The New Genetics
Chapter 3: Life's Genetic Tree
In all of biology, there is one thing that always stays the same. That thing, believe it or not, is change itself!
The millions of different living things on Earth—plants, bacteria, insects, chimps, people and everything else—all came to be because of a process called biological evolution, in which organisms change over time.
Because of biological evolution, early humans gained the ability to walk on two feet. Because of evolution, air-breathing whales can live in the ocean despite being mammals like us. Because of evolution, some bacteria can live in scalding water, others can survive in solid ice and still others can live deep in the Earth eating only rocks!
Evolution happens every day, and it affects every species—including us. It changes entire populations, not individuals. And it has a big impact on medical research.
To understand evolution, let's go back in time a century and a half to 1854, when the British naturalist Charles Darwin published The Origin of Species, a book that proposed an explanation for how evolution works.
The main concept in evolution is that all living things share a common ancestor. The very earliest ancestor of all life forms on Earth lived about 4 billion years ago. From that early organism, millions of types of creatures—some living and some now extinct—have evolved.
Evolution requires diversity. You can tell that living things are diverse just by walking down the street and looking around you. Individual people are very different from one another. Chihuahuas are different from Great Danes, and Siamese cats are different from tabbies.
Evolution also depends on inheritance. Many of our unique characteristics are inherited—they are passed from parent to offspring. This is easy to see: Dalmatian puppies look like Dalmatians, not Chihuahuas. Petunias grow differently from pansies. Evolution works only on traits that are inherited.
Finally, as you probably already know, evolution favors the "fittest." Through a process called natural selection, only some offspring within a given generation will survive long enough to reproduce.
As an example, consider houseflies, each of which lays thousands of eggs every year. Why haven't they taken over the world? Because almost all of the baby houseflies die. The flies that survive are the ones that can find something to eat and drink ... the ones that avoid being eaten, stepped on or swatted ... and the ones that don't freeze, drown or land on a bug zapper.
The flies that survive all these ways to die have what it takes to outlive most of their brothers and sisters. These inherited traits give an organism a survival edge. Those who survive will mate with each other and will pass on to the next generation some of their DNA that encoded these advantageous traits.
Of course, not all aspects of survival are determined by genes. Whether a fly gets swatted depends on genes that affect its reflexes—whether it's fast enough to avoid the swatter—but also on the environment. If there's no human around waving the swatter, the fly is quite likely to survive, regardless of its reflexes.
Evolution often takes a long time to make a difference. But it can also happen very quickly, especially in organisms with short lifespans. For example, as you read earlier, some bacteria have molecular features that let them survive in the presence of antibiotics. When you take an antibiotic medicine, antibiotic-resistant bacteria flourish while antibiotic-sensitive bacteria die.
Because antibiotic resistance is a growing public health threat, it's important to take the whole course of antibiotic medicine, not stop when you feel better. And you should take antibiotics only when they're needed, not for colds or other viral infections, which antibiotics can't treat.
Scientists doing medical research are very interested in genetic variants that have been selected by evolution. For example, researchers have discovered a rare genetic variant that protects people from getting AIDS. A genetic variant is a different version of a gene, one that has a slightly different sequence of nucleotides.
Scientists think that the rare variant of a gene called CCR5 originally may have been selected during evolution because it made people resistant to an organism unrelated to HIV.
Montgomery Slatkin of the University of California, Berkeley, has used mathematical modeling techniques to show that natural selection over time could explain the frequency of the CCR5 variant in human populations. The work indicates that the CCR5 gene variant's ability to protect against AIDS may contribute to keeping it in the human gene pool.
So, through evolution, living things change. Sometimes, that's good for us, as when humans understand HIV resistance in hopes of preventing AIDS. But sometimes the changes aren't so great—from a human perspective, anyway—as when bacteria become resistant to antibiotics.
Whether the consequences of evolutionary change are good or bad, understanding the process can help us develop new strategies for fighting disease.
Clues from Variation
Scientists know quite a bit about how cells reshuffle genetic information to create each person's unique genome. But many details are missing about how this genetic variation contributes to disease, making for a very active area of research.
