The Ancestor Hunter - Pacific Standard

The Ancestor Hunter

The University of Arizona's Michael Hammer is using advanced DNA techniques to figure out where we came from. Which, apparently, is not just one place, or even one species.
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Maybe it's the scooter propped in the corner of his office, or the fact that he's wearing a T-shirt and denim cargo shorts while sporting a gold hoop in his left ear, but Michael Hammer definitely looks more like a surfer than one of the world's leading gene detectives. The maps are a giveaway, though. His tiny cell of an office, which looks out onto a grove of lazily waving palm trees, is decorated with several maps of the planet. He has more maps — colorful wall-sized affairs — in his various labs scattered around the University of Arizona campus. Standing back from one of these maps, Hammer can look deep into human history. He sees the movement of ancient Asians into the New World and the rapid expansion of seagoing peoples across the Pacific 3,000 years ago. He can even discern the migrations of our early ancestors out of Africa 60 millennia or so back in time.

For Hammer, a population geneticist, it is a story told in our DNA, the nucleic acid that transmits the information encoded in genes down through generations. Curled up tightly into chromosomes, DNA is a long, twisting ladder-like chain of thousands of simple molecules called nucleotides, lined up in pairs. These base pairs occasionally drop out or repeat in distinctive ways as the DNA is passed from parent to child.

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Scientists can figure out when these base pair variations — single nucleotide polymorphisms — diverged from one another, allowing them to build elaborate family trees stretching back tens of thousands of years. In a 2008 paper, for example, Hammer found chromosomal evidence that throughout human history, men have generally produced more offspring than women. (He calls it the Clint Eastwood effect after the legendary actor/director, who fathered seven children with five women.)

In plumbing this and other mysteries, Hammer and his collaborators rely on thousands of samples of DNA — mostly in the form of cheek swabs — they have collected from people all over the world. "It's genealogy at the level of families, genealogy at the level of distant cousins, genealogy at the level of populations that migrated in the last 3,000 years, all the way back to the genealogy of modern and archaic humans," Hammer explains.

In a series of recent studies, Hammer and his collaborators have found a unique sequence on the X chromosome suggesting that as anatomically modern humans arrived in Asia, they interbred with archaic hominids called Homo erectus. It's a controversial claim, given the prevailing view that modern humans emerging from Africa replaced Homo erectus without cross-mating. To Hammer, the interbreeding makes perfect biological sense, especially if one questions the assumption that Homo erectus and Homo sapiens were genetically isolated species.

More likely, he says, they existed on a genetic continuum. He notes that members of baboon species that diverged as long as 4 million years ago can still mate and produce viable offspring.

"If there's occasional interbreeding, and one form, the modern human, is outnumbering the archaic form, we might expect little pieces of our genome to trace back to the archaic form," Hammer says. "Those pieces of the genome would be fairly divergent from the rest of the genome."

If Hammer's parsing of the genetic code often aims to untangle humanity's deepest history, it also has practical application. He's used his skills to probe the ancestry of modern-day Japanese and to try to identify Mexican immigrants who died while attempting to cross southern Arizona's blistering Sonoran Desert on foot. And he has set up a nonprofit foundation to build a genetic database of Holocaust survivors that may help descendants know their family histories. Even when his studies focus on the real world of the 21st century, though, they never roam far from that largest of philosophical questions: Where did we come from?

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Sitting in his office on a warm Tucson day, Hammer treats me to a dazzling two-hour cram course in modern genetics. The field has come a long way in a generation. When Hammer started 30 years ago — he's now 55 — scientists painstakingly crossbred animal or plant specimens to isolate specific genes, and they needed massive amounts of tissue to extract small amounts of genetic material. Today, automated gene sequencers can unravel the nucleotide sequence of a bacterium in a few hours. These technical advances make it possible to study an entire genome, as opposed to a handful of selected targets, but they also create a mind-boggling amount of data.

"We're in the business now of figuring out how we grind all that data," Hammer says. "We're using supercomputers, trying to figure out statistical methods that will allow us to take this huge amount of data and analyze it."

