Main Genetics 101: From Chromosomes and the Double Helix to Cloning and DNA Tests, Everything You Need...
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Ibrahim Uba Zango
Student of animal breeding and genetics
14 September 2020 (08:23)
TRANSCRIPTION AND RNA Copying the Recipe We’ve been talking about DNA as a collection of recipes. In this section, we get to see how those recipes actually get made. Many of our recipes, or genes, are instructions for making specific proteins. We’ll learn more about proteins in the “What Proteins Do” section, but for now you just need to know that we make a ton of different ones. Your muscles, for example, owe their strength to proteins called actin and myosin that can contract to shorten the muscle. Your blood can carry oxygen to keep you alive thanks to a protein called hemoglobin in your red blood cells. And your digestive tract can break down food thanks to a variety of digestive enzymes produced by the stomach, pancreas, and small intestine. Each of these proteins, and thousands more, needs to be carefully built from the instructions contained in your genes. The two major steps in making the protein are: 1. Copying the gene by creating a new molecule of RNA with a matching sequence of bases. This is called transcription. 2. Building the protein according to the instructions in the RNA. This step is called translation. If it’s hard to remember which one is which, remember that when we transcribe something in real life, we are usually writing down something that happened in a recording. Both the speech and the writing are in the same language. Similarly, the RNA is in the same “language” of nucleotides as DNA—just a different dialect, as we’ll see. But converting the language of nucleotides into the language of protein is a tougher job, and it really is more like translation. Or you can just remember that in the alphabet, the c (in transcription) comes before the l (in translation). That works too. The Central Dogma In 1957, Francis Crick, already famous for his role in discovering the structure of DNA, gave a lecture in which he explained a hypothesis he had: that “the main function of the genetic material is to control . . . the synthesis of proteins.” He argued that the inf; ormation in a nucleic acid like RNA can be used to make proteins, but not vice versa, and called this idea the “Central Dogma” of molecular biology. A variation on this, the rule of thumb that DNA is transcribed into RNA, and that RNA is translated into protein, is part of every genetics student’s education today. The only problem is that it’s not really a dogma. Dogma is a religious term for a set of principles that some authority declares to be true and everybody must believe it. That’s not how science works! An idea only sticks around for as long as it is backed up by evidence. Crick later admitted that he misunderstood the word—but it was too late. The name stuck. WHAT IS RNA? RNA is ribonucleic acid. Compare that to DNA’s full name, deoxyribonucleic acid. These two molecules are very close relatives. Like DNA, RNA is made of nucleotides that in turn are each made of a phosphate, a sugar, and a nitrogenous base. In DNA, the sugar portion is a type of sugar called deoxyribose. In RNA, it’s ribose. The difference, as you might guess from the name, is that ribose has an extra oxygen atom that deoxyribose does not. This chemical difference has consequences. RNA breaks down more easily, while DNA is more stable. (Be glad that your genome is stored on DNA!) RNA is also more flexible than stiff and stuffy DNA, so you’ll find RNA in all kinds of shapes, not just a long double helix. Thanks to this folding, RNA can also base-pair with itself, so it doesn’t need another strand to act as its partner. In some of the sections to come, we’ll see some of the ways RNA takes advantage of these features. Finally, RNA and DNA also differ in their nucleotide code. You’ll recall that in DNA, adenine matches up with thymine, and guanine matches up with cytosine. But RNA doesn’t use thymine, so adenine binds with uracil instead. (Guanine and cytosine still work the usual way.) DIFFERENCES BETWEEN DNA AND RNA DNA RNA Sugar: deoxyribose Sugar: ribose Base pairing: A/T, G/C Base pairing: A/U, G/C Double stranded Usually single stranded, but may fold back on itself in a variety of shapes Very stable Easily broken down WHY TRANSCRIBE? In our cells, most of our DNA lives in a compartment called the nucleus. But the proteins are made outside of that nucleus, in the main part of the cell called the cytoplasm. The process for making proteins doesn’t really work with double-stranded DNA, anyway, so we copy the gene’s information into a strand of RNA called messenger RNA, or mRNA. Think again of our DNA as a valuable set of cookbooks. They’re heavy and kind of a pain to deal with, and you certainly wouldn’t want to splash spaghetti sauce on them in the kitchen. So, you leave them on the shelf in the living room and copy the recipe you want onto a scrap of paper. Time to get cooking! Bacteria don’t keep their DNA in a nucleus, but they still transcribe their genes into messenger RNA. Controlling when genes get transcribed is a good way to control when a gene’s product is made, so the transcription step turns out to be handy for every form of life, whether they have a nucleus or not. HOW IT HAPPENS Our cells have enzymes whose job is to transcribe DNA into RNA copies. These enzymes are made of protein, and their shapes allow them to grab onto DNA and RNA and do all the little microscopic actions required to make the transcript. And yes, these proteins were themselves made by the process of transcription and translation. One important enzyme is called an RNA polymerase, because it can chain nucleotides together to make the polymer we know as a full-blown RNA strand. It waits for the nucleotide to float into the right spot, pairing to the DNA; then RNA polymerase locks it to the growing RNA chain so it can’t get away. There are about one hundred other proteins that work in a team to get transcription started, including helicase, which unzips the double helix to let the other proteins get to the DNA so they can do their work. A complex of RNA polymerase and some of these other proteins actually moves as it works, chugging along the DNA as it creates the RNA chain. After they finish, the proteins leave the DNA strand, and the double helix zips back up. FINISHING TOUCHES After we’ve created the transcript, we’re still not done. That transcript needs a bunch of finishing touches, so other proteins and special RNAs gather around to give it a little RNA makeover. One important step is splicing. Bacteria are lucky; their genes contain just the right amount of information, so their mRNAs go straight from the transcription step to translation. But ours are far too long! They contain useful chunks of genetic instructions, and we call those chunks the exons. But in between those exons are long stretches of RNA that don’t help code for the protein. These garbage sequences are the introns, and the purpose of splicing is to cut out the introns and get rid of them. So wait, why do we have introns in the first place? Often because the gene can be read multiple ways. Cut out these introns, and you have one protein. Or cut out a different set of introns, and you’ll get something else entirely. This is called alternative splicing. Other kinds of processing happen too. For example, a team of enzymes adds a “tail” of hundreds of adenosine nucleotides to the mRNA. This tail protects the mRNA from being degraded, or broken down, too quickly. It also helps other proteins to recognize the mRNA as something that’s ready to be carried out of the nucleus. Once the mRNA has been created, processed, and edited, it’s time for the mRNA to leave the nucleus and head out to where the ribosomes are waiting. Thank you for downloading this Simon & Schuster ebook. Get a FREE ebook when you join our mailing list. Plus, get updates on new releases, deals, recommended reads, and more from Simon & Schuster. Click below to sign up and see terms and conditions. CLICK HERE TO SIGN UP Already a subscriber? Provide your email again so we can register this ebook and send you more of what you like to read. You will continue to receive exclusive offers in your inbox. YOUR CELLS’ INSTRUCTION MANUAL What DNA Does DNA is what makes us who we are. But how does it do that? To answer that question, we have to zoom in to a level even smaller than what microscopes can see. DNA is a long, stringy molecule whose job is to carry information. To understand that, think for a minute about this book. It’s just letters, one after another, that taken together form words and sentences and chapters. A DNA strand is made up of millions of chemical components that function like letters, spelling out an instruction manual with all the information it takes to build and run a human body. (Or an animal’s body or even a plant or a bacterium. Every living thing has DNA.) Noncoding DNA There’s more to our DNA than just recipes, though. Think of the genome as a deluxe cookbook with a ton of extra information, like how to plan a dinner party or suggested menus for a week’s dinners. That information is helpful so you know when to make the recipes. But it’s also a sloppy cookbook: there might be three versions of the same dish, and only one of them is worth making. Perhaps there are even some recipe cards and scraps of paper tucked into the pages, things that you’re not quite sure where they came from but you’re not sure if it’s okay to throw them away. Our DNA has scraps like that too. There is far more information in DNA than in a book, though. If you printed it out, our genome—all the information carried in our DNA—would fill twelve thousand books this size. Our genome isn’t just one string of DNA; it’s actually split into pieces called chromosomes. I like to think of our twenty-three chromosomes as a recipe collection in twenty-three enormous volumes. Like a real cookbook, DNA contains short sets of instructions—think of them as recipes. Each recipe, or gene, contains the instructions to make one tiny piece of who we are. Since we are all different, our recipes vary slightly. My genes include instructions on how to make a brown pigment and put it into my hair follicles. But your hair may be colored differently from mine if your genes encode a recipe for a different pigment. Or perhaps that page in your recipe book is blank, and you don’t put any pigment in your hair at all. You have two copies of this cookbook encyclopedia in each cell of your body. Cells are, in a sense, the kitchens where the recipes are made. WHAT IS A CELL? Your body contains over thirty-seven trillion cells. That’s a huge number, right? You have more cells in your body than there are dollars in the national debt or stars in the Milky Way. You have skin cells, muscle cells, fat cells, nerve cells, and bone cells, just to name a few. They’re all so small you can only see them with a microscope. Every time you scratch an itch, hundreds of skin cells flake off, and you don’t even notice. Nearly every one of those cells contains all of the DNA we just talked about. Double that, actually, since you keep two copies around—the one you got from your mom and the one you got from your dad. Mitochondria Have DNA Too Most of our organelles are pretty boring, but there’s a special one called the mitochondrion (plural: mitochondria) that helps turn food into energy. It’s so special that it has its own DNA that it doesn’t share with us. Scientists think this is because mitochondria used to be free-roaming bacteria that one day got eaten—but not digested—by a larger cell. After millions of years, we’re like best friends: inseparable. Our cells have different compartments, or organelles, separated from each other by membranes. We keep those two full sets of our DNA in their own organelle called the nucleus. This way they’re safe from all the chaos going on in the rest of the cell. (Think of it like a special library for our cookbook collection.) CHOOSING RECIPES If all of our cells have the same cookbook collection, why aren’t they all following the same instructions all the time? If they did that, all thirty-seven trillion of our cells would look alike. What actually happens is that skin cells only use the genes that are necessary to do skin cell things. Muscle cells only use the genes that help them do muscle cell things. (Skin cells and muscle cells have plenty of things in common, of course, so some recipes are used by both.) Even in a single cell type, things change all the time. Brain cells use different