Mystery in the Map
. . . the most important, most wondrous map ever produced by humankind.-president bill clinton,
Announcing the completion of the draft human genome sequence
On June 26, 2000
A map is not the territory it represents. -alfred korzybski
My cab wove through the midafternoon traffic, tracing an arc along the frozen shore of Lake Michigan. On my right, the buildings of one of the world's tallest cities stabbed toward the sky, steel and glass growing out of the Illinois prairie like modern incarnations of the grass and trees that once lined the lake. A thriving metropolis of nearly three million people, Chicago boasts an airport that was once the world's busiest (it's now second), with over 190,000 passengers a day passing through its terminals-including, on this particular day, me. This sprawling city prides itself on its dynamic, forward-looking culture-the "tool maker" and "stacker of wheat," as Carl Sandburg called it. Not the most obvious place to come looking for the past.
The lake took me back in time, though-way back, before it was even there. Lake Michigan is actually a remnant of one of the largest glaciers the earth has ever seen. During the last ice age, the Laurentide ice sheet stretched from northern Canada down along the Missouri River, as far south as Indianapolis, with its eastern flank covering present-day New York and spilling into the Atlantic Ocean. When it melted, around 10,000 years ago, the water coalesced into the Great Lakes, including Michigan. Looking out the window of my cab, at the strong winds ripping across the expanse of ice reaching out from the Chicago shoreline, I felt like history might be rewinding itself. The ice age could have looked a bit like this, I thought.
This wasn't just idle musing; I've spent my life studying the past, effectively trying to rewind history. I became obsessed with it as a child, and devoured anything and everything on ancient Egypt, Greece, and Rome, the great empires of the Middle East, and the European Middle Ages. In high school biology classes I started to think about much more ancient history, its actors playing their parts on a geological stage. I added the history of life to my passion for written history, and when I got to college I decided to study the record written in our own history book-our DNA. The field I became interested in is known as population genetics, which is the study of the genetic composition of populations of living organisms, using their DNA to decipher a record of how they had changed over time. The field originated as an attempt to piece together clues about how our ancestors had moved around, how ancient populations had mixed and split off from each other, and how they had diversified over the eons. In short, really ancient history.
And my quest had brought me here, for the second time. My last visit to the University of Chicago-where I was headed from O'Hare-had been eighteen years earlier, in February 1989, when I was considering going there for graduate school. The lake was frozen then as well, and my early-morning walks to meetings at the university in single-digit temperatures played a small role in my decision to head to school in the somewhat warmer city of Cambridge, Massachusetts. Despite my decision, the University of Chicago was, and is, an outstanding university. Its faculty boasts brilliant researchers and thinkers in many fields, from economics to literature to physics. I had come back to visit one of them.
Jonathan Pritchard had been a graduate student at Stanford when I was a postdoctoral researcher there, and I still clearly remember his early presentations to our group. His mathematician's mind, coupled with his deep understanding of the processes of genetic change, made him a real asset to the group. We overlapped again briefly when I was at Oxford, but we lost touch over the years, although I followed his work from the papers he published in scientific journals. It was one such publication that led me to get in touch with him to discuss his findings.
This paper, published in the journal PLoS Biology (PLoS stands for Public Library of Science, a prestigious family of scientific journals available on the Web), described a new method his team had developed to look at selection in the human genome. Selection is the Darwinian force that has created exquisite adaptations like the eye and the ear, as well as most of the other really useful traits we humans have. As Darwin taught us, small changes that are advantageous in some way give an organism a greater chance of surviving and reproducing in the perpetual rat race that is life. Since all of these selected characteristics ultimately have their origin in the way our DNA is put together, it is logical to look to our genes to find out about what made us the way we are.
The search for selection at the genetic level has a long history, dating back to way before Watson and Crick deciphered the structure of DNA in the early 1950s. Pioneering scientists such as Theodosius Dobzhansky, a Russian immigrant to America who helped create the modern science of population genetics back in the early twentieth century, were obsessed with looking for genetic changes that could be explained only by invoking Darwin's seemingly magical force. In the days before DNA sequences could be studied directly, though, researchers observed large-scale changes in the structure of fruit fly chromosomes. (Fruit flies being the geneticist's favorite model organism, mostly because their huge salivary gland chromosomes made their patterns of genetic variation easy to study in the days before DNA sequencing.) But while they found some evidence for the past action of selection in fruit flies, the ultimate cause of the patterns they observed remained elusive.
Once it was known that DNA was the ultimate source of genetic variation, and its structure had been discovered and methods developed to determine the actual sequence of the chemical building blocks that make up the double helix (I'm glossing over about fifty years of pioneering research here), population geneticists began to look at DNA sequences directly. In the early days (only around twenty-five years ago), because of technical limitations, they could examine just a few small regions in the genome (the sum total of the genetic building blocks in an individual), and the search for evidence of natural selection usually proved fruitless. It was only with the completion of the Human Genome Project in the late 1990s, and the massive technological breakthroughs that it spawned, that scientists could finally start to reassess the issue that had obsessed Dobzhansky and his colleagues nearly a century before: Is it possible to find evidence of selection at the DNA level and, perhaps more interestingly, can we figure out why it has taken place?
I paid the cab driver and got out near the University of Chicago bookstore, taking in the surroundings. Gothic-style edifices, constructed during Chicago's earlier building boom, toward the end of the nineteenth century, surrounded me on all sides. It had been a conscious attempt on the part of the new university-it was founded in 1890, with funds provided by the oil baron John D. Rockefeller-to connect with an older tradition of learning. I felt as though I were back among the gleaming spires of Oxford, running between undergraduate tutorials. My destination, however, was a much newer structure.