What scientists do know is that most of the human genome is the same in all of us. A little bit of genetic variation—differences that account for much less than 1 percent of our DNA—gives each of us a unique personality, appearance and health profile.
The parts of the human genome where the DNA sequences of many individuals vary by a single nucleotide are known as single-nucleotide polymorphisms (abbreviated SNPs and pronounced "snips").
For example, let's say that a certain nucleotide in one of your genes is A. In your uncle, however, the nucleotide in the same place on the same gene might be G. You and your uncle have slightly different versions of that gene. Scientists call the different gene versions alleles.
If two genes sit right next to each other on a chromosome, the SNPs in those genes tend to be inherited together. This set of neighboring SNPs is called a haplotype (see drawing to the right).
Most chromosome regions have only a few, common haplotypes among all humans. As it turns out, these few haplotypes—in different combinations in each person—appear to account for most of the variation from person to person in a population.
Scientists can use haplotype information to compare the genes of people affected by a disease with those of unaffected people. For example, this approach revealed a genetic variation that substantially increases the risk of age-related macular degeneration, the leading cause of severe vision loss in the elderly. Scientists discovered that a single SNP—one nucleotide in the 3 billion-nucleotide human genome—makes some people more likely to get this eye disease. The discovery paves the way for better diagnostic tests and treatments.
What about other diseases? In 2007, an international scientific team completed a catalog of common human haplotypes. Since then, researchers have been using the catalog to identify genes associated with susceptibility to many common diseases, including asthma, diabetes, cancer and heart disease.
But not all SNPs are in genes. Scientists studying genetic variation have also found SNPs in DNA that doesn't encode proteins. Nonetheless, some of these SNPs appear to affect gene activity.
Some researchers suspect that the "cryptic" (hidden) variation associated with SNPs in non-coding DNA plays an important role in determining the physical characteristics and behaviors of an organism.
Loren Rieseberg of Indiana University in Bloomington is one scientist who would love to take the mystery out of cryptic variation. He wants to know how this non-coding genetic variation can help organisms adapt to new environments. He's also curious about whether it can create problems for some individuals.
You might be surprised to learn that Rieseberg's principal research subject is the sunflower. Although many plants produce only one generation a year, plants like sunflowers can be very useful tools for researchers asking fundamental questions about genetics. Because their genetic material is more malleable than that of many animals, plants are excellent models for studying how evolution works.
Wild sunflowers appealed to Rieseberg because there are several species that live in different habitats. Two ancient species of wild sunflowers grow in moderate climates and are broadly distributed throughout the central and western United States.
Three recently evolved sunflower species live in more specialized environments: One of the new species grows on sand dunes, another grows in dry desert soil and the third species grows in a salt marsh.
To see how quickly new plant species could evolve, Rieseberg forced the two ancient sunflowers to interbreed with each other, something plants but not other organisms can do. Among the hybrid progeny were sunflowers that were just like the three recently evolved species! What that means is that Rieseberg had stimulated evolution in his lab, similar to what actually happened in nature some 60,000 to 200,000 years ago, when the newer species first arose.
That Rieseberg could do this is pretty amazing, but the really interesting part is how it happened. Scientists generally assume that, for a new species with very different characteristics to evolve, a lot of new mutations have to occur.
But when Rieseberg looked at the genomes of his hybrid sunflowers, he was surprised to find that they were just cut-and-pasted versions of the ancient sunflower species' genomes: large chunks had been moved rather than many new SNPs created.
Rieseberg reasons that plants stash away unused genetic material, giving them a ready supply of ingredients they can use to adapt quickly to a new environment. It may be that human genomes can recycle unused genetic material to confront new challenges, as well.
The Genome Zoo
Scientists often use an image of a tree to depict how all organisms, living and extinct, are related to a common ancestor. In this "tree of life," each branch represents a species, and the forks between branches show when the species represented by those branches became different from one another. For example, researchers estimate that the common ancestor of humans and chimpanzees lived about 6 million years ago.
While it is obvious just by looking that people have a lot in common with our closest living relatives, chimpanzees, what about more distant species? If you look at an evolutionary tree, you'll see that humans are related to mice, worms and even bacteria. The ancestral species that gave rise to both humans and bacteria was alive a lot longer ago than the ancestor of humans and chimpanzees, yet we still share hundreds of genes with bacteria.