genes during the day than at night, for example. Your stomach cells use different genes when you’re digesting food than they do during those long stretches between meals. And you’ll use a different mix of genes as an adult than when you were a baby. ATOMS AND MOLECULES The Building Blocks of DNA DNA is a huge molecule, made of millions of atoms. The best way to understand the difference between atoms and molecules is to sit down with a molecular model kit. You can sometimes find these in chemistry classrooms or college bookstores, which makes them seem very serious, but in reality, a molecular model kit is just a very fun toy. Try Building Alcohol If water is too boring, you can make ethanol, which is the kind of alcohol that’s in beer and wine. Start with a carbon and add three hydrogens. On the fourth toothpick, stick another carbon, and give that carbon two hydrogens. The second carbon should now have three toothpicks in it, so for the fourth toothpick you’ll add the hydroxyl group, which is just an oxygen atom that has a hydrogen attached. That -OH group is what makes it an alcohol. If you don’t have one, that’s fine! You can play along at home with a bag of gumdrops and a box of toothpicks. Let’s start with a simple molecule: water. You probably know water’s chemical formula already: H2O. That means it has two hydrogen atoms and one oxygen atom. If you’re doing the candy version of this exercise, grab a red gumdrop and stick two toothpicks into it. That red gumdrop is your oxygen atom. Take two white gumdrops to represent the two atoms of hydrogen and stick them at the other end of each toothpick. You’ve just made H2O. If you’re lucky enough to have a model kit, the hydrogen atoms will be built with just one socket where a connector can fit in. The oxygen atoms will have two sockets. That’s because in real life, oxygen can (normally) only make two bonds. Hydrogen makes just one. The Atoms We’ll Be Working With Most of the molecules in our cells can be made with just six atoms. Think of them as your organic chemistry starter kit: • Carbon (4 bonds) • Hydrogen (1 bond) • Oxygen (2 bonds) • Nitrogen (3 bonds) • Phosphorus (it’s complicated) • Sulfur (likewise) Of these, you only need the first five to build DNA. Carbon, on the other hand, can make four bonds, so the little black spheres that represent carbon will have four sockets in them. That’s the advantage of the model kit: each piece has an appropriate number of sockets. If you’re using gumdrops, you have to remember, on your own, how many toothpicks to put into each atom. WHAT ARE ATOMS? Have you ever heard of the periodic table of elements? It’s that weird-shaped chart with one square for each known element. Some are things you’ve heard of: carbon, hydrogen, and oxygen, for example. Others are metals, and you’ve heard of a lot of these too: gold, silver, aluminum, copper. Neon, the gas that fills the tubes in light-up neon signs, is also an element. These elements are really just the flavors that atoms can come in. What determines the flavor of an atom? It’s the number of protons the atom has. Hydrogen has one proton, helium has two, and so on. If you’re wondering about some of the elements we’ve already met, carbon has six protons, nitrogen has seven, and oxygen has eight. Gold has seventy-nine, and uranium has ninety-two. Protons have a positive charge, so the more protons an atom has, the more negatively charged electrons it can collect. You don’t need to understand protons and electrons (or their neutrally charged buddies, neutrons) to be able to understand this book, so if this sounds like too much chemistry all at once, don’t sweat it. We just mention them because the electrons are what determine the number of bonds an atom can make. GIANT MOLECULES As you tinker with your gumdrops and toothpicks, you might get carried away and decide to make the biggest molecules you can. And if you have a mega-sized bag of gumdrops, you’ll find that molecules can be enormous! For example, say you look up how to make a molecule of glucose—it forms a ring, so it looks kind of like a spiky crown. Make a bunch of these, and you can start chaining them together to build starch, the carbohydrate that provides most of the calories in foods like bread, pasta, and rice. Molecules like starch that are made from repeats of smaller building blocks are called polymers. DNA is another polymer, but it’s a bit more complicated than starch. Instead of one building block that repeats over and over, DNA has four different types of building blocks. Its pieces also come together in a way that makes a unique structure called a double helix. We’ll learn more in the next sections about how this molecule is put together. BUILDING BLOCKS We’ve done a lot of building today, and we’re about to do some more. Here’s your cheat sheet for what builds what: • Atoms are the smallest possible piece of an element. They are the building blocks of molecules. • Molecules are the smallest possible piece of a compound, such as water or DNA. (Imagine a glass of water; the smallest item in the glass would be a single H2O molecule.) • Glucose, a sugar, is the building block of starch. • Amino acids are the building blocks of proteins. • Nucleotides are the building blocks of DNA. BABIES OF THE FUTURE Reproductive Tech and “Designer” Babies If the scary movie model for de-extinction is Jurassic Park, then the corresponding movie for designer babies is 1997’s Gattaca. There aren’t currently any “designer babies,” but that’s the term that gets thrown around when any genetic or genomic technology emerges that could potentially be used to let parents dictate or choose traits of their offspring-to-be. SCREENING EMBRYOS In Gattaca, a dystopian movie about how widespread DNA sequencing might change our society, parents don’t edit their children’s genomes. They just get the opportunity to choose between a variety of embryos produced with their own eggs and sperm, but whose genomes have been sequenced for a peek into their future. This is fiction, but something similar is available for parents who carry alleles for certain genetic diseases. The technique is called preimplantation genetic diagnosis (PGD). Here’s how it works: when an embryo has only eight cells, you can remove one cell to test its DNA, and the embryo will still develop as normal. This type of screening was first used in 1990 to select female embryos for a couple who was at risk of passing down X-linked genetic disorders to their male offspring. Since then, PGD has been used to test for specific genes including those for Huntington’s disease and cystic fibrosis. Technicians will test multiple embryos for the disease and only implant those that don’t have the affected allele. Some European countries prohibit PGD, including Austria, Germany, Ireland, and Switzerland. Other countries, including France, Greece, and the United Kingdom, allow it for medical reasons only. The United States does not regulate the technique. GENE EDITING Another ethical dilemma is the idea of human germline editing. The germline means any cells that will eventually become a person. It includes eggs and sperm and also embryos themselves. If a parent is doomed to give their child a disease-causing gene, CRISPR could be used to fix that gene at the embryo stage. This becomes an ethical minefield: if it’s okay to fix a lethal disease, is it also okay to edit an embryo to change its risk for less serious conditions? What about edits that would make a resulting child taller or better at sports? So far the only published CRISPR experiment on a human embryo was done with cells that did not develop into a baby. The experiment was a mixed success: the scientists successfully made edits to the cell, but in some embryos the edit did not take, and in others, the embryo ended up with unwanted random mutations. THE ETHICS OF DESIGNING YOUR BABY Screening for genetic diseases has been around longer than the ability to edit embryos. Even before PGD, pregnant people have been able to get tests, such as amniocentesis, to check on their developing offspring’s DNA. Amniocentesis involves taking a sample of the amniotic fluid surrounding a fetus. It’s a risky procedure, since it carries a small risk of miscarriage. But it can reveal whether the fetus has a normal number of chromosomes, or if it has Down syndrome or another condition related to the number of chromosomes. The bigger ethical dilemma surrounding genetic and genomic testing for babies is whether it’s okay to change or select an embryo based on genes that don’t relate to lethal or serious genetic disorders. For example, parents might want to have a baby that is smart, or tall, or attractive, or good at sports—or all of the above. We don’t have to worry about this kind of genetic engineering yet, simply because we don’t know all of the genes that go into making somebody smart or tall or attractive or good at sports. Hundreds of genes influence height, for example. Meanwhile, we have no idea how many genes influence intelligence or attractiveness, in part because nobody can agree on what intelligence or attractiveness really are. But gene editing techniques are becoming more advanced, and sequencing is getting cheaper and cheaper. Some scientists and bioethicists treat embryonic gene editing as an issue we must be prepared for, saying it’s likely that one of these days somebody will try it. In Gattaca, people whose genomes had been screened before birth were considered to be a higher, more privileged class of people. Ethicists worry that something along those lines really could happen, regardless of how sound the science is behind it. Not long ago, in the early 1900s, some scientists were calling for the science of genetics to be used to encourage people with “good” genes to have offspring, and for people who were poor, disabled, or had criminal records to be sterilized. We don’t need a return to those days. But the science is moving fast, and only time will tell what will happen with reproductive technology in the age of gene editing and cheap sequencing. GENETICALLY MODIFIED CROPS Not So Scary After All Genetic modification is a tool; it’s not a bad thing in itself. When you ask people what they think of genetically modified organisms, or GMOs, the response is usually negative. But if you ask people why they don’t like GMOs or don’t want to eat them, the replies often aren’t really about GMOs. People tend to say they are concerned about pesticide residue in their food or the effects pesticides have on the environment. Or perhaps they don’t like the business tactics of Monsanto, one of the highest-profile companies in the GMO crop business. These are all separate from the issue of whether a crop owes some of its traits to genetic engineering technology. The truth is that genetic modification in crops is not inherently good or inherently bad. In this section, we’ll look at some of the common types of GMOs, and what they really mean for agriculture and for health. CORN AND SOY ARE OFTEN GENETICALLY MODIFIED Chances are, you probably ate food made from genetically modified crops today. But that’s not because most crops are genetically modified; it’s because a few of our most commonly consumed crops are often grown from genetically modified varieties. Here are some of the most commonly grown crops that have genetically modified varieties on the market. Corn Most of the corn grown in the US is grown as a grain. (The corn we’re talking about is different from the sweet corn you might eat off the cob, slathered with butter.) This corn is the source of cornstarch, corn syrup, and tons of other corn-related products. It also makes up most of the diet that chickens, cows, and other livestock eat. The majority of corn grown this way is genetically modified to stave off insects or to tolerate being sprayed with weed killers, or both. Soy Soy is another major component of our food, providing a few protein-containing foods like tofu and the little soy chips in protein bars. It’s also the source of more than half of our vegetable oil, and it’s also a major component of animal feed. Most soy is genetically modified to resist insects or to tolerate being sprayed with weed killers. Cotton Cotton plants make our clothes, but they are food crops too: cotton seed oil is edible. Like corn and soy, cotton plants are often genetically modified to resist insects or to tolerate weed killers. Potatoes Potatoes are another commonly grown crop, but most potatoes we eat aren’t genetically modified. There is one GMO potato variety that was approved in 2017. Its naturally occurring enzyme for browning (which happens when