08-fertilized-egg

I Eight Back to When You Were Just a Fertilized Egg ’m reminded of a cartoon where one lab-coated scientist is telling the other, “You know how you’re on the phone, and the other person wants to get off but won’t say it, so they say, ‘Well, you probably need to get going,’ like you’re the one who wants to get off, when it’s really them? I think I found the gene for that.” This chapter is about progress in finding “the gene for that.” — Our prototypical behavior has occurred. How was it influenced by events when the egg and sperm that formed that person joined, creating their genome—the chromosomes, the sequences of DNA—destined to be duplicated in every cell in that future person’s body? What role did those genes play in causing that behavior? Genes are relevant to, say, aggression, which is why we’re less alarmed if a toddler pulls at the ears of a basset hound rather than a pit bull. Genes are relevant to everything in this book. Many neurotransmitters and hormones are coded for by genes. As are molecules that construct or degrade those messengers, as are their receptors. Ditto for growth factors guiding brain plasticity. Genes typically come in different versions; we each consist of an individuated orchestration of the different versions of our approximately twenty thousand genes. This topic carries two burdens. The first reflects many people being troubled by linking genes with behavior—in one incident from my academic youth, a federally funded conference was canceled for suggesting that genes were pertinent to violence. This suspicion of gene/behavior links exists because of the pseudoscientific genetics used to justify various “isms,” prejudice, and discrimination. Such pseudoscience has fostered racism and sexism, birthed eugenics and forced sterilizations, allowed scientifically meaningless versions of words like “innate” to justify the neglect of have-nots. And monstrous distortions of genetics have fueled those who lynch, ethnically cleanse, or march children into gas chambers.1 But studying the genetics of behavior also carries the opposite burden of people who are overly enthusiastic about the subject. After all, this is the genomics era, with personalized genomic medicine, people getting their genomes sequenced, and popular writing about genomics giddy with terms like “the holy grail” and “the code of codes.” In a reductionist view, understanding something complex requires breaking it down into its components; understand those parts, add them together, and you’ll understand the big picture. And in this reductionist world, to understand cells, organs, bodies, and behavior, the best constituent part to study is genes. Overenthusiasm for genes can reflect a sense that people possess an immutable, distinctive essence (although essentialism predates genomics). Consider a study concerning “moral spillover” based on kinship.2 Suppose a person harmed people two generations ago; are this person’s grandchildren obliged to help his victims’ grandchildren? Subjects viewed a biological grandchild as more obligated than one adopted into the family at birth; the biological relationship carried a taint. Moreover, subjects were more willing to jail two long-lost identical twins for a crime committed by one of them than to jail two unrelated but perfect look-alikes—the former, raised in different environments, share a moral taint because of their identical genes. People see essentialism embedded in bloodlines—i.e., genes. This chapter threads between these two extremes, concluding that while genes are important to this book’s concerns, they’re far less so than often thought. The chapter first introduces gene function and regulation, showing the limits of genes’ power. Next it examines genetic influences on behavior in general. Finally we’ll examine genetic influences on our best and worst behaviors. W PART I: GENES FROM THE BOTTOM UP e start by considering the limited power of genes. If you are shaky about topics such as the central dogma (DNA codes for RNA, which codes for protein sequence), protein structure determining function, the three-nucleotide codon code, or the basics of point, insertion, and deletion mutations, first read the primer in appendix 3. Do Genes Know What They Are Doing? The Triumph of the Environment So genes specify protein structure, shape, and function. And since proteins do virtually everything, this makes DNA the holy grail of life. But no—genes don’t “decide” when a new protein is made. Dogma was that there’d be a stretch of DNA in a chromosome, constituting a single gene, followed by a stop codon, followed immediately by the next gene, and then the next. . . . But genes don’t actually come one after another—not all DNA constitutes genes. Instead there are stretches of DNA between genes that are noncoding, that are not “transcribed.”