Scientists use the term comparative genomics to describe what they're doing when they compare the genomes of different species to see how similar (or how different!) the species' DNA sequences are. Sequences that the species have in common are the molecular footprints of an ancestor of those species.
Why are "old" DNA sequences still in our genomes? It turns out that nature is quite economical, so DNA sequences that are responsible for something as complicated and important as controlling gene activity may stay intact for millions of years.
Comparative genomic studies also have medical implications. What would you do if you wanted to develop new methods of preventing, diagnosing or treating a human disease that animals don't get?
If people have a gene that influences their risk for a disease, and mice have the gene too, you could study some aspect of the disease in mice, even though they don't ever have the symptoms of the disease. You could even study the disease in yeast, if it has the gene, as well.
Starting All Over Again
Stem cells—what embryos are made up of just days after an egg is fertilized by a sperm—have the amazing ability to develop into any kind of cell in the body, from skin to heart, muscle and nerve.
Intrigued by the potential of these masterful cells, researchers want to know what gives stem cells their ability to change into a specific cell type upon the body's request, but stay in the "I can do anything" state until asked.
Some researchers are trying to figure out how stem cells work by using a unique model system: tiny, freshwater worms called planarians. These worms are like stem cells in the sense that they can regenerate. You can cut a planarian into hundreds of pieces, and each piece will grow into a complete worm.
Planarians' resemblance to stem cells isn't just coincidental. Scientists have discovered that planarians can perform the amazing act of regeneration due to the presence of, yes, specialized stem cells in their bodies.
Developmental biologist Alejandro Sánchez Alvarado of the University of Utah School of Medicine in Salt Lake City used the gene-silencing technique RNAi (see RNA Interference) to identify planarian genes essential for regeneration. He and his team hope to figure out how these genes allow the specialized stem cells to travel to a wounded site and "turn into" any of the 30 or so cell types needed to recreate a mature worm.
Although humans are only distantly related to planarians, we have many of the same genes, so these findings could reveal strategies for regenerating injured body parts in people, too.
Scientists have also learned how to genetically reprogram human skin cells (and other easily obtained cells) to mimic the stem cells of embryos. In theory, these so-called induced pluripotent stem cells could generate any type of cell and be used to treat diseases. But to realize this potential, we need a much better understanding of the properties of these cells and how to efficiently produce cells that are safe for therapeutic uses.
Genes Meet Environment
If toxins from the environment get into our bodies, they don't always make us sick. That's because liver enzymes come to our rescue to make the chemicals less harmful. The genes that encode those enzymes are under constant evolutionary pressure to adapt quickly to new toxins.
For example, certain liver enzymes called cytochrome P450 proteins metabolize, or break down, hormones that our bodies make as well as many of the foreign substances that we encounter. These include harmful molecules like cancer-causing agents as well as beneficial ones, like medicines. In fact, just two genes within the cytochrome P450 family, abbreviated 3A4 and 3A5, encode proteins that process more than half of all of the medicines that are sold today.
Since the chemicals to which people are exposed vary so widely, a scientist might predict that there would be different variants of cytochrome P450 genes in different human populations. Using comparative genomics, researchers such as Anna Di Rienzo of the University of Chicago have shown that this is indeed the case. Di Rienzo has found many sequence differences within these genes in people living throughout the world.
It turns out that one variant of the gene that encodes the cytochrome P450 3A5 protein makes this enzyme very efficient at breaking down cortisol, a hormone that raises salt levels in the kidneys and helps the body retain water. Di Rienzo compared the DNA sequences of the 3A5 gene in DNA samples taken from more than 1,000 people representing over 50 populations worldwide. She was amazed to find a striking link between the existence of the gene variant and the geographic locale of the people who have it.
Di Rienzo discovered that African populations living very close to the equator were more likely than other populations to have the salt-saving version of the 3A5 gene. She suggests that this is because this gene variant provides a health advantage for people living in a very hot climate, since retaining salt helps ward off dehydration caused by intense heat.
However, there seems to be a cost associated with that benefit—the 3A5 gene variant raises the risk for some types of high blood pressure. That means that in environments in which retaining salt is not beneficial, evolution selects against this gene variant.