the potato is bruised) no longer works, so the potato doesn’t get black spots. This potato also produces less acrylamide, a chemical that is formed when food is fried or cooked at high temperatures. Papayas Most papayas on the market today are genetically engineered to be resistant to the papaya ringspot virus. The GMO papaya may have saved the papaya industry; before it came along, the virus devastated papaya crops. One You Won’t See One crop that’s not on this list: tomatoes. A genetically modified tomato was among the very first GMO crops to be approved, so you may see news articles on GMO crops illustrated with pictures of tomatoes. But the GMO tomato didn’t work out commercially. Its makers stopped growing it shortly after it was introduced, and it’s been off the market since 1997. INSECT-RESISTANT CROPS Crops can be genetically engineered to be resistant to insects, like caterpillars, that would otherwise eat them. The first commercial success, and currently very common in crops, uses a toxin from Bacillus thuringiensis. B. thuringiensis, often nicknamed Bt, is a bacterium. Some strains of Bt can produce a toxin that forms sharp, pointy crystals inside the guts of caterpillars. Since the 1920s, farmers and gardeners have used spores of the bacteria as a natural insecticide. If you buy Thuricide at the garden store, for example, that’s a solution of bacterial spores meant to spray on your plants. The toxin only affects certain insects, so it’s considered a natural and safe pesticide and is allowed in organic farming. The first genetically engineered Bt corn was approved in 1996. It makes a toxin that targets a common corn pest called the European corn borer. To make this type of corn, scientists copied the gene from Bt bacteria that produces the toxin and inserted that gene into the genome of the corn plant itself. The effect is similar to constantly spraying Bt bacteria all over corn, except without the spraying. The plant itself makes its own insecticide, and as a result, farmers can spray less chemical insecticide. HERBICIDE-TOLERANT CROPS The other major category of GMO crops includes herbicide-resistant plants. Herbicides are weed killers. When the corn or soy in a field is resistant to a certain herbicide, you can spray the herbicide over the whole field and expect that it will only kill weeds, while leaving the crop unharmed. While insect-resistant crops tend to let farmers spray less insecticide, herbicide-resistant crops tend to result in more spraying of herbicides. That’s why it’s best to be wary of claims that GMO crops are all good or all bad; it depends on what kind of crop it is and how it is cultivated. The first herbicide-tolerant GMO crops were “Roundup Ready” soybeans, created to tolerate the herbicide glyphosate, sold by Monsanto under the brand name Roundup. Glyphosate kills plants by interfering with an enzyme that makes amino acids they need to live. So scientists inserted a gene into soybeans so they could make a bacterial version of that enzyme, instead of the usual plant version. The bacterial version can still work even in the presence of glyphosate. The widespread use of these crops meant that the use of Roundup became more common. Just as bacteria can develop resistance to antibiotics, weeds can also develop resistance to weed killers. Glyphosate is a common pesticide; you can buy it in garden stores for your own use, no GMO plants required. Thanks to GMO soybeans, though, its use became even more common. Over time, seed companies like Monsanto and Dow have come up with other combinations of herbicides and herbicide-tolerant plants to give farmers more options. Still, resistant weeds are a constant issue. [image: Image] Adams Media An Imprint of Simon & Schuster, Inc. 57 Littlefield Street Avon, Massachusetts 02322 www.SimonandSchuster.com Copyright © 2018 by Simon & Schuster, Inc. All rights reserved, including the right to reproduce this book or portions thereof in any form whatsoever. For information address Adams Media Subsidiary Rights Department, 1230 Avenue of the Americas, New York, NY 10020. First Adams Media hardcover edition July 2018 ADAMS MEDIA and colophon are trademarks of Simon & Schuster. For information about special discounts for bulk purchases, please contact Simon & Schuster Special Sales at 1-866-506-1949 or email@example.com. The Simon & Schuster Speakers Bureau can bring authors to your live event. For more information or to book an event contact the Simon & Schuster Speakers Bureau at 1-866-248-3049 or visit our website at www.simonspeakers.com. Cover design by Katrina Machado Cover images © Clipart.Com; Getty Images/Saemilee, Sfischka Library of Congress Cataloging-in-Publication Data Skwarecki, Beth, author. Genetics 101 / Beth Skwarecki. Avon, Massachusetts: Adams Media, 2018. Series: Adams 101. Includes index. LCCN 2018011664 (print) | LCCN 2018012734 (ebook) | ISBN 9781507207642 (hc) | ISBN 9781507207659 (ebook) LCSH: Genetics--Popular works. | Science--Popular works. | BISAC: SCIENCE / Life Sciences / Genetics & Genomics. | SCIENCE / Life Sciences / Human Anatomy & Physiology. | SCIENCE / General. LCC QH437 (ebook) | LCC QH437 .S59 2018 (print) | DDC 572.8--dc23 LC record available at https://lccn.loc.gov/2018011664 ISBN 978-1-5072-0764-2 ISBN 978-1-5072-0765-9 (ebook) Many of the designations used by manufacturers and sellers to distinguish their products are claimed as trademarks. Where those designations appear in this book and Simon & Schuster, Inc., was aware of a trademark claim, the designations have been printed with initial capital letters. INTRODUCTION Less than two centuries ago, all people really knew about genetics was that children tend to look like their parents and that careful breeding of dogs or horses or crops can result in bigger and better dogs or horses or crops. We’ve learned a lot since then. In the 1800s, a monk named Gregor Mendel figured out that traits of pea plants—like whether peas were yellow or green—were passed down from parent to child in a way that could sometimes hide traits so they appeared to skip a generation. He figured out how to predict whether and when a hidden trait would show up next. Around the same time, naturalist Charles Darwin figured out that species evolve over time. The traits of pets and crops are influenced by a farmer who breeds them, but according to Darwin’s theory of evolution by natural selection, it is nature, rather than human judgment, that determines which creatures live long enough to have offspring. Darwin knew the whole idea hinged on some mysterious way that parents can pass down traits to their children, but he had no idea how that might work. And then, in the 1950s, Rosalind Franklin managed to form DNA into a crystal and take an x-ray photograph that revealed its structure. James Watson and Francis Crick built on her work to deduce that the DNA molecule had the shape of a double helix and that DNA’s structure was uniquely suited to pass down traits from one generation to the next. Over the remaining decades, scientists have worked out the details of exactly how DNA makes us who we are—and how we can tinker with it. This book will explain genetics, which is the study of how living things give their offspring the instructions, or genes, for particular traits. We’ll also talk about genomics, which is a related field that studies the totality of all the information contained in your DNA. Along the way, we’ll cover other bits of biology as needed. We’ll do all this with a focus on you and what’s going on in your body, plus a few things you might see in the news. Along the way, we’ll take some detours to visit the genomes of animals, plants, bacteria, and even viruses. You have more in common with all of these creatures than you probably realize. First, we’ll learn about the nuts and bolts of deoxyribonucleic acid—DNA—itself. It’s a stringy substance that, on a smaller-than-microscopic scale, is an incredibly long molecule. You have forty-six of these strands stuffed into the nucleus of each cell in your body, and each strand contains instructions for building and maintaining every part of your body. These instructions are in a chemical language that we’ll learn to decode. We’ll see how your cells read that code and carry out the instructions. Often the instructions tell the cells to build a protein, so we’ll learn what these proteins do too. Some of them give your eyes and hair and skin their distinctive colors. Some help your body to process food and drugs. Some are so important to the way your body functions that if they aren’t built in exactly the right way, you could end up with an increased risk for cancer or other health conditions. We’ll also learn about how your DNA got to you in the first place: how it was passed down from your parents and what it can tell you about your family tree. And we’ll see what you can learn from personal genomics services that promise to reveal your deepest secrets based on a sample of saliva. Finally, we’ll take a look at what scientists and companies are doing with DNA, from genetically modifying crops to improving treatments for cancer. HOW MUCH DNA DO YOU SHARE WITH A STRANGER? A Lot, It Turns Out There’s a huge amount of human diversity across the world. Even if we’re only looking at traits that are genetic (or mostly genetic), we can see many different features. People can be tall or short, light-skinned or dark-skinned, or anything in between. We can have straight hair or curly hair, in shades of blond, red, brown, or black, with a variety of textures. Some people are more prone to cancers or other diseases, while other populations’ genetics protect them at least a little bit. We have different shapes of noses, lengths of fingers, textures of earwax. There are so many things that make each of us unique. And yet—our DNA is, at minimum, 99 percent identical. Imagine meeting your counterpart from halfway around the world who is different from you in every genetic way you could think of. (Assume for the moment that they have the same chromosomes as you—so if you’re XX and don’t have any trisomies, they are the same way.) If you both get your genomes sequenced and compare notes, you’ll find you aren’t that different at all. You and that totally completely different person are still going to have more than 99 percent of your DNA in common. WHAT’S IN OUR DNA? The human genome, you might remember, is about three billion base pairs long. In other words, that’s the number of nucleotides on all twenty-three of our chromosomes put together. (How many you personally have depends on whether you have both an X and a Y chromosome, but either way this number is approximately correct.) There are about twenty-two thousand genes, or sets of instructions, for making proteins, and about three thousand for making functional RNAs (like ribosomal RNA, tRNA, and others that do specialized jobs). That’s a pretty small number, especially when you consider our body makes close to 100,000 proteins. It turns out a lot of our genes can be alternatively spliced: the same instructions, followed in a slightly different way, can make two or more different products. Conserved Mutations occur all the time, but not all areas of the genome are equally subject to change. A mutation that occurs in the middle of an important gene or regulatory region could result in the organism dying. Meanwhile, a mutation in a noncoding area, or in a gene that we could live without, is more likely to be passed on without any problems. That means that the more important a region of DNA is, the less likely it is to change over time. We call these regions or genes “conserved,” because they are preserved while the DNA around them changes. All of those instructions put together are called the protein-coding regions of DNA (because they contain the code for building proteins). And they only add up to 1.5 percent of our genome. Even when you consider all the parts of DNA that don’t make proteins or RNAs, but that are important for regulating gene expression, we’re only looking at another 6 percent of the genome. These regions are the conserved noncoding elements, and we know they are important because they are similar between people and, often, between species. Only a little bit of our DNA actually makes a difference to our phenotype. Compared to other species, we have a “low gene density,” meaning that any given stretch of DNA contains occasional genes in a sea of noncoding sequences. LARGE PARTS OF OUR CHROMOSOMES DON’T CODE FOR ANYTHING It’s tempting to call the rest junk, but much of it does have a function, albeit indirectly. In 2012, a project called ENCODE