* And now a flabbergasting number— 95 percent of DNA is noncoding. Ninety-five percent. What is that 95 percent? Some is junk—remnants of pseudogenes inactivated by evolution.3 But buried in that are the keys to the kingdom, the instruction manual for when to transcribe particular genes, the on/off switches for gene transcription. A gene doesn’t “decide” when to be photocopied into RNA, to generate its protein. Instead, before the start of the stretch of DNA coding for that gene is a short stretch called a promoter—the “on” switch. What turns the promoter switch on? Something called a transcription factor (TF) binds to the promoter. This causes the recruitment of enzymes that transcribe the gene into RNA. Meanwhile, other transcription factors deactivate genes. This is huge. Saying that a gene “decides” when it is transcribed* is like saying that a recipe decides when a cake is baked. Thus transcription factors regulate genes. What regulates transcription factors? The answer devastates the concept of genetic determinism: the environment. To start unexcitingly, “environment” can mean intracellular environment. Suppose a hardworking neuron is low on energy. This state activates a particular transcription factor, which binds to a specific promoter, which activates the next gene in line (the “downstream” gene). This gene codes for a glucose transporter; more glucose transporter proteins are made and inserted into the cell membrane, improving the neuron’s ability to access circulating glucose. Next consider “environment,” including the neuron next door, which releases serotonin onto the neuron in question. Suppose less serotonin has been released lately. Sentinel transcription factors in dendritic spines sense this, travel to the DNA, and bind to the promoter upstream of the serotonin receptor gene. More receptor is made and placed in the dendritic spines, and they become more sensitive to the faint serotonin signal. Sometimes “environment” can be far-flung within an organism. A male secretes testosterone, which travels through the bloodstream and binds to androgen receptors in muscle cells. This activates a transcription-factor cascade that results in more intracellular scaffolding proteins, enlarging the cell (i.e., muscle mass increases). Finally, and most important, there is “environment,” meaning the outside world. A female smells her newborn, meaning that odorant molecules that floated off the baby bind to receptors in her nose. The receptors activate and (many steps later in the hypothalamus) a transcription factor activates, leading to the production of more oxytocin. Once secreted, the oxytocin causes milk letdown. Genes are not the deterministic holy grail if they can be regulated by the smell of a baby’s tushy. Genes are regulated by all the incarnations of environment. In other words, genes don’t make sense outside the context of environment. Promoters and transcription factor introduce if/then clauses: “If you smell your baby, then activate the oxytocin gene.” Now the plot thickens. There are multiple types of transcription factors in a cell, each binding to a particular DNA sequence constituting a particular promoter. Consider a genome containing one gene. In that imaginary organism there is only a single profile of transcription (i.e., the gene is transcribed), requiring only one transcription factor. Now consider a genome consisting of genes A and B, meaning three different transcription profiles—A is transcribed, B is transcribed, A and B are transcribed —requiring three different TFs (assuming you activate only one at a time). Three genes, seven transcription profiles: A, B, C, A + B, A + C, B + C, A + B + C. Seven different TFs. Four genes, fifteen profiles. Five genes, thirty-one profiles.* As the number of genes in a genome increases, the number of possible expression profiles increases exponentially. As does the number of TFs needed to produce those profiles. Now another wrinkle that, in the lingo of an ancient generation, will blow your mind. TFs are usually proteins, coded for by genes. Back to genes A and B. To fully exploit them, you need the TF that activates gene A, and the TF that activates gene B, and the TF that activates genes A and B. Thus there must exist three more genes, each coding for one of those TFs. Requiring TFs that activate those genes. And TFs for the genes coding for those TFs . . . Whoa. Genomes aren’t infinite; instead TFs regulate one another’s transcription, solving that pesky infinity problem. Importantly, across the species whose genomes have been sequenced, the longer the genome (i.e., roughly the more genes there are), the greater the percentage of genes coding for TFs. In other words, the more genomically complex the organism, the larger the percentage of the genome devoted to gene regulation by the environment. Back to mutations. Can there be mutations in DNA stretches constituting promoters? Yes, and more often than in genes themselves. In the 1970s Allan Wilson and Mary-Claire King at Berkeley correctly theorized that the evolution of genes is less important than the evolution of regulatory