Hammer has a particular knack for looking above the details supplied by technology to ask deep questions about human origins — to be able to see the genetic forest for the trees. Through the years he has collaborated with paleontologists, linguists and anthropologists, eager to answer the big questions about human origins in a multifaceted way.

Hammer's journey began in Highland Park, Ill., where he was one of three children raised by a stay-at-home mother and a father who was in the steel business. He was interested in marine biology but graduated from Lake Forest College with a liberal arts degree. After a stint as a technician in a molecular biology lab at the University of Chicago, he was accepted into a graduate program in evolution run by the late Allan C. Wilson at the University of California, Berkeley.

Wilson, who pioneered the use of molecular biology to understand evolutionary mechanisms, made a big impact. "I thought, 'This is the guy I want to work with,'" Hammer recalls. "He was working on things like the evolution of gene expression. He was basically trying to explain what were the key genetic changes that tracked the major things we see in life."

Hammer, who earned his doctorate in 1984, started out researching how house mice evolved the ability to use lysozyme, an enzyme that the body normally uses to attack bacteria, to help them digest plants. But in his eyes, the biggest mystery back then — as now — revolved around how, when and where modern humans arose.

In the 1980s, paleontologists who studied skeletal remains were divided into two camps. Pretty much everyone agreed that a wave of early Homo erectus had spread out of Africa across the Eurasian landmass — Peking Man and Java Man being some of the better-known examples. The "multiregional" school of thought held that Homo erectus and Neanderthals (Homo neanderthalensis) evolved into modern humans continuously in many places across Eurasia. The other view — dubbed the "Out of Africa" model — contended that anatomically modern humans evolved from H. erectus somewhere in Africa and migrated out in a second wave, entirely supplanting the earlier human population.

Meanwhile, in Wilson's Berkeley lab, researchers Rebecca Cann and Mark Stoneking were studying human mitochondrial DNA. The DNA in our mitochondria — tiny energy powerhouses in our cells — mutates at a higher rate than the rest of our genome, providing a magnified view of evolutionary change. In 1987, the Berkeley researchers published a paper in Nature that decisively weighed in on the side of the "Out of Africa" hypothesis. Genetics was starting to answer questions hitherto reserved for other disciplines.

But mitochondrial DNA, which is usually passed only through the mother and is distinct from our nuclear DNA, tells only part of the story. Hammer, who was in Wilson's lab when Cann and Stoneking were carrying out their research, developed an interest in the Y chromosome, which is passed from father to son.

In post-doctoral work at Princeton and in the Harvard lab of Richard Lewontin, another giant in genetics and evolutionary biology, Hammer mastered newly developed methods of teasing apart DNA into smaller, more manageable elements.

One was the polymerase chain reaction, a method of quickly copying DNA segments that has become a standard tool in genetic analysis. Another was the use of "four-cutter" restriction enzymes (so named because they recognize places in a DNA chain that are four specific nucleotides long) to isolate and identify short fragments of DNA. These small sections of the chromosome sometimes rearrange the ordering of their base pairs, either through selective evolutionary pressures or a process of random shuffling known as genetic drift.

Geneticists have learned to track these base pair reorderings, known as polymorphisms, to see how the genome has changed through time.

Now Hammer brought these techniques to bear on the Y chromosome, which was slow in giving up its secrets. In fact, the earliest investigators thought that unlike all other chromosomes, the Y had no polymorphic diversity — which would have made it a peculiar exception. But Hammer proved them wrong. "It turns out that's not the case," Hammer says. "There were just very low levels of diversity on the Y, and we just needed to look at lots and lots of DNA in sequence to find it. I started finding some variation with these four-cutter filter methods. In the meantime, PCR had become a real technique, and so I started switching over to PCR and direct DNA sequencing, and found some of the first polymorphisms on the Y."

Just as had happened with mitochondrial DNA, Hammer started to build a family tree of Y polymorphisms (today more than 700 are known), leading back to a common male African ancestor something like 110,000 years ago.