announced that 80 percent of the human genome has some kind of function. A few years later, another team of scientists said no, the functional stuff is less than 10 percent. Both teams were correct, but they were each using different definitions of “functional.” Most scientists agree that the smaller number is a better way of describing how much of our genome has a function that relates to gene expression. Let’s take a quick look at that 80 percent. The ENCODE scientists got that number by including segments of DNA that are often methylated, which means they are turned off. However, that means that our cells are paying specific attention to those segments and adding the methyl groups—so they’re not passive pieces of junk but sequences that, in a sense, we do something with. The scientists also counted sequences of DNA that are wrapped around histones (a lot of our DNA is wrapped around histones, just to keep it from getting tangled). As well, they counted sequences that look like they bind to proteins, even if we don’t have any evidence that those proteins exist or that they do anything interesting after they bind. So most of our DNA isn’t actually functional. Among the extra stuff, we have sections of chromosomes that have gotten duplicated and reinserted. We also have repetitive sequences, just the same few letters over and over again. Nearly half of our genome is made of transposons, sequences that can actually remove themselves from our genome and reinsert themselves elsewhere. These sequences are probably left over from ancient viruses that infected us but turned out to be mostly harmless. Because they can copy themselves, we end up with multiple copies of their DNA. One class of retrotransposons, or elements that can copy and paste themselves, is the long interspersed repeat sequences, or LINEs. These are each a few thousand base pairs long, and together they make up 21 percent of our genome. There are also short interspersed repeat sequences, or SINEs, that make up another 6 percent. EVOLUTION How It Happens “Nothing in biology makes sense except in the light of evolution,” biologist Theodosius Dobzhansky once wrote. Evolution explains how species are related to each other, and it also explains why each living thing has particular features and quirks. Here are some examples of evolution: humans today have bigger brains than our ancestors who existed millions of years ago. The finches on the Galápagos Islands today have different beak sizes than the finches that lived on those islands just a few hundred years back. And—to bring this a bit closer to home—the bacteria in your throat look different after you’ve taken a weak dose of antibiotics (oops, should have taken all the doses as prescribed) than they did at the start of your illness. Here’s what all of these cases have in common: they all represent a population whose gene pool has changed over time. In the human example, more of us have the genes that allow for bigger brains than that ancient population had in the past. In your throat, perhaps only a few individual bacteria had antibiotic resistance genes at the start. But after applying a selection pressure for a little while—weak doses of antibiotics—you have shifted that balance so that far more of the bacteria have those resistance genes. This is what evolution really means: it’s the change in allele frequencies in a population over time. Forget any images you might have of individual humans or bacteria slowly changing. Evolution doesn’t happen to individuals. It’s a property of multigenerational groups. Let’s take a look at a few things that can cause evolution to happen. MUTATION A mutation occurs when a new allele is added to the gene pool. For example, there was probably once a time when all humans were lactose intolerant; none of us had the ability to keep producing the lactase enzyme after childhood. Then somebody was born who had a mutation in the lactase gene. As soon as that mutation appeared, the population’s gene pool had automatically changed: there was now one more allele than there had been before. Mutations can become more common over time. Sometimes that’s just a matter of chance; maybe the gene doesn’t make much of a difference to survival, but the people who have it just happen to have a few more children. Other times, the mutation becomes more common for a specific reason, including some of the other items on this list. MIGRATION Evolution happens to populations, so it’s significant if individuals move into or out of a population. If there’s an island where all the birds have large beaks, and then a new group of the same species birds moves in, and they have small beaks, the gene pool of birds on that island has changed. Migration doesn’t change features on a species-wide level, but it can influence what happens in that one population. SHRINKING POPULATION Populations can grow and shrink in size over time. For example, a population suddenly shrinks when there is an epidemic of a deadly disease. The people who were left in Europe after the Black Death killed 30 to 60 percent of the continent’s population may have carried different alleles than the larger group of people who were present before the pandemic. Or take a look at any endangered species: by the time you get down to just a few hundred or a few dozen individuals, those individuals only represent a small sample of the original, larger gene pool. Even if they reproduce enough to bring the population back to its original numbers, the restored population won’t have anywhere near the same diversity of alleles. NONRANDOM MATING Allele frequencies can also change if individuals don’t mate at random. For example, if female peacocks prefer males with long tails, the genes related to long tails are likely to become more common in the population. NATURAL SELECTION All of the forms of evolution we mentioned previously are random. They happen, and they result in a changed population, but they don’t reflect any direction or intention. They just happen because they happen, and that’s that. Natural selection, on the other hand, is what Charles Darwin was talking about when he first wrote about the concept of evolution. His book On the Origin of Species by Means of Natural Selection, published in 1859, described not just evolution but also adaptation, the phenomenon whereby living things become more suited to their environment. Darwin had no idea that genes were a thing and would never have dreamed that there might be a molecule called DNA at the heart of his theory. But his basic ideas made so much sense that they’re still considered to be roughly correct today. Here’s how he described the process of natural selection: First, there is variation within a population. Darwin was thinking in terms of phenotypes; so, for example, a population of birds might include individuals with larger and smaller beaks. Next, those variations can be inherited. Darwin didn’t know about Mendel’s work, so he wasn’t familiar with the idea of a gene. But he had a sense that birds with large beaks would tend to have offspring with large beaks. We know now that genes are responsible for those variations. If scientists are studying evolution or population genetics today, they don’t settle for just observing characteristics of the creatures they’re studying. Instead, they can also test DNA for characteristics they’re looking for. Plant breeders, for example, use DNA tests to decide which individuals to breed together to make offspring with the traits they’re looking for. Finally, for natural selection to occur, the population has to be in a situation where not everyone survives to leave offspring. Think about a pond full of frogs. A pair of bullfrogs could easily produce over ten thousand eggs each year, and each parent lives an average of about eight years. Out of all the eggs they produce, only two need to survive to adulthood to replace their parents. If the population of bullfrogs in the pond stays the same from year to year, that means that many thousands of each frog’s offspring will die. Those numbers set up some stiff competition among the baby frogs. If one tadpole doesn’t swim quite as well as the rest, it’s more likely to get eaten by a fish than its many brothers and sisters. The two frogs that survive are likely to be fast swimmers, good at hiding, and also good at obtaining food and other resources to take care of themselves. Some of their characteristics are likely to be genetic. There are surely genes related to swimming ability, for example. As the slower tadpoles get eaten, the alleles related to fast swimming become more common in the population. Over time, the population of frogs will have more and more of the faster-swimming allele. SPECIATION So populations change over time, both for random reasons and because of natural selection. But that doesn’t explain, by itself, why we have so many species. Why are there humans and chimpanzees in this world? Once upon a time we and chimpanzees had the same ancestors. What made our family tree branch? Two populations can form where there was originally one. All it takes is millennia of separation. Perhaps an island becomes separated from a continent, and now the creatures on the mainland can no longer reach the island. The populations can’t interbreed anymore, and so they evolve separately in their own ways. This explains why islands that have been isolated for a very long time tend to have species found nowhere else. Take the lemurs of Madagascar, for example, or the unique marsupials found in Australia. Populations can also be separated by invisible barriers. Perhaps a few individuals in a population get their internal clocks mixed up, and they mate in the fall while their relatives mate in the spring. Pretty soon you’ll have two separate populations that don’t mate with each other, but live in the same place undergoing the same pressures. MITOCHONDRIAL DNA That Other Chromosome We’ve spent a lot of time talking about the chromosomes that reside in the nucleus of your cells: in other words, your nuclear DNA. But you actually have another source of DNA inside every cell: mitochondria. If you were a plant, you’d have two: mitochondria and their photosynthesizing counterparts, chloroplasts. We’ll focus on the mitochondrial DNA in this section. Let’s zoom out just a little to take a look at our cells. Inside each one—whether it’s a bone cell, a muscle cell, a skin cell, or a brain cell, just to name a few—we have a nucleus that contains the DNA we’ve been talking about. As well, there are other structures in the cell, most of them enclosed in their own membranes, just like the cell itself is held together by a membrane. The mitochondria (singular: mitochondrion) provide energy to the rest of the cell. Think of them like little generators: you can shovel in fuel, and they give you back energy you can use to power just about anything. When you talk about burning the calories from your food, you’re really talking about what these little powerhouses do. They can use carbohydrates, proteins, or fats as fuel, and they supply the rest of the cell with energy-rich molecules called ATP. The ATP, in turn, can give muscles the energy they need to contract, or enzymes the energy they need to build more parts of you. We only have one nucleus in each of our cells (for the most part), but mitochondria have no such limit. It’s not unusual to find cells with hundreds of mitochondria, or even thousands. Sperm pack light for their trip through the female reproductive tract: they only have about one hundred mitochondria. But egg cells are enormous—at about 0.1 millimeters long, they are just barely large enough to be visible to the naked eye. They’re so big because they need to contain the raw materials for making an embryo, for its first few days at least. And so the egg contains a whopping 100,000 mitochondria (or more!) alongside its single nucleus. Burning Calories Mitochondria convert food to energy with the use of oxygen, so we call their job aerobic respiration. If you squat down and pick up something heavy—half of your friend’s couch, let’s say—your muscles will need a sudden burst of energy. They can actually get that energy anaerobically, without the mitochondria’s help. But if you go for a run, or even a walk, or even if you just lie in bed and sleep, most of your calories will be burned in the mitochondria, with the help of oxygen. The mitochondria can use almost anything we eat as fuel—sugar, carbs, proteins, fats—as long as other parts of the cell have prepared tiny chunks of those nutrients to feed to the mitochondria. If you think of nuclear DNA as being truly