sequences upstream of genes (and thus how the environment regulates genes). Reflecting that, a disproportionate share of genetic differences between chimps and humans are in genes for TFs. Time for more complexity. Suppose you have genes 1–10, and transcription factors A, B, and C. TF-A induces the transcription of genes 1, 3, 5, 7, and 9. TF-B induces genes 1, 2, 5, and 6. TF-C induces 1, 5, and 10. Thus, upstream of gene 1 are separate promoters responding to TFs A, B, and C—thus genes can be regulated by multiple TFs. Conversely, each TF usually activates more than one gene, meaning that multiple genes are typically activated in networks (for example, cell injury causes a TF called NF-κB to activate a network of inflammation genes). Suppose the promoter upstream of gene 3 that responds to promoter TF-A has a mutation making it responsive to TF-B. Result? Gene 3 is now activated as part of a different network. Same networkwide outcome if there is a mutation in a gene for a TF, producing a protein that binds to a different promoter type.4 Consider this: the human genome codes for about 1,500 different TFs, contains 4,000,000 TF-binding sites, and the average cell uses about 200,000 such sites to generate its distinctive gene-expression profile.5 This is boggling. Epigenetics The last chapter introduced the phenomenon of environmental influences freezing genetic on/off in one position. Such “epigenetic” changes* were relevant to events, particularly in childhood, causing persistent effects on the brain and behavior. For example, recall those pair-bonding prairie voles; when females and males first mate, there are epigenetic changes in regulation of oxytocin and vasopressin receptor genes in the nucleus accumbens, that target of mesolimbic dopamine projection.6 Let’s translate the last chapter’s imagery of “freezing on/off switches” into molecular biology.7 What mechanisms underlie epigenetic changes in gene regulation? An environmental input results in a chemical being attached tightly to a promoter, or to some nearby structural proteins surrounding DNA. The result of either is that TFs can no longer access or properly bind to the promoter, thus silencing the gene. As emphasized in the last chapter, epigenetic changes can be multigenerational.8 Dogma was that all the epigenetic marks (i.e., changes in the DNA or surrounding proteins) were erased in eggs and sperm. But it turns out that epigenetic marks can be passed on by both (e.g., make male mice diabetic, and they pass the trait to their offspring via epigenetic changes in sperm). Recall one of the great punching bags of science history, the eighteenth- century French biologist Jean-Baptiste Lamarck.9 All anybody knows about the guy now is that he was wrong about heredity. Suppose a giraffe habitually stretches her neck to reach leaves high in a tree; this lengthens her neck. According to Lamarck, when she has babies, they will have longer necks because of “acquired inheritance.”* Lunatic! Buffoon! Epigenetically mediated mechanisms of inheritance—now often called “neo-Lamarckian inheritance”— prove Lamarck right in this narrow domain. Centuries late, the guy’s getting some acclaim. Thus, not only does environment regulate genes, but it can do so with effects that last days to lifetimes. The Modular Construction of Genes: Exons and Introns Time to do in another dogma about DNA. It turns out that most genes are not coded for by a continuous stretch of DNA. Instead there might be a stretch of noncoding DNA in the middle. In that case, the two separate stretches of coding DNA are called “exons,” separated by an “intron.” Many genes are broken into numerous exons (with, logically, one less intron than the number of exons). How do you produce a protein from an “exonic” gene? The RNA photocopy of the gene initially contains the exons and introns; an enzyme removes the intronic parts and splices together the exons. Clunky, but with big implications. Back to each particular gene coding for a particular protein.10 Introns and exons destroy this simplicity. Imagine a gene consisting of exons 1, 2, and 3, separated by introns A and B. In one part of the body a splicing enzyme exists that splices out the introns and also trashes exon 3, producing a protein coded for by exons 1 and 2. Meanwhile, elsewhere in the body, a different splicing enzyme jettisons exon 2 along with the introns, producing a protein derived from exons 1 and 3. In another cell type a protein is made solely from exon 1. . . . Thus “alternative splicing” can generate multiple unique proteins from a single stretch of DNA; so much for “one gene specifies one protein”—this gene specifies seven (A, B, C, A-B, A-C, B-C, and A-B-C). Remarkably, 90 percent of human genes with exons are alternatively spliced. Moreover, when a gene is regulated by multiple TFs, each can direct the transcription of a different combination of exons. Oh, and splicing enzymes are proteins, meaning that each is coded for by a gene. Loops