Chapter 3
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