you, then it might help to think of mitochondria as your tiny pets. They have minds of their own—or, to be accurate, DNA of their own. They’re part of the family too: mitochondria probably started out as independent creatures, which our cells swallowed and somehow didn’t kill. But we’ve lived with our mitochondria for so long that we’ve actually swapped some DNA; our nuclear DNA includes genes that mitochondria need to survive and do their job. The mitochondria are here to stay. THANKS, MOM Our mitochondrial DNA comes entirely from one parent: the one who contributed the egg cell. The egg attacks and destroys the sperm’s mitochondria during fertilization, and so the sperm probably doesn’t contribute any mitochondria to the embryo at all. (It’s possible that a tiny bit of the sperm’s mitochondrial DNA might survive this attack, but if so, it’s only a tiny percentage of the mitochondrial DNA in your cells.) Once that initial fertilized egg begins to divide, those 100,000 mitochondria end up in the resulting cells. Mitochondria reproduce themselves by dividing. If you’re thinking of them as pets, imagine that you have 100,000 cats and routinely give half of them away, but the ones that remain are always having kittens, so your house is always full. Every cell in your body today, if it has mitochondria—and almost all of them do—contains descendants of the mitochondria that your mother gave you. You have the same mitochondrial DNA that she does too. WHAT’S IN MITOCHONDRIAL DNA? Mitochondrial DNA is a circular chromosome—yep, a complete loop—about 16,000 base pairs long. It includes thirty-seven different genes, or sets of instructions for RNAs and proteins. Thirteen of these make proteins that are involved in respiration, or calorie burning. The other genes in the mitochondrial chromosome make ribosomal RNAs and transfer RNAs that are needed to make the proteins. (See earlier sections for more on how proteins are made.) There are no introns in human mitochondrial DNA. There is only one place on each strand where transcription starts, so when the DNA is transcribed, the result is a massive piece of RNA, which is then cut into pieces. The tRNAs are different than the ones in the main part of our cells, so they actually have a different code than ours. For example, if an mRNA made from our nuclear (regular) DNA contains the codon AUA, that matches up with a tRNA that carries the amino acid isoleucine. But the same codon in mitochondria would attract a tRNA that carries methionine, instead. The stop codon UGA is another one that’s different; in mitochondria, it doesn’t mean “stop.” It means “add a tryptophan and keep going.” Mitochondrial tRNAs also allow for more “wobble,” which means imperfect matching between a codon and its tRNA. It turns out that most mutations in the third letter of a codon (like the A in UGA) don’t really matter. This is a little bit true with human tRNAs, and much more so in the mitochondria. MITOCHONDRIAL MUTATIONS If something goes wrong in mitochondrial DNA, a person with that mutation can have a health condition as a result. This would be a genetic disease, but it’s not related to any of the genes on our autosomes or sex chromosomes. You would only expect to inherit a condition like this from your mother, since an embryo gets nearly all of its mitochondria from its mother. Severity of a mitochondrial disease also depends on how many of a person’s mitochondria contain the affected DNA. Remember, we have hundreds or thousands of mitochondria per cell. They aren’t all identical; they’re a bunch of individual organisms that each have babies on their own schedule. They might all have identical genomes, but then again, you might have some mitochondria with a certain mutation and some without. If you only have a few affected mitochondria, you might not have symptoms of the disease. If you have many, you may have more severe symptoms. Cytochrome c oxidase deficiency is one example of a mitochondrial disease. Several mitochondrial genes are needed to build a multi-protein complex called cytochrome c oxidase. This large enzyme performs one of the essential steps in converting food to ATP. Someone with a mutation in one of these genes will not be able to make enough cytochrome c oxidase, and the result can be cell death in cells that require a lot of energy, such as heart and brain cells. Maternally inherited diabetes and deafness (MDD) is another mitochondrial disease. It’s caused by mutations in the MT-TL1, MT-TK, or MT-TE genes, which carry the instructions for certain tRNAs. These mutations slow down protein production. This condition causes diabetes because the cells in the pancreas that release insulin depend on mitochondria to help them figure out when to do it. The mitochondria can’t respond quickly because they have trouble producing proteins very well. We don’t know yet why this condition also causes deafness. [image: Image] Molecules are collections of atoms bound to one another. For example, when you combine two atoms of hydrogen (symbol H) with one atom of oxygen (symbol O) you get a molecule of water: H2O. Everything in a cell is made of molecules, from the membrane enclosing the cell to the DNA that carries genetic information. Photo Credit © Getty Images/virusowy [image: Image] This diagram shows the different parts of a cell. One of the most important parts is the nucleus, which contains the coiled strands of DNA that are present in all living things. Photo Credit © Getty Images/lvcandy [image: Image] The chromosomes seen here are structures within cells that contain genetic information. Each of these chromosomes has been duplicated into two chromatids, which remain attached at their centromere. When the cell divides, the sister chromatids will be pulled apart, one into each daughter cell. Photo Credit © Getty Images/BlackJack 3D [image: Image] Animal and plant cells divide through a process called mitosis. In this process, the chromosomes in the cell duplicate themselves and move to opposite ends of the cell’s nucleus. The cell then separates, creating two cells, each with an identical set of chromosomes. Cell division was first observed in 1835 by Hugo von Mohl (1805–1872), and scientists’ understanding of it grew better during the nineteenth and twentieth centuries. Photo Credit © Getty Images/man_at_mouse [image: Image] Deoxyribonucleic acid (DNA) contains the genetic instructions for building a living organism. It consists of two strands, each made up of nucleotides that contain one of four bases (cytosine, guanine, adenine, or thymine) joined to a sugar and a phosphate group. Although the structure seems simple, the order of the bases creates a kind of informational code that contains the genetic instructions for the organism. Bonds between the sugars and phosphates create the backbone of each strand. Photo Credit © Getty Images/macrovector [image: Image] Through the study of DNA and genetics, we’ve learned a great deal about diagnosing and treating diseases. Scientists study the sequence of nucleotides (the complex organic molecules that make up the strands of DNA) in various organisms. By doing this, they’re able to see the nature of harmful mutations, or changes in the molecules. Chief among diseases caused by such mutations is cancer. Here are cancerous cells of a patient with acute myeloid leukemia. Photo Credit © Getty Images/OGphoto [image: Image] Gregor Mendel (1822–1884), a Moravian friar, founded the science of genetics. By experimenting with peas—crossing short and tall plants, as well as peas of different colors—he discovered that certain characteristics can be predictably passed from one generation to another. Photo Credit: © Wikimedia Commons / Public Domain [image: Image] The Empress Alexandra of Russia (1872–1918) carried the gene for hemophilia, a disease that prevents blood clotting. Even though she wasn’t a hemophiliac, she passed this disease to her son, Alexei. In an effort to treat the disease, she and her husband, Tsar Nicholas II, turned to a “holy man,” Rasputin, who became increasingly unpopular because of the power he wielded at court. He was assassinated in 1916, but his influence over the Tsar and Tsarina probably contributed to the overthrow of the monarchy the following year. Photo Credit: © Wikimedia Commons / Public Domain [image: Image] Francis Crick (1916–2004) and James Watson (b. 1928) discovered that DNA, the most important molecule in all living things, consists of two molecular strands wound about each other in a double helix. Every cell in the human body contains instructions, coded in DNA, on how to build a human being. Watson and Crick’s discovery was a tremendous boost for genetics, since it showed how genetic information reproduces itself and where mutations can occur in the process. Photo Credit © Marc Lieberman derivative work: Materialscientist (This file was derived from Francis Crick.png:), via Wikimedia Commons / Public Domain [image: Image] James D. Watson Photo Credit © James_D_Watson_Genome_Image.jpg: Cold Spring Harbor Laboratory derivative work: Jan Arkesteijn, via Wikimedia Commons / Public Domain [image: Image] Rosalind Franklin (1920–1958) was a researcher at King’s College London in the 1950s. A highly skilled scientist, she created the clearest set of images of the x-ray diffraction patterns of DNA molecules that had been produced up to that point. Without her knowledge or permission, her supervisor (with whom she was feuding) later showed these images to Watson and Crick, who looked at the images and realized they supported the idea that DNA was shaped like a double helix. Photo Credit © Museum of London TRANSLATION AND PROTEINS Time to Get Cooking We’ve made it through transcription, so now we have an mRNA with neatly edited instructions for building a protein. Next, the mRNA has to find a ribosome. Each ribosome is a gigantic, multipart complex of protein and RNA. That’s right—the factory that reads RNA is itself made mostly, about 60 percent, out of RNA. There are two main pieces to the ribosome. One is larger than the other, and they look kind of like a hamburger bun, with a smaller flat part at the bottom and a larger dome-shaped top bun. The mRNA goes between them like the meat of a sandwich. (It’s a lot longer than the bun, though—imagine a mile-long hot dog.) When the mRNA gets out into the cytoplasm, all kinds of molecules bump into it. Eventually, one of those is the small portion of the ribosome. It’s shaped in just the right way so it can stick on to a certain point at the beginning of the mRNA. Once that sticks, the larger top bun can join, and now we have the machinery we need to make a protein. But we also need some supplies. Proteins are made of amino acids, so we need a bunch of those. And we also need some way of figuring out which amino acids the recipe is calling for. tRNAS AND CODONS Now we just need to understand how the sequence of letters in the mRNA tells the ribosome which amino acids to string together. Since there are only four bases in RNA (A, U, G, and C) but twenty different amino acids, it takes three bases to spell out each amino acid. Each three-base sequence is called a codon, because it is a segment of the “code” that we can translate from the language of RNA to the language of protein. There are sixty-four possible codons, and sixty-one of them code for a specific amino acid. The other three are stop codons, which tell the ribosome its job is done. So, remember those amino acids that were just floating around the cell? The ones that are ready to be built into proteins actually have something special going on. They are each attached to a tRNA. (The “t” stands for “transfer,” because they carry, or transfer, amino acids to the protein in progress.) A tRNA is a piece of RNA, as you probably guessed. On one end, it’s attached to an amino acid. Because RNA molecules can easily fold back on themselves, a tRNA has a twisted shape that actually looks a little like a letter “T.” And on one part of that RNA strand, three bases stick out, not bound to any of the other bases on the tRNA. These three bases are free to pair with any other RNA or DNA that the tRNA comes across, and it’s about to bump into our nice long strand of mRNA. THE PROTEIN-BUILDING PROCESS Once the hamburger buns of the ribosome are attached to the beginning of the mRNA, the first three bases are available for a tRNA to bind to. The tRNA binds to the first codon, rather than to a random spot later along the mRNA, because the ribosome has a special binding site to help it stick. The new tRNA fits into the slot on the ribosome and matches up with the first codon of the mRNA. At this