Another scientist who studies interactions between genes and the environment is Serrine Lau of the University of Arizona in Tucson. She studies a class of harmful molecules called polyphenols, present in cigarette smoke and car exhaust, that cause kidney cancer in rats, and perhaps, in people.
Lau discovered that rats and humans who are more sensitive to some of the breakdown products of polyphenols have an unusual DNA sequence—a genetic signature—that increases their risk of developing cancer. She suspects that the gene that is affected encodes a tumor suppressor: a protein that prevents cancer from developing. In people and rats with the genetic signature, she reasons, the tumor suppressor doesn't work right, so tumors grow.
Taking this logic one step further, it may be that certain people's genetic make-up makes them unusually susceptible to DNA damage caused by exposure to carcinogens. If doctors could identify those at risk, Lau says, such people could be forewarned to avoid contact with specific chemicals to protect their health.
However, think about this scenario: Who should make those decisions? For example, would it be ethical for an employer to refuse to hire somebody because the person has a genetic signature that makes him or her more likely to get cancer if exposed to a chemical used in the workplace? Tough question.
Genetics and You: You've Got Rhythm!
What do waking, sleeping, eating, reproducing and birds flying south for the winter have in common? These are all examples of nature's amazing sense of rhythm. All living things are equipped with molecular timepieces that set the pulse of life.
If you've ever crossed the country or an ocean by plane, you know about the importance of these clocks. You probably experienced that traveler's misery called jet lag, where the body is forced to adapt quickly to a new time zone.
But did you know that certain forms of insomnia and manic-depressive illness are associated with biological clocks not working properly? And biological rhythms may be the reason why some medicines and surgical treatments appear to work best at certain times of day.
The human body keeps time with a master clock called the suprachiasmatic nucleus or SCN. Situated inside the brain, it's a tiny sliver of tissue about the size of a grain of rice, located behind the eyes. It sits quite close to the optic nerve, which controls vision, and this means that the SCN "clock" can keep track of day and night. Given enough time, your SCN can reset itself after you fly in an airplane from one time zone to another.
The SCN helps control sleep by coordinating the actions of billions of miniature "clocks" throughout the body. These aren't actually clocks, but rather are ensembles of genes inside clusters of cells that switch on and off in a regular, 24-hour cycle—our physiological day.
Scientists call this 24-hour oscillation a circadian rhythm. ("Circadian" comes from the Latin words meaning "approximately a day.") Researchers have discovered that all living things—plants, animals and bacteria—have circadian rhythms. Many researchers working with insect and other model systems have identified genes that are critical for keeping biological time.
Understanding circadian rhythms will help scientists better understand sleep disorders. If we have the opportunity, most of us sleep 7 or 8 hours at night, and if we don't get enough rest we may have a hard time getting things done the next day. Some people, however, routinely get by with only 3 to 4 hours of sleep. Researchers have noted that this trait seems to run in families, suggesting a genetic link.
As it turns out, fruit flies need even more sleep than people. Neuroscientist Chiara Cirelli of the University of Wisconsin-Madison did a genetic search for fruit fly mutants that don't sleep much. She discovered that flies with a variant of a gene called shaker sleep only 3 to 4 hours per night.
Although the shaker flies don't appear sleep-deprived, Cirelli found that they have a different problem: They don't live as long as flies without the mutation. She is now studying this new connection between sleep and lifespan.
Her work may also pave the way for improved sleep aids and effective remedies for jet lag.
Animals Helping People
Using technology that grew out of the Human Genome Project, scientists have read the sequences of the genomes of hundreds of organisms: dogs, mice, rats, chickens, honeybees, fruit flies, sea urchins, pufferfish, sea squirts, roundworms and many bacteria and fungi. Next in line are dozens of additional species, including a marmoset, a sea skate, an alpaca, an anteater and many reptiles.
What effect will all this gene sequence information have on medical research? We've already talked about the fact that people share many of their genes with other species. This means that when scientists read the sequence of another species' genome, they're likely to discover that the organism has many of the genes that, in humans, cause disease or raise disease risk when mutated.