By 1991, Hammer had moved to the University of Arizona, where he was charged with developing the university's core genomics laboratory. In 1994, Russian research geneticist Tatiana Karafet joined Hammer's lab. Karafet had spent a lot of time collecting demographic information and DNA samples from Siberian tribes. "It was obvious we had great resources for studying the source populations for Native Americans," Hammer says. They set about collecting Native-American DNA to match against the Siberian samples. That proved difficult because many Native Americans object to being research subjects, Hammer says.

In 1986, a trio of prominent researchers had proposed that there were three waves of migration from Asia into the New World via the Bering Land Bridge. They drew on dental and genetic data, as well as the fact that all the languages in North and South America seem to fall into three "superfamilies."

In 1997, though, Hammer and Karafet looked at the Y chromosomes in their more than 1,600 samples. Their data pointed to a single migration of ancestral Native Americans, probably originating in the Altai Mountains of central Asia. "Today we could do a lot more with the genomic data," he says. (A study of whole-genome DNA recently published in the journal Molecular Biology and Evolution reached the same conclusion as Hammer's team.)

All in all, the era of Y-chromosome research was a heady time. "We suddenly were turned loose," Hammer says. "We had a cottage industry. We could type these Y markers, and we could look at populations all over the world. I got very interested in the peopling of Japan. I got interested in Jewish groups and the Jewish Diaspora and the peopling of Europe. It's like there are a million stories in the naked city."

In the early 1990s, Hammer had discovered a 300 base-pair element on the Y chromosome that had a very unusual pattern of expression. It shows up in 50 percent of sub-Saharan Africans and at very low frequencies in Europe and most of Asia. But some 35 percent of Japanese carry it, as do isolated groups in Tibet and the Andaman Islands. How had such widely separated groups come to have the same genetic marker?

Collaborating with some Japanese researchers, Hammer sampled DNA from throughout the Japanese islands and discovered a trend: People in Okinawa and Hokkaido, the southernmost and northernmost areas respectively, had the highest concentration of the rare variation, but it was lowest in central Japan, at the point closest to Korea.

Hammer thought this supported a hypothesis that the Japanese are actually a hybrid of two ancient migrations. The first people, about 10,000 years ago, were known as the Jomon, a hunter-gatherer group that also made a distinctive style of pottery. "They were able to probably just walk over to Japan from the continent of Asia because sea levels were lower," Hammer says. "Then, as the glacial maximum passed and sea levels rose again, the archipelago was isolated from Asia for 8,000 years."

But about 2,000 years ago, a new wave of rice-cultivating immigrants arrived from Korea by boat — the Yayoi. "Probably the Yayoi descend from one of these groups that extended out from southern China with rice agriculture," Hammer says. "They brought their genes with them, and they were different genes, different Y chromosomes."

Hammer believes the rare Y-chromosome marker came to Japan with the Jomon. "The Jomon origin probably goes back to somewhere in central Asia, and that's why we find that marker on the Y in Tibet," he says.

"In most of our history, up through the past couple of hundred years, people really did sit where they were," Hammer says. "They really didn't move very far. So you get this nice gradient of variation that reflects these old, old migratory processes. I think it's one of the nicer examples of that."

Jews, whose Diaspora started with the Babylonian exile and continued through the Roman occupation, are something of an exception, having dispersed widely in western Eurasia and northern Africa. That prompted Hammer to wonder whether modern Jews retain close genetic links to their ancestors. "Are contemporary Jews descendants of Middle Eastern or biblical Jews?" Hammer asks. "Are they really converts? Was there so much intermarriage that the Middle Eastern genetic signal was diluted out?"

In a 2000 paper, Hammer and his colleagues reported that a comparison of Y-chromosome markers showed most Jewish groups were closely related to one another, despite having been scattered across central Europe, North Africa, Spain and Yemen. They showed only slight genetic admixture with their neighboring non-Jewish populations, but they turned out to be closely related to contemporary Palestinians, Lebanese and Syrians.

Earlier, in 1997, Hammer co-authored the first paper showing that there was a genetic marker on the Y chromosome that seemed to correlate with a shared common paternal ancestor for the Kohanim — the Jewish priestly caste — a finding that gained widespread news coverage.

For all the information he has managed to wring from the Y (or male) chromosome, Hammer in recent years has joined his peers in using markers from the X chromosome and the 22 pairs of non-sex chromosomes in a cell's nucleus, which are known as autosomes.