point, the ribosome chugs down the mRNA, one three-base step at a time. Each time the ribosome advances, the next tRNA that is needed finds its binding space. The ribosome connects the new amino acid to the previous ones, and in time we have a huge, growing chain. When a tRNA has done its job and no longer is attached to its protein, it gets to float away. (It may pick up another amino acid and end up doing its job all over again.) By the time the ribosome gets to the other end of the mRNA, an entire protein has been produced. It can then fold up and be transported to wherever it needs to go—maybe another part of the cell, or maybe it will even be packaged so that it can leave the cell. Not Every Gene Makes a Protein So far, we’ve been talking about genes as recipes for proteins, but some genes just make an RNA that doesn’t turn into a protein at all. These special RNAs come in many different types, but we’ve already seen two: the tRNAs, and the RNA components of ribosomes. WHY DO WE NEED THE mRNA AT ALL? • We can make several copies of the same gene and work on them all at the same time. • The RNA will degrade over time, and when it’s gone, the protein won’t be made anymore. This is a way to automatically turn off protein synthesis. (If you want to keep making the protein, you can just keep transcribing it.) • The cell can control how much of the protein it makes by turning transcription on or off. This way, the protein-building machinery doesn’t have to care about when it’s time to make what protein. • While that ribosome was doing its job, a bunch of other ribosomes were likely at work, each making their own copy of the protein from that same mRNA transcript. Contents Cover Introduction Your Cells’ Instruction Manual Atoms and Molecules Nucleotides The Double Helix How all that DNA Fits into Cells Transcription and RNA What Proteins Do Translation and Proteins Turning Genes On and Off Mutations What RNA Can Do Chromosomes and Cells Bacteria and the Microbiome Viruses Mushrooms and Yeast Plants and Crops Making More Cells DNA Replication Making Sperm Cells Making and Fertilizing Egg Cells Sex Chromosomes Why Two Copies? How We Inherit Our Traits Dominant and Recessive X-Linked Traits Mitochondrial DNA Family Trees and Autosomal Inheritance Patterns Special Inheritance Patterns Nature Versus Nurture Epigenetics Traits Caused by Many Genes Simple and Not-So-Simple Traits Personal Genomics Understanding Your Disease Risk Where Humans Came From How Much DNA Do You Share With a Stranger? How Personal DNA Ancestry Services Work Race, Ethnicity, and Ancestry Relating to Your Relatives A Family Tree for All Life Evolution DNA Repair Cancer Genetics Pharmacogenomics Antibiotic Resistance Questions and Ethical Quandaries Genetically Modified Crops Genetic Engineering Tools CRISPR and Gene Editing Cloning and De-Extinction Babies of the Future Glossary Photographs About the Author Index Copyright Guide Cover Start of content VIRUSES Little Packages of DNA or RNA Viruses are even smaller than bacteria. In fact, scientists don’t always agree on whether they should count as forms of life or not. For now, it’s probably most accurate to say they are not truly alive. However, they have their own genetic material—sometimes DNA, sometimes RNA—so we’ll at least give them their own section. Viruses only have two components: a protein shell and a nucleic acid payload. The viruses that cause smallpox, herpes, and chicken pox all contain double-stranded DNA as their genetic material. In that way, they’re like us. Others have RNA as their genetic material. HIV is one example of an RNA virus. Whether a virus’s nucleic acid is RNA or DNA, it’s enclosed in a package made of protein. That’s all a virus is: just packaged-up nucleic acid. You could argue that it’s not a living creature, just a packet of chemicals. However, when a virus infects a cell, those proteins and nucleic acids spring into action. They hijack the cell’s own machinery, so that instead of transcribing and translating its own DNA, the cell uses its precious resources to transcribe and translate the virus’s genes. SOME VIRUSES AND THEIR TYPICAL GENOME SIZES Influenza single stranded RNA 14,000 bases Measles single stranded RNA 15,894 bases Adenovirus (common cold) double stranded DNA 36,000 base pairs Rotavirus (diarrheal disease) double stranded RNA 18,000 base pairs Variola (smallpox) double stranded DNA 186,000 base pairs HOW A VIRUS INFECTS A CELL First, the virus approaches the cell. Many viruses take the shape of an icosahedron, so they look like little jagged circles under an electron microscope. (At just a few nanometers wide, most are too small to be seen through a regular light microscope.) Every virus has a preferred cell, or type of cell, that it likes to infect. Some viruses that infect bacteria, called bacteriophages, have a slightly different structure. On the bottom of the icosahedron-shaped package, they have a tube and six legs that appear to stick out like a spider’s legs. The whole thing has the appearance of the spacecraft that landed on the moon in 1969. The virus has to find a way to attach to the cell. Bacteriophages can inject their DNA directly into the bacteria they infect, but many of the viruses that infect humans have proteins on their surface that recognize specific proteins that they expect to encounter on the surface of human cells. They attach to those proteins and try to trigger them to allow the virus in. For example, a rhinovirus, one of several viruses that can cause the common cold, tricks the cell into thinking it’s time to ingest something and bring it inside the cell. The virus then tries to break out of its little digestive chamber. Most cells aren’t fooled, or if they do get infected, our immune system manages to kill off the infected cell before the virus can spread. But if we get sick, that’s because some virus managed to get through. HOW A VIRUS REPLICATES Once a virus’s DNA or RNA is inside the cell, it takes advantage of the cell’s tools for transcribing and translating genes. If the viral genome is made of DNA, and it’s infecting a eukaryote like a human, that DNA has to reach the nucleus. That’s where our transcription machinery is, after all. If the virus is a retrovirus that contains RNA, it encodes a reverse transcriptase. Ribosomes find the viral RNA and translate it, creating the reverse transcriptase that can then make a DNA copy of the viral genome. Either way, a successful infection results in the virus’s genes being transcribed and translated in much the same way as our own genes. In one version of the viral life cycle, called the lytic cycle, the cell is soon using all its resources to make new viruses, and the viruses eventually burst out of the cell, killing it. But there is another way: the lysogenic cycle. In this case, the virus inserts its DNA into the host cell’s genome. Then it may lie in wait, getting copied whenever the host cell’s genome gets copied. One day in the future, it can activate and cause a new batch of viruses to be made. This is what the virus that causes cold sores does. You can’t get rid of the virus, but you’ll only notice outbreaks when the virus decides to take action. This happens most often when the host immune system lets its guard down—for example, when you’re stressed. Just like a squirrel might bury a nut in the fall and forget to come back for it, some viruses that went the lysogenic route “forgot” to ever pop out and make us sick. Over the millennia, we’ve actually acquired quite a few defunct viruses in our genome, comprising somewhere between 1 percent and 8 percent of human DNA. DNA REPAIR Fixing Mistakes A job as complicated as copying DNA isn’t going to go without a hitch. The enzyme that adds new nucleotides to a DNA strand tends to make a mistake every 100,000 nucleotides or so. Then once all that DNA is sitting around in a cell, stuff can happen to it. Free radicals can bump into it, or ultraviolet light from the sun can damage it. Radiation from hazardous materials or even the small doses in x-rays can cause damage to DNA as well. Preventing DNA damage is important. That’s why we wear sunscreen, avoid smoking, and trust our doctors not to order any more imaging tests than we really need. But when that damage inevitably happens, it’s a good thing that our body knows how to fix it. FIXING ERRORS IN DNA COPYING DNA polymerase isn’t perfect; it screws up one of every 100,000 nucleotides it adds. But our cells’ machinery fixes most of those errors, taking the number of mistakes down to just one in a billion. That means each cell only has about six mistakes total, when you count both copies of our DNA. Not bad! One process, DNA proofreading, happens during replication. When the DNA polymerase inserts the wrong nucleotide, it doesn’t match up perfectly to the base on the other side of the strand. As a result, the new, wrong nucleotide’s 3' hydroxyl group—the place where the next nucleotide will attach—doesn’t fit into the right place on the DNA polymerase. The enzyme can’t move forward until it removes the new, wrong nucleotide. Occasionally, the DNA polymerase can move past an incorrect nucleotide. But that leaves a bump in the DNA, a wonky-shaped place where the nucleotides don’t match up correctly. (Remember, each nucleotide only has one partner that enables it to fit properly in the double helix.) The enzymes that do this job, called mismatch repair, can spot the mistake because they know which is the old strand and which is the new one. That’s thanks to methylation, one of the modifications discussed in the “Epigenetics” section. The new strand isn’t methylated until after mismatch repair, so the enzymes can recognize the unmethylated strand as the new one. These repair mechanisms are aimed at single nucleotide mutations, where a base pair is clearly mismatched. Mismatch repair can sometimes also catch a tricky mistake called a trinucleotide repeat. In these, a sequence like “CAGCAGCAGCAG” can cause trouble. If the two strands of DNA are separated, the trinucleotide sequence can fold and bind to itself, making a hairpin shape that hangs off the main DNA strand. If it’s not caught, the next time this stretch of DNA is copied, the extra-long strand might be copied correctly, resulting in a sequence that is too long on both strands. Over time, this repeated sequence can accumulate more and more repeats. Some genetic diseases, including fragile-X syndrome and myotonic dystrophy, result from repeats like this that get out of hand. FIXING DAMAGE TO DNA Damage is easier to spot than errors, since the result is often a stretch of DNA that is not shaped or does not act like a normal double helix. For example, pyrimidine bases (T or C) that are next to each other on one strand of the DNA can end up covalently bonded to one another after they have been exposed to ultraviolet light. That’s obviously a problem, because DNA’s bases aren’t supposed to be attached to each other side to side. Some organisms, including bacteria, can spot these pairs and separate them. But the human approach is to just cut out both of the mangled bases and replace them. In this and other cases where only one strand is damaged, enzymes can remove the bases that don’t belong. When a single base is damaged, they can remove just that one. When multiple bases are involved, they often remove at least a dozen bases on the affected side of the strand. Amazingly, our cells can even repair DNA when both strands have been damaged or broken. Because we have two copies of almost every chromosome (sorry, XY folks), double-stranded damage can often be fixed by matching up the broken ends to their homologous partners. This is almost exactly the same process that happens during meiosis, when pairs of chromosomes undergo recombination, or crossing over. In this case, each strand finds its partner on the homologous chromosome, and enzymes repair the DNA as the strands separate. WHEN DAMAGE CAN’T BE FIXED A cell with damaged DNA is a liability to our health. Think about what happens when we get too much sun over the course of our lives, or if we are exposed to carcinogenic chemicals or radiation. Some cells will be so badly damaged that they must die; others can end up causing cancer. Cells are programmed not to replicate their DNA unless it is intact and undamaged. After that comes another point where the cell will not divide unless the DNA was properly replicated. Finally, there is another checkpoint during mitosis, at metaphase, where the spindle won’t pull the chromosomes to each side of the cell unless each chromatid is appropriately attached to a microtubule. If a damaged