by Lone Frank
More than anything, the genome project is the emerging seedling of a genetic-industrial complex. Once the initial vision was fulfilled, the international machinery of discovery that had been established at large research institutes could not just stand idle, and scientists pinpointed new projects to throw into the works. They shifted their focus from creating a map of our basic, common genetics to investigating individual variation. The goal was to catalog all the differences found in our DNA because they, of course, are central to understanding the differences between people.
The first big enterprise, HapMap, aimed to throw light on the variation between the large geographic groupings we traditionally call “races.” To see if these groupings correspond to actual genetic differences, HapMap mapped the genomes of people from five major ethnic groups. The effort yielded the first catalog in which point mutations – substitutions of one base for another in the genome – appear. These commonly studied mutations have gained an idiomatic abbreviation, “snip” (SNP or single nucleotide polymorphism). It is estimated that there are somewhere in the neighborhood of fifteen million SNPs in the human genome, though just over three million have been identified and conscientiously entered into the international SNP database.
Future steps will involve cataloging variation in ever finer detail, by sequencing as many complete genomes as scientists can get into their labs. At the end of 2010, the list of published, freely accessible genomes stood at two dozen and included the genomes of celebrities such as Bishop Desmond Tutu and actress, Glenn Close. Research institutions hold unpublished records of almost two hundred more people. But that’s only the beginning. The 1000 Genomes Project is sequencing the genomes of over a thousand volunteers for public use, and the even more ambitious Personal Genome Project is endeavoring to collect a hundred thousand genomes. These genome collectors are pursuing all types of variation.
We humans do not just carry around small, discrete SNPs, with an A in one and a G in another, ready to be noted and entered on a database. We also carry far more drastic mutations: large pieces of DNA may have fallen out, been duplicated one or more times, or simply have moved around and landed in different places in the genome. For the mutation hunters in the research community, the preferred tracking tool of recent years is the so-called genome-wide association study. Association studies are supposed to highlight which genes influence certain diseases or other human characteristics. They are incredibly simple in their design. A group of volunteers suffering from a particular disease, or possessing a particular trait, is compared to a control group that does not have that disease or trait. Both groups are tested for a number of known SNPs, using a “gene chip.” Inside this ingenious, postage-stamp sized device, small pieces of DNA are placed, which flutter like sea grass on the ocean floor. Current gene chips can typically test between half a million and a million SNPs, drawn from across the landscape of chromosomes. This massive quantity of data is fed directly into a computer, and software is used to find patterns in the chip’s genetic observations.
The question posed by such bioinformaticists is basic: does one SNP (or more) recur far more frequently in the sick subjects than in the well ones? If it does, the mutation is considered a marker associated with the disease. Once scientists know where the marker is to be found in the genome, they can use its placement to work out which gene it is associated with. They can also calculate how much the presence of the marker increases the risk of developing the disease. This method makes it possible to study the causes of a disease without first forming a hypothesis of where the problem resides. It’s the equivalent of casting a large, finely meshed net across the genome and seeing what comes in with the catch. As soon as the bioinformaticists and their computers have hit on an association, the biologists can run to the lab and investigate the identified gene. By clarifying the gene’s role in the organism’s tissue, researchers hope to gain insight into the biological mechanisms of the disease and, eventually, discover new treatment methods and drugs.
One early, and very well-known, association study whetted appetites in the field. In 2005, a team led by Robert J. Klein of Rockefeller University was able to show that a serious eye condition, age-related macular degeneration, is clearly associated with a SNP variant in a very particular gene already known to produce a protein that regulates inflammation. The result killed two birds with one stone: not only was there a connection that could be used to identify people with a high risk of getting the disease but also a threshold that could be used to clarify its mechanisms.
Two years later, the first truly significant association studies were published in the journal Nature. In the first, scientists from McGill University in Montreal tried to locate the genetic factors involved in type 2 diabetes, one of the major lifestyle-associated diseases of our time. After testing nearly four hundred thousand SNPs, the McGill group found many associations – notably variations in two already well-documented genes. Later that year, the Wellcome Trust, in the UK, backed similar studies for type 1 diabetes, type 2 diabetes, high blood pressure and cardiovascular disease, rheumatoid arthritis, Crohn’s disease, and bipolar disorder. Two hundred researchers analyzed data from seventeen thousand people, healthy and sick, and revealed a number of new genetic associations.
To date, association studies have provided more than four hundred associations between particular gene variants and everything from prostate cancer, to kidney stones, to curly hair, and even to something as esoteric as the ability to smell digested asparagus in urine.
NICE. BUT CAN anything practical come of finding the gene that makes some of us super-sensitive to après-dîner asparagus fumes? It happens that the ever-cheaper technology for sequencing genes, studying genetic variation, and running association studies has given birth to a brand new creature living beyond the laboratory. As the well-known American psychologist Steven Pinker strikingly remarked: “We have entered the era of consumer genetics.”