These days, he's collaborating with Steve Lansing, a University of Arizona social anthropologist, on the Austronesian Societies Project, which uses genetics, linguistics, anthropology and mathematical modeling to trace the expansion of Austronesian-speaking people through the Indonesian archipelago.

"We're using genetics more like the fossil record," Hammer says. "You're studying recent linguistic change happening on a very recent time scale, and there's no fossil record for language. We've kind of turned it on its head and used genes to reconstruct the movements of people, then superimposing their languages on top of the population history."

Lansing, who has known Hammer since 1999, says that just as Hammer can use his tools to reconstruct large-scale migrations that took place thousands of years ago, the Indonesian research is working on the scale of individual villages within the past few hundred years.

Meanwhile, Lansing says, he and Hammer are joining with mathematicians at the Santa Fe Institute, where Lansing also has an appointment, to study the microevolution of the malaria parasite. They plan to replicate the bug from blood samples drawn from villagers, then study how its genome has evolved over time. That in turn could give medical researchers insights into new strategies for fighting the disease.

The big, established centers for population genetics may be at major research universities like Harvard and Stanford, Lansing says, but Hammer has made a name for himself nonetheless. "Michael set up this little shop in Arizona, and it seems to keep turning out all these interesting results," Lansing says. "He's a one-man band."

In recent years, Hammer has revisited the question of modern human origins addressed two decades ago by his Berkeley colleagues. He saw shortcomings with both the prevailing "Out of Africa" model and the multiregional theory that Homo erectus evolved into modern humans all over Eurasia. "I think both models are overly simplistic," he says. "The truth lies somewhere in the middle. I think we're more towards the African origin and replacement — clearly there was a huge advantage for much of our genome to fit that model, but not all of it. It's the exceptions that are going to be the most interesting in revealing what humans were like biologically and behaviorally, a hundred thousand years ago."

Previous research that had focused on mitochondrial DNA and the Y chromosome had found no evidence that Homo erectus or Neanderthals had contributed to the modern human genome, Hammer says. But in the past five years, Hammer and his collaborators have found that a 2-million-year-old variation of RRM2P4 "pseudogene" on the X chromosome is much more common in east Asia than anywhere else. (Pseudogenes are defunct relatives of known genes that no longer seem to have a cellular function but provide clues about when and how the genome changed. Like other genes, their names derive from their function and their location on the chromosome.) They interpret this as evidence of interbreeding in Asia that would, to some extent, undermine the "Out of Africa" theory.

One problem with the "Out of Africa" theory (also known as the Single Origin theory) is that it tends to assume anatomically modern humans evolved in Africa at a particular moment, within a small, isolated population — a proverbial Garden of Eden. "That would be very unbiological, in a lot of ways of thinking about it," Hammer says. "Most species do not have pure, isolated origins. Why would humans be different?"

Hammer acknowledges that the single example of RRM2P4 doesn't prove his case. "You really need to find evidence from more than one part of the genome," he says. "What we're finding is there are other regions of the genome that show that pattern, but they don't necessarily show Asian populations versus African populations. We're seeing this pattern within Africa."

In other words, it's possible that as anatomically modern humans were mingling with archaic hominids across Eurasia, the same thing was happening within Africa involving as-yet-unidentified groups, perhaps the African version of Homo erectus or the Neanderthal. "We may use genetics here as a predictor of what the paleontologists might find," Hammer says.

The University of Arizona lists Hammer as a research scientist, relieving him of teaching duties, although he does lecture and work with graduate students in a number of different departments. He presides over a multifaceted operation, serving as director of the university's Genomic Analysis and Technology Core facility, which provides centralized training and DNA services, and the Human Origins Genotyping Laboratory, which performs high-volume DNA testing for both academic and private-sector clients.

After hours, Hammer shares child-care duties for his 13-year-old daughter and 9-year-old son with his former wife. His daughter was born with severe autism and epilepsy that has left her with minimal communication skills. Over veggie spring rolls at an off-campus Vietnamese eatery, he tells me that he, his children and their mother have contributed their DNA to a study an associate is conducting. "If I were to go to school again, I'd go into neurogenetics because I think that is the next frontier in terms of understanding human disease, biology and behavior," he says. "For personal reasons, I'd like to know what kinds of genetic changes can lead to the kinds of dysfunction that I see in my daughter."

