmitter responsible for the sense of pleasure humans derive from sex, drugs, music, sunsets, ice cream sundaes, roller coasters, warm baths, books, and any other wonderful thing you care to name.

Before we continue, perhaps we should all take a minute to thank dopamine, because it’s almost impossible to name an activity humans engage in that this chemical does not facilitate. We are, after all, continually driven by our desire for some pleasurable reward, be it in the short term (eating at a nice restaurant, watching a funny movie) or long term (exercising to feel healthier, working long hours for financial gain and/or personal satisfaction). Thanks, dopamine!

Along with its duties in the reward centre of the brain, dopamine plays an important role in cognition, voluntary movement, sleep, attention, and memory. It is a truly versatile molecule, but its ability to induce pleasure is the attribute for which, arguably, it is most famous.

The human body contains more than one kind of dopamine receptor. There are five types known at present, labelled D1 through D5. Current research has indicated the possible presence of dopamine receptors D6 and D7 as well, although the results remain inconclusive. Our focus is on receptor D4. In order to understand why, we must elucidate on an important element of heredity called an allele.

Alleles and Polymorphisms

Perhaps, while sitting in biology class or watching the news or scanning an article in a popular science magazine, you have come across these two seemingly contradictory facts: a) chimpanzees and humans share approximately 98 percent of their genes,[11] and b) children share 50 percent of their genes with their mother and the other half with their father. Both of these facts are true. Ostensibly this suggests that, genetically speaking, you are much more closely related to the chimp you saw gallivanting about the zoo as a child than you are to either one of your parents. I hope you approach this conjecture with some skepticism, as it is, to say the least, suspicious.

How can facts A and B both be valid? The problem lies with the word gene, which is being used in an entirely different manner in each case.

For fact A, “98 percent of genes” actually refers to 98 percent of the genome, meaning that, should one draw a DNA sample from a human and a chimpanzee, document every base pair of nucleotides in their possession, and match them up, those pairs would be identical 49 times out of 50. This may seem surprising, but it’s actually quite logical. For a molecule that divides and replicates so rapaciously, DNA is remarkably stable. Mutations that slip by uncorrected are rare, and when they do happen, it is often in old age, when healthy, uncorrupted versions of the mutated sequence have long since been passed down to the next generation.

Fact B takes the similarities trumpeted by fact A for granted. Using the same logic as fact A, humans are all well over 99.9 percent identical, genetically speaking. That similarity is essential to our continued survival, as it allows humans to breed with humans and not with other animals. Your genome matches 99.9 percent (or 999 base pairs out of 1,000) to your mother and your father.

So what does fact B’s 50 percent refer to? Small but critical distinctions between humans called alleles.

Shuffling the Deck

As we have mentioned, a developmentally typical human has 46 chromosomes,[12] of which he inherits 23 from his mother and 23 from his father. Each person receives two copies of chromosomes 1 to 22 (called autosomal chromosomes), plus two sex chromosomes that bear no numeric title. These latter chromosomes are called X and Y, and they determine a person’s gender. Women get two copies of the X chromosome, while men get one X and one Y. During meiosis (the creation of gametes, or sperm and eggs), one chromosome of each type is selected at random. The same goes for sperm. During reproduction or fertilization (acts instigated by dopamine, the great motivator!), the two payloads combine, creating a new organism with a full set of chromosomes, a quarter of which (give or take a chromosome or two) came from each of its four grandparents.

Think of your genes as a deck of playing cards. Each deck contains 46 cards divided into two different suits. One suit came from your mother — call it clubs — and the other from your father — let’s say spades — meaning you got 23 cards from each of them. When creating reproductive cells, your body sorts through your genetic deck, selecting one card from each of the 23 pairs at random. The result is a half-deck containing one copy of cards 1 to 23, some of them clubs and some of them spades.

Now say you meet a partner of the opposite sex, hit it off, and reproduce.[13] His (or her) half deck combines with yours, contributing its own set of cards 1 to 23, compiled at random from his own maternal and paternal suits (call them diamonds and hearts). The resulting child has a full deck of 46 cards, 23 from you and 23 from your partner. Technically, the 23 cards your child inherited from you are themselves of two different suits — clubs and spades from your mother and father, respectively — but they have become, for all practical purposes, one suit. Genetic inheritance is thus the piecemeal combination of traits from various ancestors. With each subsequent generation, the level of genetic relatedness between elder and younger is roughly halved. After as few as six generations, there is a decent chance that a person doesn’t have a single chromosome in common with their ancestor, despite the order of their nucleotides remaining, as with all humans, 99.9 percent identical.