The Great Leap Forward to consumer genetics came in 2008, when the masses were finally invited to join James Watson, Craig Venter, and a handful of celebrities, at the sequencing party. In a heated race to be the first to the market, two companies, the deCODEme, in Iceland, and the 23andMe, in the US, began selling personal gene profiles. If you mailed in a bit of saliva or a cheek swab, deCODEme or 23andMe would test your sample, searching for between half a million and a million genetic markers. Your SNPs would then be compared with results from several high-profile association studies – checking to see if your genes match those associated with, for example, cardiovascular disease, diabetes, or Alzheimer’s disease. Association studies are not cut and dried, however. You aren’t receiving a genetic diagnosis, informing you that you have or are very likely to get a genetically determined disease. On the contrary, you’re getting a risk assessment, a collection of indicators that compare your chances of getting a disease to the general population’s:
According to your genetic profile, dear customer, you have an 8.7% risk of developing disease X at some point in your life. This risk is twentyfive percent higher than the average for people of your ethnic background.
With your genetic risk assessment in hand, you can devote yourself to goal-directed prevention. Like Chinese parents sending their children off to genome-testing summer camp, you can study your genetic makeup and work out what you should do to optimize your health and longevity, if not your career prospects. To make the process as technologically efficient (and perhaps cost-effective) as possible, everything is served up virtually, without human contact, via the Internet in a format in which you can not only browse your own genome but invite your “friends” as well.
This is genetics as Facebook. Information that has always been hidden and unobtainable is now visualized and displayed, and what was broadly considered ultimately personal is now readily shared and compared. Presently, we’re in the Wild West of personal genetic services – young, exciting, and full of golden opportunities. In fact, in just its first few years, the scope of the indus
try has grown beyond the comprehension of the average consumers it is trying to lure. There are somewhere in the neighborhood of 1500 distinct genetic tests in which mutations in a single gene are mapped, and almost just as many businesses that offer them.
Beyond those who are peddling tests, there are websites where you can orient yourself with your genetic results, and advice bureaux that offer to take you by the hand and, with the help of some questionnaires, identify the genetic tests and package deals best suited to your needs, exactly as if you were considering a cruise holiday, a flat-screen television, or a washing machine. As in any booming industry, the genetic supermarket is stocked with ever more goods each day. And the store is open twenty-four/seven.
As we get used to shopping, our genetic interest in ourselves and each other will reach widely and in many directions. It may well be that James Watson is right, and disease research will have the highest priority and get the most funding. But as the price of genetic testing falls and entrepreneurial opportunities rise, the demand for studying normal traits will become insistent. We will put the spotlight on behavioral genetics, that once-controversial field that asks the cheeky questions about how tiny differences in individual genes can explain how people think, react, and act differently. Questions that go to the very heart of human nature.
That should not be surprising. Our DNA is, in its way, our most intimate history. In the future, we will read the development of our species through comparisons of our genome with those of other species, and trace human kinships far and wide as they are inscribed in the alphabet of the four bases. When we want to, or need to, we will seek out our identity and our affiliations directly in our genes.
2
Blood kin
Being born in a duck yard does not matter, if only you are hatched from a swan’s egg.
HANS CHRISTIAN ANDERSEN
“EXCUSE ME, FRÄULEIN, but are we related?”
I’m not sure what the man at the counter is saying. I’m exhausted after the trip from Cold Spring Harbor, New York, to Frankfurt, Germany, and I’ve simply asked him for a window seat on the plane to Copenhagen. Why is some random airline clerk asking me about my relatives?
“Frank,” he says, pointing to his nametag. “My name is Frank, too. Eberhard Frank.” He persists: “I come from Pomerania; could we be related?”
I look at him but can’t see any particular resemblance. We’re both pale and have the mousy-brown hair typical of many northern Europeans, but then, it’s typical because half the population at these latitudes has it. What can I say – I’ve never been to Pomerania and have no idea whether I have distant German relatives there. I settle on a moderately amicable, “I doubt it.”
When I think about it, I realize I know embarrassingly little about where I come from and have not previously given it much consideration. Like most people, I’m familiar with about three generations of my family tree: my parents, my grandparents and my great-grandparents – or, rather, some of my great-grandparents. I was lucky enough to meet two of my great-grandmothers and one great-grandfather at an age when I was capable of forming memories of them. The others died before I was born. Beyond that, everything is lost in a fog. Ask me about my great-great-grandparents, and I could tell you nothing.
Before I started on my quest to probe into my genome, I never had a sense that kinship – genetic kinship – was especially important to identity. Obviously, your close family is important, because you have a personal relationship. But whether I shared DNA sequences with people I did not know or a throng of people long dead had seemed to me emotionally meaningless. Almost hypothetical.
“I am what I do,” I always say, emphatically. My identity is my work. Where is the logic in defining oneself in terms of some randomly transmitted molecules?
Still, you can’t get around it. There is something very powerful and identity-producing in our DNA. Biology – bloodlines – means something, even if it might not have much to do with your daily routine or your social network. It reminds me of A. M Homes’s observations on biology and culture in her memoir The Mistress’s Daughter. As an adult, Homes, who is adopted, meets her biological parents – a couple of opportunists whom she finds she does not actually like. She becomes suddenly and enormously interested in exploring their roots, and thus her own. Homes writes:
I note to myself that I am not as interested in digging into the story of the mother and father I grew up with, and I don’t really know why. Is there something physically unique about discovering this new biological tale?