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We walk across campus to Bio 5, the university's state-of-the-art research complex, where Matt Kaplan supervises the Human Origins Genotyping Laboratory. Kaplan, one of Hammer's former graduate assistants who took part in some of the Jewish population research, shows me how robotic equipment processes newly arrived cheek swabs through several steps into testable samples of DNA. The lab tests between 1,000 and 4,500 samples a week, Kaplan says. Each person's DNA is extracted from a comb-like plastic swab that scrapes cells from the inside of the cheek.

Many of the swabs, sealed into small, fluid-filled tubes, come from Family Tree DNA, a Houston-based commercial testing venture for which Hammer also serves as chief scientist. Family Tree and Kaplan's lab are handling the public testing for The Genographic Project, a five-year research effort sponsored by IBM and National Geographic to create an inventory of DNA collected from around the world. Kaplan estimates the lab has tested more than 260,000 samples for the project since 2005.

Kaplan shows me a National Geographic map created depicting ancient migration routes around the world as deduced from Y chromosome and mitochondrial DNA. "You can actually swab your cheek and find out which one of those lines on the map is your paternal lineage," he says matter-of-factly. "It isn't magic. This is stuff we have been doing as academic researchers for years."

Hammer co-founded the DNA Shoah Project, which is using Kaplan's genotyping laboratory to create a database of genetic material from Holocaust survivors and their immediate descendants. The nonprofit organization hopes to make it possible for descendants to find displaced relatives and learn about their biological families.

The project is a partnership with Syd Mandelbaum, a businessman and the son of Holocaust survivors, who read a news story in 2005 about the discovery of World War II-era remains in Germany and realized there was no genetic database available to help identify and repatriate them. "The idea is not that we're going to try to test the genetic material in the bones directly, but build a database — a 'build it and they will come' sort of thing," Hammer says. "What we would like to do is store the survivors' DNA. Unfortunately there's only a thousand (samples collected) now, and there's a couple hundred thousand to get. Getting the word out and getting funded to do this has been slowing us down." He estimates that the project will need about $500,000 to get fully up to speed.

Hammer notes that in the next 15 years the last of the Holocaust survivors will be gone. "I almost feel like we have to do it because we can," he says. Although "Shoah" is the Hebrew word for the Holocaust, the project would be open to all victims of the Nazi genocide — Poles, Gypsies and Russians as well as Jews, Hammer says. "Anybody who's a survivor of the Holocaust can get their DNA taken for free and stored, and we take all the information about their family history."

Hammer has also consulted with the Pima County Medical Examiner's office, which is storing the bodies of more than 200 people who died in the desert while trying to cross illegally from Mexico into the U.S. "We'd like to be able to help families in Mexico get their bodies back," he says. "In the meantime, while they're not identified, they sit in the morgue for years, and then they're cremated. It costs the county money. It costs the families grief. ... If we could just make a database of the families and then type the bones, we could actually match them up."

In the meantime, Hammer hopes to add nuance to the "Out of Africa" model of human origins, looking at how genes might have flowed as diverging populations occasionally came back into contact and hybridized. "In plants, there's a huge amount of novelty that comes from hybridizing," he points out. "I don't see why that couldn't be something that was part of our history. Populations that were ecologically suited for one region in Africa or another could have shared their genes to give rise to a progenitor that had the advantages of both ancestors. The novelty is coming from not being in a special place and uniquely experiencing one environment, but from the multiple experiences of the groups."

Hunting for clues to support his hunch, Hammer will examine more odd and overlooked bits of DNA that may speak to unexpected patterns of human mating and migration. "Clearly the bulk of the genome is telling us something that is fairly well accepted. What we don't know will be discovered by looking at these other, exceptional regions.

"I believe that they're there at some rate," he says. "We'll be able to learn more about our ancestry.

"It may be more complicated than what the current model will accommodate."

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