Though we have two copies of each autosomal chromosome, the pairs are by no means identical. If they were, the entire process of chromosomal shuffling would be useless. Every functioning chromosome is largely similar to others of its type, in that it codes for the same genes, is essentially the same length, and for the most part contains the same nucleotide sequences. However, certain genes have mutations that vary from person to person, causing them to function in a different manner. For example, almost everyone has the gene necessary to determine eye colour, but not everyone’s eyes are the same shade. Some have genes that code for brown eyes, while others have genes that code for green, or hazel, or blue. Genes with multiple derivatives are called polymorphisms, and they are responsible for the astounding variety of traits between humans. Since human beings have two copies of each chromosome, they have two copies of each polymorphic gene. The precise type (or types) they possess is called an allele.

Sometimes humans have two copies of the same allele, in which case they are homozygous. In other cases, they have two different alleles of the same gene, making them heterozygous. In these cases, the two alleles can interact in a number of ways, the most famous of which was discovered by an Austrian monk named Gregor Mendel. Mendelian genetics divides alleles into dominant and recessive types. When an individual possesses both a dominant and a recessive allele of the same gene, the result is not a compromise between the two. An individual with one brown eye allele and one blue eye allele will not develop murky blue irises, or one brown eye and one blue eye.[14] Rather, the dominant trait supersedes the recessive trait, which lies unexpressed in the gene, awaiting the opportunity to perhaps show itself in a subsequent generation. In the case of eye colour, blue eyes are recessive and brown eyes are dominant.[15] A man with one brown-eye allele (symbolized by a capital B) and one blue-eye allele (symbolized by a lower case b)[16] will have brown eyes. Say that man meets a brown-eyed woman who also has a recessive blue-eye allele, and together they have a child. The child’s eye colour genes could look one of four ways. She could be homozygous for the brown-eye allele (BB), heterozygous for the brown and blue-eye alleles (Bb or bB, depending on which allele comes from which parent), or homozygous for the blue-eye allele (bb). In the first three cases, the child, like her parents, will have brown eyes, as the presence of the dominant allele (B) overpowers that of the recessive allele (b). In the latter case, though, the dominant allele is not present, and so the child will have blue eyes.

Very few traits (including the one in our example) truly fit the Mendelian mould of single-gene origin and dominant/recessive binary.[17] Most traits require multiple genes to develop, and some single gene traits vary in their degrees of expressivity, or the extent to which the “dominant” trait dominates. Still others are co-dominant, meaning that neither allele overwhelms the other. Nevertheless, Mendel’s insights were remarkable, considering all he had to work with were a few pea plants and his own powers of observation. With these humble tools, Mendel documented the first evidence of genetic inheritance, paving the way for what would become arguably the biggest scientific undertaking of the 20th century: mapping the human genome.

DRD4

As we’ve already learned, DRD4 (the gene) codes for DRD4 (the receptor), and DRD4 allows the human brain to dole out jolts of positive reinforcement in the form of dopamine. Its connections to drug addiction and depression seem obvious — drugs being a pharmacological shortcut to euphoria, and depression being a chemical imbalance precluding one’s ability to experience pleasure — but what links DRD4 to ADHD, heart disease, or any of the other conditions to which it is accused of contributing? Moreover, why DRD4 and not DRD3 or DRD5? The answer lies in the allele.

Within the third exon (or section of codeable, non-“junk” DNA) of DRD4 sits a nucleotide sequence 48 base pairs long. This sequence repeats from 2 to 10 times, depending on the allele, contributing to DRD4’s reputation for being one of the most variable genes in the human genome. The 48 base-pair repeat is not the only repeated sequence in DRD4, nor is it the longest, but it is nevertheless the focus of a great deal of scientific scrutiny.

The most common number of repeats found in DRD4 are 3 and 4, but for susceptibility to depression, addiction, and a host of other maladies, 7 seems to be the magic number. For reasons that continue to elude us, the 7-repeat allele increases a person’s predisposition toward risk-seeking behaviour, which includes typical “high-risk” activities, such as drug use, illicit sex, and gambling, but also extends to extreme sports and high-pressure business decisions. This creates an odd schism in public opinion on the 7-repeat allele. While considered an albatross around the necks of junkies and problem gamblers, it can be seen as a positive attribute when possessed by athletes and successful business people, both of whom thrive in high-risk environments.

5-HTTLPR

We’ve already thanked dopamine for our ability to experience pleasure; it’s only fair we now give serotonin its due.

Though a neurotransmitter much like dopamine, serotonin is principally found in the gut, where it regulates intestinal movements. In the brain, it serves a very different function, facilitating feelings of happiness and well-being. The link between digestion and contentment may seem tenuous, but from an evolutionary standpoint, it’s actually quite logical. If one considers pleasure outside its cultural trappings, it’s ultimately an incentive for continued survival. Pleasure has become far more decadent in modern society, where basic necessities are freely available. But at its humble roots, pleasure is derived from activities necessary for the propagation of our species: sex, warmth, sleep, and, most importantly, food. As a result, we are genetically inclined to feel a sense of contentment when these needs are met, and a drive to meet them when they’re not. Serotonin helps us achieve this end.