Take fruit flies as one example. According to biologist Ethan Bier of the University of California, San Diego, 30 percent of the currently identified human disease genes most likely have functional counterparts in none other than Drosophila melanogaster, a fruit fly species widely used in genetic research (see Living Laboratories).
Currently, Bier and other scientists are using experimental flies to investigate a wide range of genes involved in conditions such as blindness, deafness, mental retardation, heart disease and the way in which bacterial toxins cause illness.
By reading the DNA sequences of many other species, researchers hope to find model systems that are even better than fruit flies for studying some aspects of human disease.
Sometimes, the genes that we don't have in common with other species are as important as the genes we share. For example, consider the fact that humans and chimpanzees have remarkably different abilities and physical features. But the chimpanzee genome is 99 percent identical to our own.
And did you know that chimpanzees don't get malaria or AIDS?
So a tiny portion of our genome determines whether we look and behave like a person or a chimp, and whether we are susceptible to malaria or AIDS.
My Collaborator Is a Computer
We've made the case that comparing genomes can offer fresh insight on the basic genetic ingredients for health and the causes of disease. But what does a scientist actually do when he or she compares gene sequences? Does this mean staring at thousands of pages of genetic letters, looking for those that are the same or different?
Yes and no. Comparative genomics does involve looking for similarities and differences, but it isn't something that scientists do by hand. Certainly not for thousands of genes at a time.
Rather, the gigantic task of comparing the nucleotides that make up the genomes of two or more species is the perfect job for a computer, a natural multitasker. If you consider that the human genome contains 3 billion nucleotides, you can easily see why this is work well suited to a machine (with a human operator, of course).
Researchers called computational biologists help analyze genomic data. These scientists develop software programs that enable computers to perform genome comparisons. Among other things, the programs can figure out where in the DNA sequences a gene starts and stops: its "boundaries."
Other researchers who work in the field of bioinformatics mine genomic information hidden in the masses of data. They are looking for scientific treasure in the form of new biological knowledge. These experiments can zero in on previously hidden patterns and reveal links between different fields of research.
Bioinformaticists and computational biologists are in high demand because they play a very important role in 21st-century medical science. These scientists must be fluent in both computer science and biology.
The Tools of Genetics: Unlimited DNA
You might be amazed to learn that a microbe that lives in a boiling hot spring in Yellowstone National Park is the essential ingredient for one of the most important biological research tools ever invented.
Thermus aquaticus is a bacterium that makes a heat-resistant enzyme, which is why it can thrive in hot springs. The enzyme, Taq polymerase, is essential to a laboratory technique called the polymerase chain reaction, or PCR. And PCR is essential to lots of things that life scientists do—and to many other fields, too. PCR's inventor, Kary Mullis, won the 1993 Nobel Prize in chemistry.
PCR is a quick, easy method for generating unlimited copies of tiny amounts of DNA. Words like "revolutionary" and "breakthrough" are not an exaggeration of its impact.
PCR is at the heart of modern DNA sequencing methods. It is essential for pinpointing mutations in genes, so it is the basis for much of the research discussed in this booklet. PCR has done for genetic material what the invention of the printing press did for written material. It makes copying easy, inexpensive and widely available.
PCR underlies many diagnostic techniques, like testing individuals for genes that cause breast cancer. It can also help diagnose diseases other than cancer, such as infections by HIV and hepatitis C.
PCR is a key element of "genetic fingerprinting," which has helped free prisoners who relied on it to prove that they were innocent of the crimes that got them locked up. Conversely, it has provided scientific evidence that helped convict criminals.
PCR has even revolutionized archaeology by helping to analyze badly damaged ancient DNA—sometimes thousands of years old—which can reveal new information about past people and cultures.
Scientists predict that future uses of PCR technology will enhance medical treatment, enabling better diagnosis and more accurate subtyping of disease.
Discuss reasons why research studies with identical twins can provide valuable information about health and disease.
Humans and mice share over 80 percent of the same genetic material: for chimps and humans, it's more than 99 percent. Why are people and animals so different, if their genes are so similar?
You are a scientist and you want to learn more about how humans age. Is there a way you can address your research question without spending many decades studying people?
Can you think of an experiment using fruit flies that could help researchers better understand jet lag?