cell cannot be repaired, it self-destructs. This process is called apoptosis, and it results in small fragments of cells that can be gobbled up by our white blood cells (which already patrol our body looking for bacteria and other invaders to eat). The real problem comes when a cell is damaged beyond repair but apoptosis does not occur. This can happen if a person has a mutation in one of the enzymes responsible for making apoptosis happen. For example, variations in the “tumor suppressor” gene that makes the p53 protein can cause a syndrome called Li-Fraumeni, where affected people have a 50 percent chance of developing some kind of cancer by the time they turn thirty, and a 90 percent chance by the time they are seventy. Even if most of your cells have perfectly intact tumor suppressor genes, cancer cells can get a foothold if they end up with damage to their tumor suppressor genes. Cancer cells often have multiple mutations that help them keep growing when they shouldn’t. These typically include mutations in one or more tumor suppressor genes. CLONING AND DE-EXTINCTION Cloning Means Never Having to Say Goodbye To a genetics nerd, there has probably been no movie more thrilling than the 1993 Jurassic Park. Not only were there dinosaurs, and not only were the dinosaurs more realistic than movies typically made them at the time, but the whole story was based on some fairly plausible genomic science. To be clear, it’s not super plausible; we’re not going to see supersized velociraptors running around any time soon. But the idea of bringing an extinct creature back to life is something scientists are still thinking about. Is it ethical? Is it possible? If we can sort those questions out, what’s the best way to do it? CLONING In Jurassic Park, scientists started with dinosaur DNA found in the blood in the belly of a mosquito preserved in amber. They injected this DNA (uh, somehow) into the egg of a modern-day emu or ostrich, creating an embryo that was able to divide and develop into a hatchling dinosaur. We can’t yet clone extinct animals this way, but living animals have been cloned. In 1996, just a few years after Jurassic Park, a team of biologists in Scotland managed to clone a sheep. To do this, they took an egg cell from one adult female sheep and removed its nucleus. They replaced it with the nucleus from another cell, taken from the mammary gland of a second sheep. Since the nucleus they transferred was from a somatic (body) cell and contained a complete diploid set of chromosomes, no sperm was needed. This technique is called somatic cell nuclear transfer. A mild electric shock triggers the cell to start dividing. The scientists implanted the resulting embryo into the uterus of a third sheep who would carry the pregnancy. As a result, Dolly, the world’s first cloned sheep, had three mothers and no father. Are Clones Healthy? Dolly died at age six, younger than the typical lifespan for her breed, and at first the scientists were worried that clones weren’t as healthy as naturally conceived sheep. But other cloned sheep lived longer lives than Dolly did, and recent studies showed that the arthritis in her knees—at first thought to be a sign of premature aging—was actually in the normal range for a six-year-old sheep. Since then, other animals have been cloned—but nobody has attempted a human. The first cloned horse, Prometea, was born in 2003. The rules around Thoroughbred horse racing don’t permit clones, but other valuable horses have been cloned. Polo star Adolfo Cambiaso won a match riding six clones of his deceased favorite horse, Cuartetera. Cloned animals aren’t always identical to their parent, though. People who have cloned their pets (for prices ranging from $25,000 to $100,000) report that the resulting animals often have a different personality and sometimes slightly different markings on their fur. Remember, DNA doesn’t determine everything about you, and that’s true of animals too. BRINGING BACK EXTINCT SPECIES Our cells do a lot of work to keep DNA in good shape. So when cells die, the DNA can become damaged, and nobody is there to patch it back up. Once DNA has been sitting around for thousands or millions of years in a fossil, it’s somewhere between fragmented and obliterated. That’s a big part of why dinosaur cloning is still more fantasy than science fiction. But some species died off more recently. The Neanderthal Genome Project was able to recover enough DNA from a bone that was over fifty thousand years old to deduce that Neanderthals were 99.7 percent similar to modern Homo sapiens, and that today’s Europeans may have inherited up to 4 percent of their DNA through Neanderthal ancestors. In 2000, the world’s last Pyrenean ibex died in a nature preserve in Spain. Scientists had already saved a sample of tissue from her ear, and in 2003 they implanted the nuclei of some of her cells into egg cells from goats. Only one of the embryos was born, and it died shortly after birth from a lung defect. They could try again, but even if they successfully clone this female ibex, there are no males of her species to breed with. There is, however, a related species called the Southeastern Spanish ibex, so a hybrid would be possible. Another animal that became extinct recently is the quagga, a subspecies of zebra that had stripes on the front half of its body but was a plain brown in back. Since it’s the same species as modern zebras, scientists hypothesized that all the genes necessary to make a quagga already exist in living zebras; the challenge is just to bring them together in one animal. The Quagga Project is an attempt to recreate the quagga—or at least something that looks like a quagga—through selective breeding. The woolly mammoth is another animal that scientists, including Harvard geneticist George Church, are considering bringing back. No intact cells of woolly mammoths exist, so cloning isn’t possible. But mammoths only died out a few thousand years ago, and there are some extremely well-preserved specimens. Some mammoths lived in places that were cold enough that their bodies froze shortly after death, and they have remained frozen ever since. A baby mammoth was found in 2013 with hair, muscle tissue, and liquid blood still recognizable. Church’s team believes they can recreate a mammoth by analyzing mammoth DNA and determining where it differs from modern elephants—for example, finding the genes that cause mammoths to grow fur. Then they plan to use gene editing techniques like CRISPR to create an elephant embryo with mammoth DNA in just the right places, and grow it in an artificial womb. It’s an ambitious project, and only time will tell if it’s truly possible. ANTIBIOTIC RESISTANCE How Bacteria Outsmart Us with Evolution Antibiotics are a critical part of medicine in modern times. Because of these bacteria-killing chemicals, we no longer fear bubonic plague or scarlet fever the way we used to. Minor injuries no longer routinely lead to life-threatening infections. But antibiotics don’t kill all bacteria. More and more infections these days are drug resistant, and it’s all due to what’s going on in the germs’ genetics. The First Antibiotic Penicillin, the first antibiotic, was not invented; it was discovered. Alexander Fleming, a bacteriologist in London, returned from a vacation in 1928 to find that one of his Petri plates of Staphylococcus bacteria had some mold on it. And in a halo around this bit of fungus, no bacteria were growing. It took over a decade of lab work to figure out how to extract and purify the drug from the fungus in great enough quantities to use it in medicine. The word antibiotics means “against life,” but the way most people use the word, it means antibacterial drugs. There are also antifungal drugs, antiviral drugs, and antibacterial chemicals that aren’t drugs. Their stories are similar, but in this section we’re looking at bacteria-killing drugs. The more than one hundred antibiotics used in medicine come in different classes. All the antibiotics in a class work approximately the same way. Here are some of the major types, including some drugs you may have heard of (or taken!): • Beta-lactam antibiotics: All cells, including bacteria, have a cell membrane around the outside. But some types of bacteria also have a cell wall, a thick barrier made of proteins and sugars that acts as the cell’s armor. To build the cell wall, the bacterium has to link chains of proteins together. An enzyme called PBP does this job, grabbing a certain kind of amino acid chain and using it to lock the proteins together. Beta-lactam antibiotics like penicillin are roughly the same shape as the amino acids PBP needs. But when the PBP grabs the antibiotic, the antibiotic gets stuck. That PBP is now out of commission and can’t finish building the wall. With enough of the antibiotic around, the bacteria can’t build their cell walls, and they can’t survive. This enzyme is named after the antibiotic, by the way: PBP stands for penicillin-binding protein. Beta-lactam antibiotics include penicillin, amoxicillin, cephalosporins, and carbapenems. • Macrolide antibiotics: Bacteria, like other forms of life, use ribosomes to translate mRNA transcripts into proteins. Macrolide antibiotics attach to bacterial ribosomes, which fortunately are built just a little differently from human ribosomes (so the medicine kills the bacteria, but doesn’t kill us). Erythromycin is one example of a macrolide. If you’ve ever taken a Z-Pak, you’ve had azithromycin, another macrolide. • Quinolone antibiotics: When bacteria divide, they have to duplicate their DNA (so do we, of course). To do this, they have to separate the two strands of DNA, but this is a tricky job when you remember that DNA is twisted. Next time you happen across a ball of yarn, try grabbing the middle of a strand and pulling it apart. The fibers of the yarn are wrapped around each other, and when you pull them, they’ll end up curling even tighter. Bacterial DNA is a continuous circle, so the strands can’t unwind on their own. They have enzymes whose job is to carefully cut and mend the strands of DNA during replication so they don’t get too twisted. Quinolone antibiotics stop this enzyme from doing its job. Quinolones include the fluoroquinolone antibiotics levofloxacin and ciprofloxacin (Cipro). RESISTANCE IS ALL ABOUT BACTERIAL GENES Each class of antibiotics works on a certain bacterial protein: penicillin binds to PBP, macrolides mess with ribosomes, and quinolones jam up the enzyme that unwinds DNA. That means that bacteria can dodge the effects of these drugs if they can just change how they make these enzymes. In other words, they can benefit if they get just the right mutation in their DNA. Some of the bacteria that could be killed by beta-lactam antibiotics contain some special genes for enzymes called beta-lactamases. These enzymes can destroy the antibiotic molecule, ripping it apart. Even though penicillin has only been used medically since the 1940s, the fungus that makes it must have been around a lot longer. The beta-lactamase enzymes may be over a billion years old. Another tactic to dodge the damage of beta-lactam drugs is to tweak PBP so that the antibiotic can’t bind as well. This is how MRSA, or methicillin-resistant Staphylococcus aureus, accomplishes the methicillin resistance that is its claim to fame. Macrolide resistance usually comes from a change to the ribosome. But it’s not a genetic change; the ribosome’s RNA sequence remains the same. Instead, another gene makes a protein called Erm that can add a methyl group to a certain spot on the ribosome. With that small addition, the ribosome is less susceptible to the effects of the antibiotic. Quinolone resistance can result from mutations that change the DNA unwinding enzyme to make it less susceptible. Another common means of resistance is for the bacterium to acquire efflux proteins. These are pumps that can move antibiotic molecules out of the cell. Efflux pumps can remove many different kinds of chemicals, so if a cell can pump out quinolones, it can often pump out other antibiotics too. The mutations mentioned here are only some of the sources of antibiotic resistance. Bacteria often accumulate multiple mechanisms of resistance: making several changes to the DNA unwinding enzyme, for example, or having genes for more than one type of beta-lactamase. SURVIVAL OF THE LEAST SUSCEPTIBLE The genetic changes that lead to antibiotic resistance don’t always occur on the bacterium’s main chromosome. Remember how bacteria can transfer tiny circular bits of DNA, called plasmids, to one another? Antibiotic resistance genes often occur