Studies have linked serotonin levels to food availability, which, in social animals, also relates to one’s place in the social hierarchy. When injected with excess serotonin, animals with diminutive statuses in the hierarchy display uncharacteristically aggressive behaviour. In normal circumstances, a crayfish, when faced with a bigger opponent, will perform a supplicating tail-flip gesture that forces it backward, allowing it to flee. However, when injected with serotonin, it becomes more aggressive and attacks its opponent. Curiously, the opposite is true of dominant crayfish. When they receive a boost of serotonin, their behaviour becomes more fearful.

With this in mind, it is interesting to note the number of studies that link 5-HTT to a host of behavioural disorders in humans and other primates, including both anxiety and excess aggression. There is a wide gulf of evolutionary difference between people and prawns! But the effect of certain chemicals on the neurological system can be remarkably similar across species. The connection is purely speculative, but worth considering.

Unlike DRD4, 5-HTT is not itself a gene, but only a section of one. It sits on the promoter region of SLC6A4, which codes for a group of serotonin transporters. They affect the efficiency with which the human body can reabsorb and reuse serotonin after it has sent its first chemical message to the receptors. Since 5-HTT codes for the SLC6A4 promoter, it decides how much serotonin the body can reclaim. There are only two allelic variations — long (l) and short (s) — but they work in conjunction. Each person has two alleles of any one gene. With two copies of the gene and two possible forms the gene can take — long and short — there are four possible combinations a person can have: long/long, long/short, short/long, and short/short. For the sake of brevity, we will refer to these as l/l, l/s, and s/s (l/s and s/l amount to the same thing, so there is no point in distinguishing between them).

MAO-A

Though less of a key player than either DRD4 or 5-HTT, the MAO-A gene bears consideration, especially since its function is tied into that of the other two genes. MAO-A codes for monoamine oxidase A, an enzyme that breaks down neurotransmitters like serotonin and dopamine. Its function, or lack thereof, directly affects the amount of dopamine and serotonin in the human body.

Like DRD4, MAO-A has multiple allelic variations based on the number of times it repeats a particular sequence of nucleotides — in this case, one 30 base-pairs long. Humans can have anywhere from 2 to 5 repeats. Of these, the 4-repeat allele is considered high reactive, meaning it devours serotonin and dopamine more readily than its low-reactive counterparts.

MAO-A has been dubbed “the warrior gene,” as recent studies have discovered a correlation between its low-reactive allele and aggressive behaviour in response to provocation. Researchers Rose McDermott and Dustin Tingley devised a study to document the interaction between a person’s MAO-A genotype and his response to a perceived wrongdoing. Or, more accurately, a man’s MAO-A genotype. As MAO-A sits on the X chromosome, focusing the study solely on males reduced the list of possible genotypes to either high or low. Girls have two X chromosomes, making their MAO-A alleles significantly more complicated (instead of high or low, you have h/h, h/l, and l/l). We do not currently know if one or both of women’s MAO-A genes function at any one time, or whether a high-reactive allele trumps a low-reactive allele, or vice versa. As a result, our knowledge of MAO-A-by-environment interactions pertains only to men.

Ostensibly, men completed vocabulary tests in exchange for financial rewards. However, these tests were only a pretext for a subsequent game, during which an anonymous opponent could steal a certain amount of the man’s earnings. In retaliation, men were given the ability to inflict on the thief a somewhat bizarre punishment: making them ingest an unpleasant quantity of hot sauce. If the men chose not to use the hot sauce, it could be redeemed at the end of the game for money. Punishment, therefore, held negative consequences for both the thief and the victim. The thief would be subjected to a dose of hot sauce and the victim would use up a resource that could have otherwise earned back some (but not all) of the money the thief had stolen.

But here’s the trick: the thieves didn’t exist. Experimenters manipulated the rounds in order to divide men into different test and control groups. Some men had only a small amount of their earnings “stolen” from them, while others faced significantly greater losses. The reactions of each man were recorded and compared to their level of provocation — how much was stolen from them — and their MAO-A genotype.

Not surprisingly, men with either genotype who’d had significant portions of their earnings stolen from them acted more aggressively than men who’d lost less. However, among the men who’d lost considerable amounts, those with a low-reactive MAO-A were far more likely to pursue vengeance than those with a high-reactive version of the gene. This implies that men with low-reactive MAO-A only display greater aggression when provoked by a perceived slight, and not as a result of having an inherently domineering personality.

The warrior gene theory has garnered significant criticism since its inception, particularly because low-reactive versions of the MAO-A gene are less prevalent among Caucasians than other races, lending the research an unfortunate air of racial divisiveness. It’s not within the stated purpose of this book to weigh in on that particular debate, but whether the “warrior gene” exists or not, it is, at most, only half the story. For behaviours cannot be dictated by genes alone. Genetics may determine how easy it is to push a person’s buttons, but the finger that actually pushes them belongs to the early caregiving environment — how a person was parented.