The Cummings Life Science Center was constructed in 1970; as befitted a structure meant to house scientists engaged in the advanced study of biology, then undergoing a revolution as a result of Watson and Crick's elucidation of the structure of DNA, the building's brick tower was bracingly modern, even a bit brutal. But I had come to talk to Jonathan Pritchard, who was using the most advanced techniques in genetics to look at the history of our species. The juxtaposition of this building amid a campus of older structures seemed fitting, given what I was here to discuss.
I located his office on one of the upper floors, and we chatted as he made me a cup of tea. An avid distance runner, with the intense, lanky look of a marathoner, he seemed somewhat surprised that I had made the trip just to talk to him. I asked him about his move from Oxford to Chicago, his personal life (one of his son's drawings hung above his desk), and what it felt like to have been granted tenure at one of the world's most prestigious universities at the precocious age of thirty-seven. He laughed, confident in his intellectual abilities, like so many of the mathematically gifted people I have known, and explained that his life was going well. We then moved on to the reason for my visit.
I wanted to talk shop. Or, rather, I wanted to get his take on the findings of his important research paper. In their PLoS publication, he and his colleagues had described a new method of detecting selection in the human genome. It made use of something called the HapMap, a collection of data on the so-called haplotype structure of the human genome. And to understand that we'll need to delve into the science a little.
The long string of DNA that makes up your entire genome is broken into smaller strings called chromosomes-there are twenty-three pairs of them-containing the 23,000 or so genes that direct your body to do what it does. These genes code for things like sugar-digesting enzymes in your gut, or blood-clotting proteins, or the type of earwax you have-all of the physical traits that make you who you are. The chromosomes are linear strings of DNA, composed of four chemical building blocks known as nucleotides: A, C, G, and T. The sequence of these nucleotides-AGCCTAGG, and so on, along the entire length of the chromosome-encodes the information in your genome and determines what each gene will do in your body. The nucleotides are arrayed along the chromosomes like beads on a string, a linear orchestra of musicians, each playing their own part in the symphony that is you. You get one of each of your chromosome pairs from your mother and one from your father.
Something funny happens to these musical beads, though, as they are passed from your parents to you. They shuffle-like a deck of cards-partially mixing up the original linear strings of beads your parents had. That's right: your parents' chromosomes literally exchange genetic information along their lengths, breaking and reconnecting their paired strands to produce a completely new version of a chromosome to pass on to you. This is part of the reason why you don't look identical to other members of your family, but we don't know exactly why it occurs. The best theory going is that it's probably a good thing to generate novel chromosomal arrangements of the musical beads in each generation so that your child's DNA orchestra can play a different tune if times change-think about having to evolve quickly in times of intense climatic upheaval. As it's pretty much ubiquitous in animals and plants, there's almost certainly a very good reason it's there.
Probably a few readers are wondering at this point, "If the chromosomes are paired, then why does shuffling change anything? Surely they are copies of the same beads, so wouldn't shuffling them just produce the same combinations in each of the two new chromosomes?" The reason for the new combinations is that each member of a pair is actually a slightly flawed version of the other. As the chromosomes get passed down through the generations, they have to be copied by the cellular machinery for each new organism. Although this is done with great care, and there are proofreading mechanisms to make sure the copied beads look like those on the original strand, occasionally a mistake is made. By chance, one color of bead is substituted for another-a red for a green, for instance. It doesn't happen very often-perhaps a couple of times for each chromosome in every generation-but when it does happen, these changes, which geneticists call mutations, get passed down through the generations. They serve to introduce additional variation into the gene pool. Over time the changes have accumulated to such an extent that, on average, one in every one thousand beads differs between the chromosome pairs. Thus, each chromosome that is passed on is a shuffled version of Mom's and Dad's chromosomes, with the shuffling detectable through the patterns of the variable beads. It sounds very complicated in theory, but if you think about it as beads on a string it is a bit easier to grasp.
What the HapMap project did was to assess the way the beads had been shuffled in different human populations. By looking at people from Africa, Europe, and Asia, it deduced that there was an average length to the sections of the string of beads that hadn't been shuffled. The length was a function of how old the population was, the average size of the population over time, and other factors that helped to determine exactly where on the string recombination could have occurred. The math behind all of this gets pretty tricky, but the take-home message is that there is an average length of these recombined places on the string of beads. Over time, many, many generations of recombination had produced a kind of "signature" for the bead structure of a population-a pattern that served to distinguish one population's strings of beads from another's, since people living in the same geographic region tend to share more ancestors than people from different parts of the world.
Pritchard and his colleagues had developed a new statistical method to find regions of the chromosomes that seemed to have too little shuffling. In other words, they found parts of chromosomal bead strings that had long sections that seemed too similar to each other-as if everybody was wearing a uniquely patterned necklace, except that one long section of each person's necklace was pretty much identical to everyone else's. For segments like this it was possible to infer that something had happened to produce a long section of beads that seemed to be inherited like a block among many people, as though it had spread through their necklaces like a fashion accessory. One person liked the particular combination of beads they saw in part of someone else's necklace, and copied it to include in theirs. Fashion tastes served to spread the bead pattern far and wide, and pretty soon lots of people were wearing it.From the Hardcover edition.
Excerpted from Pandora's Seed by Spencer Wells. Copyright © 2010 by Spencer Wells. Excerpted by permission of Random House Trade Paperbacks, a division of Random House, Inc. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.