To her surprise, her biological family seems more real than the adoptive one in which she had lived since just a few days after her birth. Blood mattered.
That may have something to do with our time. We are served reality television programs which transport celebrities to musty archives or distant lands to unearth a biological ancestor. In other, equally schlocky programs, adopted children learn their “true” past, locating distant relatives or ancestors with whom they share neither a language nor a culture. We are blasted with stories about sperm donors, as children of anonymous donors demand to know more about their biological parents, while some donors – such as the English firefighter Andy Bathie – have been held responsible for child support on the basis of biology alone.
Of course, genetics is about family, but it’s also about finances. One of the most distinct trends in consumer genetics is the increasing use of paternity tests. There have always been fathers who wondered whether the redheaded son with the odd nose could really be theirs, but today they can gain absolute certainty about a wife’s fidelity by purchasing an easy-to-use DNA test. In Denmark, five thousand paternity tests were conducted by private firms in 2009, a fifty percent increase in a single year. One UK company suggests that something of the order of seventy thousand paternity tests are made annually. In the United States, it is estimated that up to a half a million tests (provided by officially controlled laboratories) are conducted each year just for use in lawsuits: the number of private tests is presumably much higher.
Since 2008, it has become possible for anyone to do a paternity check simply by buying a commercial test off the shelf at the local pharmacy. The test is relatively pain-free – depending on the results. A man suspicious of his wife’s moral fiber can take the swabs supplied with the kit, scrape some cells from the inside of his and his child’s cheek, and send them off by mail. Sometimes the answer is: “Unfortunately, comparison of the DNA samples submitted cannot confirm paternity.” And what then? If he’s raised a child as his own, changed the diapers, helped with the 4 a.m. feedings, nursed the chickenpox, and coached through the multiplication tables, can the child really stop being his because they do not share his genome? Aren’t the feelings cultivated through years of living together worth something?
Not necessarily. The New York Times Magazine, for example, has described how accessible DNA tests are changing the notion of fatherhood itself, as a conflict has arisen between the traditional view of fatherhood and a strictly genetic view. Under US law, with respect to your obligations as a child’s provider, it doesn’t matter whether or not you are biologically related, but more and more “fathers” are refusing to pay child support, sometimes even abandoning children, when they discover there is no genetic kinship. The argument seems to be Why spend time and money on a relationship in which you have no biological stake? It’s not easy for the children, who lose a parent in the battle over bloodlines; they are usually unprepared for the redrawing of kinship ties. In the article, a teenager, called L learned as a nine-year-old that she had a different father from the one she had lived with all her life. “At first, it made me scared, because if my dad wasn’t related to me, then I was living with someone who wasn’t a part of my family, like a stranger,” she explained.
Biology isn’t limited to these most intimate of family relationships. In a far more diffuse form, genetics also creeps into what you might call the extended, or hyper-extended, family – that is, one’s ethnic group, o
ne’s people. The first time I was personally confronted by this was in the 1990s, when I was living on Manhattan’s Upper West Side in a venerable old building on the corner of 112th Street and Broadway. There, I was always thought to be Jewish, because my last name could be Jewish. Think, for instance, of the immortal diarist, Anne Frank.
The Upper West Side is a heavily Jewish neighborhood, where you are never far from a synagogue. On Friday evenings, I would see men wearing curled side locks and plain black clothes plodding up and down West End Avenue, trailed by wives who covered their hair with pious stiff wigs. People here took their ethnicity seriously. I didn’t know a soul in the neighborhood, but a few days after my name was placed on the apartment door, unsolicited pamphlets and leaflets bearing the Star of David and menorahs came pouring in.
There were invitations to events at the temple, and letters encouraging “Dear Ms. Frank” to join various Jewish organizations as quickly as possible. One afternoon, I ran into a diminutive older gentleman who was about to shove a pink flyer through my letter slot. I told him politely that it was a waste of time. So far as I knew, my name did not derive from Jewish ancestors. In fact, the closest I’d ever come to anything Jewish was the six months I spent as a volunteer in an Israeli kibbutz right after school – and that was more for the booze and the parties.
“That’s too bad, but of course it’s not your fault,” intoned the man sympathetically, placing a hand on my arm.
Soon after, the stream of paper dried up, but I again encountered the special connection that genetic ancestry creates – with a slightly different approach. I had met a few Jewish men who were attracted to non-Jewish women but who admitted flat out that they would never dream of marrying or having children with them. None of them could give me a good explanation as to why. When I pressed them, in my direct and brutally honest way, they said it didn’t have so much to do with culture – that’s something anyone can learn – or with religious faith, which none of them had. The closest I got to an explanation was when one mumbled, “there’s just something important about the biological connection to the past.” For him, it seemed, genes were the essence of a human being.