and loops. Transposable Genetic Elements, the Stability of the Genome, and Neurogenesis Time to unmoor another cherished idea, namely that genes inherited from your parents (i.e., what you started with as a fertilized egg) are immutable. This calls up a great chapter of science history. In the 1940s an accomplished plant geneticist named Barbara McClintock observed something impossible. She was studying the inheritance of kernel color in maize (a frequent tool of geneticists) and found patterns of mutations unexplained by any known mechanism. The only possibility, she concluded, was that stretches of DNA had been copied, with the copy then randomly inserted into another stretch of DNA. Yeah, right. Clearly McClintock, with her (derisively named) “jumping genes,” had gone mad, and so she was ignored (not exactly true, but this detracts from the drama). She soldiered on in epic isolation. And finally, with the molecular revolution of the 1970s, she was vindicated about her (now termed) transposable genetic elements, or transposons. She was lionized, canonized, Nobel Prized (and was wonderfully inspirational, as disinterested in acclaim as in her ostracism, working until her nineties). Transpositional events rarely produce great outcomes. Consider a hypothetical stretch of DNA coding for “The fertilized egg is implanted in the uterus.” There has been a transpositional event, where the underlined stretch of message was copied and randomly plunked down elsewhere: “The fertilized eggterus is implanted in the uterus.” Gibberish. But sometimes “The fertilized egg is implanted in the uterus” becomes “The fertilized eggplant is implanted in the uterus.” Now, that’s not an everyday occurrence. — Plants utilize transposons. Suppose there is a drought; plants can’t move to wetter pastures like animals can. Plant “stress” such as drought induces transpositions in particular cells, where the plant metaphorically shuffles its DNA deck, hoping to generate some novel savior of a protein. Mammals have fewer transposons than plants. The immune system is one transposon hot spot, in the enormous stretches of DNA coding for antibodies. A novel virus invades; shuffling the DNA increases the odds of coming up with an antibody that will target the invader.* The main point here is that transposons occur in the brain.11 In humans transpositional events occur in stem cells in the brain when they are becoming neurons, making the brain a mosaic of neurons with different DNA sequences. In other words, when you make neurons, that boring DNA sequence you inherited isn’t good enough. Remarkably, transpositional events occur in neurons that form memories in fruit flies. Even flies evolved such that their neurons are freed from the strict genetic marching orders they inherit. Chance Finally, chance lessens genes as the Code of Codes. Chance, driven by Brownian motion—the random movement of particles in a fluid—has big effects on tiny things like molecules floating in cells, including molecules regulating gene transcription.12 This influences how quickly an activated TF reaches the DNA, splicing enzymes bump into target stretches of RNA, and an enzyme synthesizing something grabs the two precursor molecules needed for the synthesis. I’ll stop here; otherwise, I’ll go on for hours. Some Key Points, Completing This Part of the Chapter a. Genes are not autonomous agents commanding biological events. b. Instead, genes are regulated by the environment, with “environment” consisting of everything from events inside the cell to the universe. c. Much of your DNA turns environmental influences into gene transcription, rather than coding for genes themselves; moreover, evolution is heavily about changing regulation of gene transcription, rather than genes themselves. d. Epigenetics can allow environmental effects to be lifelong, or even multigenerational. e. And thanks to transposons, neurons contain a mosaic of different genomes. In other words, genes don’t determine much. This theme continues as we focus on the effects of genes on behavior. L PART 2: GENES FROM THE TOP DOWN— BEHAVIOR GENETICS ong before anything was known about promoters, exons, or transcription factors, it became clear that you study genetics top down, by observing traits shared by relatives. Early in the last century, this emerged as the science of “behavior genetics.” As we’ll see, the field has often been mired in controversy, typically because of disagreements over the magnitude of genetic effects on things like IQ or sexual orientation. First Attempts The field began with the primitive idea that, if everyone in a family does it, it must be genetic. This was confounded by environment running in families as well. The next approach depended on closer relatives having more genes in common than distant ones. Thus, if a trait runs in a family and is more common among closer relatives, it’s genetic. But obviously, closer relatives share more environment as well—think of a child and par