on those plasmids. If you’re a bacterium, and someone gifts you a plasmid with an antibiotic resistance gene, that gives you the ability to survive just a little longer. You’ll have more opportunities to divide, and of course you’re making extra copies of the plasmid so all your children get this helpful gene too. Before long, the antibiotic resistance gene becomes a popular thing: if antibiotics are around, antibiotic-resistant bacteria will flourish while susceptible germs will die. The same is true of antibiotic resistance genes on the main bacterial chromosome. If you have a gene that gives you resistance, you’ll be able to survive longer and have more children. In many cases, antibiotic resistance genes don’t give perfect protection: if you’re totally swamped with antibiotics, they could still kill you anyway. That’s why, if you get a prescription of antibiotics from your doctor, it probably comes with a sticker warning you that you must finish the entire course of antibiotics. The idea there is to keep up a large concentration of antibiotics in your body until all the susceptible bacteria are killed. But resistance flourishes anyway. If you had a particularly tough bacterium in your body, it might be able to survive even the regular dose of antibiotics. And when you stop taking the antibiotics, that bacterium might even be able to gift its plasmid to other bacteria that come to infect you later. Even our harmless gut bacteria can get in on this gift exchange: after you take antibiotics, you’re likely to end up with some antibiotic-resistant bacteria in your gut, and they can give plasmids to other, more harmful bacteria later on. Because antibiotic-resistant bacteria are more likely to survive over time, the antibiotics represent a selection pressure that drives evolution. The process by which susceptible germs die off and resistant ones flourish is called natural selection. To prevent antibiotic resistance from becoming more common, finishing our prescriptions isn’t enough. It’s also important that doctors only prescribe antibiotics when they are absolutely necessary. That’s why your doctor might decline to give you antibiotics for a cold or flu: those are both viral illnesses, and antibiotics don’t do anything to kill viruses. Doctors are also advised to test the bacteria that cause an infection to figure out whether they are resistant, and to which antibiotics. That way, your doctor can prescribe the most precise antibiotic that will actually do the job, instead of just guessing at a prescription that might put a selection pressure on all of the bacteria in your body, including the harmless ones. Antibiotic resistance is also driven by antibiotic use on farms. Animals often get antibiotics in their feed because it helps them grow larger, which is convenient for the farmer: more meat in less time. But this means that farmers are also breeding antibiotic-resistant bacteria alongside their cows or chickens. To tackle this problem, it’s best if farmers reduce their dependence on antibiotics, and that they make sure that the ones they do use are not the same antibiotics that are commonly used in human medicine. X-LINKED TRAITS Why More Men Than Women Are Color Blind Here’s a paradox about the X chromosome: females have more X chromosomes than males, but if a health condition comes from a gene on the X chromosome, males are the ones more likely to show the phenotype. Don’t be confused—it actually makes sense when you remember how the X chromosome is inherited. People who are genetically female have two X chromosomes. Males are XY, so they only have one X. If you are female and have a recessive allele—say, one that results in color blindness—it will act just like the genes on your other chromosomes. You have two copies, so if one allele makes a functional protein and the other does not, you’ll still get the results of having the functional protein. But if you are male and inherit that recessive allele, you don’t have a second X chromosome to rely on. If your one and only X chromosome makes a nonfunctional photoreceptor in your eye, that’s it—you’re color blind. WHAT IS COLOR BLINDNESS, ANYWAY? Many genes affect color vision in humans, and researchers have found at least fifty-six where a mutation can lead to problems perceiving colors. For this example, we’re going to look at one of the more common mutations that causes color blindness, or, to use the more accurate term, color vision deficiency. This mutation happens in a gene on the X chromosome. When light hits our eyes, we only “see” it if it hits a special type of cell at the back of the eye. (That’s why we have a pupil and a lens: the lens focuses light through the pupil to project an image on the back of the inside surface of our eyeballs. That back surface is called the retina.) We have four types of these cells. One type, the rod cell, just registers whether light hits it or not, and zaps a signal down the optic nerve to the brain. The brain can perceive an image based on which rod cells got turned on and which didn’t. Think of this as a black-and-white photo: some pixels are on and appear white; others are off and appear dark. We use this type of vision a lot in the dark. Take a look around the room next time you’re falling asleep in a dark room. You can’t discern any colors, can you? As far as our brain knows, the dark is a black-and-white world. What Colors Can You See? Humans have three colors of cones, but other animals don’t see the same way we do. Most mammals have just two: one blue and one yellowish. If you’ve heard that dogs are “color blind,” that’s true in the same sense that people are often color blind. They will have trouble distinguishing red from green, but they do still see in color. Meanwhile, other creatures have different light receptors than ours. Bees can see ultraviolet light, for example, which is why flowers sometimes have spots and patterns that are invisible to our eyes—but they’re obvious to the bees! But in the daylight, the rod cells all register light, so they’re not helpful in putting together a picture. Fortunately, our cone cells are up for the job. We have three types of cone cells. Most of us, anyway. Some send their signals when they are hit by red light, others when they are hit by blue light, and the third type when they are hit by green light. Color vision deficiencies occur when one of those three cones doesn’t do its job. The two most common types of color blindness, each inherited by 1 percent of male (XY) humans, come from mutations on the X chromosome affecting the instructions for the light-sensitive proteins, or opsins, in either the green or red cones. Let’s take the green one, for example. This is the gene that most other mammals, like dogs, do not have. The gene that makes opsin for green cones is known as OPN1MW. Right next to it on the X chromosome is the gene for the red opsins, OPN1LW. We may actually have more than one copy of each of these genes, just lined up next to each other. When the X chromosomes stick together during meiosis, it’s a little too easy for the red and green opsin genes to get mixed up. The recombination process normally just swaps DNA between chromosomes, but if there are near-identical sequences too close to each other, it’s possible that they don’t match up correctly. It’s like when you button your shirt wrong: the buttonhole right below the correct one is still a buttonhole, so you can end up putting all the buttons in the wrong holes before you realize what you’ve done. When this happens to chromosomes in recombination, they can end up swapping the wrong amount of genetic material. The result can be that one chromosome is just a little too short or too long. That means the red or the green opsin genes can end up getting deleted in one of the resulting cells. Or if recombination occurs in the middle of a gene, you could end up with a hybrid protein that detects a color that is somewhere in between red and green. (As far as our eyes and brain are concerned, that color would appear as yellow.) MEN OFTEN GET COLOR VISION DEFICIENCY FROM THEIR MOTHERS A man with XY chromosomes, who is missing an opsin gene on his X chromosome, will have a color vision deficiency. If his green cone doesn’t work, he won’t be able to see green. (His red cone will still pick up some of the green light, though, since those colors are actually fairly similar wavelengths of light.) But since he’s an XY male, he gets his X chromosome from the parent that provided the egg cell. Think about it: the only place he could get a Y chromosome is from his father, so the X must come from his mother. That means his mother had at least one X chromosome with a bad green opsin gene. On the other hand, the odds are, she probably also has a fully functional green opsin gene on her other X chromosome. An XX woman could only be color blind if she inherited two X chromosomes with the same nonfunctional gene. That’s just less likely to happen. This pattern holds true for any other X-linked recessive gene, including hemophilia. It doesn’t matter if a man’s father is color blind, since an XY father can’t pass an X chromosome to his son. (If he did, the resulting embryo would be XX and thus female.) To figure out if a man is likely to be color blind, don’t look at his father; look at his mother’s other sons (who have a 50⁄50 chance of getting her affected X chromosome), or his mother’s mother’s sons. A woman who carries an affected X chromosome will see the trait show up in, on average, half of her sons. EPIGENETICS The Environmental Mark By now we’re used to thinking of DNA as a way of storing information. But the information that’s coded in the sequence of nucleotides (A, T, G, C) isn’t all. Your DNA also carries epigenetic information, which can change while the sequence of bases stays the same. Epigenetics literally means “on the genome.” The cell can make changes by adding methyl groups (a carbon and three hydrogens) to certain parts of the DNA, or it can add other groups of atoms to specific places on the histone proteins that are snuggled up next to specific parts of the DNA. These changes affect which parts of the DNA get transcribed into RNA, and thus they dictate what genes are expressed. Epigenetic modifications to the DNA are changes in gene expression that persist even when the DNA is replicated. When a cell divides, both copies end up with not just their parent cell’s DNA sequence, but also their parent cell’s epigenetic modifications: those methyl groups and histone tags that can continue to direct gene expression even after the cell divides. These changes persist when a cell divides, but that doesn’t mean you inherited them from your parents. Before an egg and sperm meet, some of their epigenetic modifications are reset, so you get the chance to come up with your own. But we do know that some epigenetic changes seem to be heritable from parents to children. Just be aware that when we talk about epigenetics, that’s only one small piece of how they work. DNA METHYLATION Specialized enzymes add methyl groups to cytosines in places where the cytosine comes right before a guanine in the DNA sequence. (These places are called CpG sites, because they have a nucleotide with a cytosine, then after the next phosphate on the DNA’s backbone they have a guanine. In other words, we’re not talking about a cytosine/guanine base pair, but rather a cytosine and guanine next to each other on the same side of the DNA.) Experiments in mice show that if they don’t have the enzymes that add these methyl groups, they can’t develop normally in utero. In mammals (including humans and mice), 70 to 80 percent of our CpG sites are methylated. The places where they aren’t methylated are usually gene promoters. Promoters are necessary to start the transcription of a gene, as we learned in the “Turning Genes On and Off” section. That means that methylating a promoter probably turns it off and is something cells do when they and their offspring aren’t likely to need that promoter again. Other places in DNA can be methylated as well, and we don’t understand all of the reasons for methylation. Shortly after egg and sperm meet, the resulting cell takes the methyl groups off most of the methylated areas of DNA, as if hitting a “reset” button. As the embryo develops, genes are methylated again, little by little. We think this process is part of how stem cells, which are able to develop into any type of cell, settle down and specialize into skin cells and other specific types of cells that we need. HISTONE MODIFICATION You remember histones, right? They are the proteins that DNA is always wrapped aro