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Learning to Tell Time

Evolutionary Geneticist Studies Mutation “Clocks” to Discover When Modern Humans Originated

By Phil Sahm

Millennia ago—perhaps as long as 200,000 years—a woman walked the Earth who was smart enough or lucky enough to outwit predators and evade disease and injury to bear children.

Her children, in turn, survived to nurture their own offspring. Today, thousands of years and generations later, a small part of the DNA of that woman who labored in the early light of human history can be traced in every living person.

One day, by studying human genes, geneticists may know for sure when the woman lived. They also may learn conclusively when the first modern humans evolved and from where they originated, according to University of Utah geneticist Lynn B. Jorde, Ph.D.

Some scientists look at old bones or pottery shards to puzzle together the human past. Jorde, professor of human genetics at the U School of Medicine and Eccles Institute of Human Genetics (EIHG), looks at genes. In particular, he studies how genes have mutated for good or ill since Homo sapiens evolved.

But, as he searches the genetic past for clues to human evolution, Jorde says that understanding the processes and causes of mutation also holds profound implications for medical science today and tomorrow.

“There is a bridge between evolution and practical applications,” he said.

That bridge, for Jorde, spans research on populations ranging from the caste system in India and genetic causes of limb malformation to frequency of diseases common to people in Finland and genetic links to hypertension in African-Americans. He has published more than 140 scientific articles and is the lead author of Medical Genetics, a widely used textbook in North America and abroad. The book’s co-authors include Raymond L. White, Ph.D., former U professor of human genetics; John C. Carey, M.D., professor of pediatrics in the medical school’s Division of Medical Genetics and adjunct professor of obstetrics and gynecology; and Michael J. Bamshad, M.D., associate professor of pediatrics in the Division of Medical Genetics and adjunct assistant professor of human genetics.

Jorde’s passion for human genetics is evident in the classroom, and U medical students several times have voted him their favorite teacher. That’s a well-deserved accolade, according to Raymond F. Gesteland, Ph.D., U vice president for research and distinguished professor of human genetics and biology.

“He’s a superb teacher,” said Gesteland, who described Jorde as a “stoic Scandinavian” with tremendous talent in mathematics and computers.

Jorde’s contributions to population genetics have earned him national and international reputations. His EIHG laboratory is engaged in two primary avenues of research: gene mapping to understand limb malformations and evolutionary genetics.

Underlying all his study is the search to understand mutation, which ultimately may reveal the story of how and when modern humans evolved.

Mutation is a change in the DNA sequence of human genes. A gene with the DNA sequence CTGA may mutate to become CTCA. These variations occur in intervals that geneticists can time.

By using population genomics—the large-scale comparison of DNA sequences among people—geneticists can estimate how many generations ago a mutation occurred. In this way, they can work back thousands of years to examine key genetic changes.

“Mutation is like a clock,” Jorde said. “The more DNA variation we observe near a specific mutation, the longer ago the mutation happened.”

By analyzing the DNA sequence variation within and near a gene called HFE, for example, geneticists have deduced that, about 1,500 years ago, a gene mutated in people of European descent, particularly northern Europeans, which causes their bodies to store too much iron if they inherit a copy of the mutation from each parent. This results in hemochromatosis, a condition that can lead to organ failure and diabetes. Hemochromatosis can be dealt with fairly simply: people who have it give blood every couple of months to purge the excess iron. Those who inherit a copy of the mutation from only one parent appear to have a survival advantage in iron-poor environments.

The HFE mutation was probably random, according to Jorde: “one of nature’s ways of trying out new possibilities.”

Fifteen-hundred years is a mere blink in human evolution. But geneticists—helped by the Human Genome Project that is sequencing DNA—can look much further back in time to study mutation, according to Jorde. As they learn more about DNA sequences and variation, geneticists can zero in on fundamental questions: When did modern humans evolve? Where did we originate? What, genetically, makes us human?

Human genes indicate we are a comparatively young species, according to Jorde.

On average, humans are identical in 99.9 percent of their DNA. That suggests we haven’t had time to develop the amount of genetic variation seen in older species, such as fruit flies and chimpanzees. Estimates of when modern humans evolved range from 100,000-200,000 years ago, or longer. Narrowing that time period probably is years away. But as the genome project continues mapping DNA, geneticists some day may state with greater precision just when modern humans evolved, according to Jorde.

One part of the evolutionary puzzle that DNA analysis is helping to examine is that of the most recent common ancestor to all living people.

By examining variation in mitochondrial DNA, which is passed only through females, geneticists estimate that the most common recent ancestor of all people today was a woman who lived 100,000-200,000 years ago. Mutation seen in mitochondrial DNA tends to verify that time estimate, Jorde said.

Similar analysis of Y chromosome data, which is passed only through males, gives a date of 60,000 years for the most recent common male ancestor.

While some researchers have concluded from mitochon-drial DNA analysis that a “genetic” Eve was the only woman alive a couple hundred of thousand years ago, that conclusion is incorrect, according to Jorde. It is likely a few thousand women were alive and breeding then, but only one woman’s genetic lineage survived to today.

Mitochondrial DNA analysis, more importantly, implies that the total human population has been relatively small for much of history, perhaps numbering only 10,000 breeding people, Jorde said. Analyses of the nucleotide differences in mitochondrial DNA indicates the human population increased dramatically approximately 70,000 years ago.

As geneticists are able to complete even larger-scale studies on DNA variations among people, they will narrow with increasing confidence the dates and time spans of human evolution and expansion.

“Every bit of DNA we look at gives us more information,” Jorde said.

Population genomics also helps geneticists address the question of where modern humans originated.

Anthropologists long have theorized the first modern humans evolved in Africa and then populated the rest of the world by replacing less evolved cousins in the evolutionary family. DNA studies support the theory that modern humans evolved in Africa, but whether they interbred with, or replaced, archaic humans in other areas of the world is open to argument.

Analysis of DNA variation shows that Africa contains the most genetically diverse group of people, indicating an older lineage than that of Europeans and Asians. Studies of mitochondrial and nuclear DNA markers are consistent with the theory modern humans arose in Africa 100,000-200,000 years ago, then colonized what is now Europe and Asia. While many geneticists and anthropologists subscribe to this theory, others don’t. Although most evidence points to an African origin, it’s less clear that people from Africa replaced other populations, according to Jorde. Ultimately, these questions will be answered when a larger sample of human DNA can be collected and analyzed through the genome project.

As geneticists reconstruct human evolution, knowledge gained from that work and the genome project is being applied in medical research today, Jorde said.

The sequencing of the human genome may lead to critical breakthroughs in understanding why genes mutate to cause, or prevent, disease. Ultimately, that may help researchers find ways to cure disease, or to determine which drugs work the best to fight specific illnesses. Much of this will depend on understanding genetic mutation and evolution.

“Without (understanding) evolution you’ve got just a whole bunch of facts,” he said. “Evolution tells you why.”

In his current research, Jorde, along with two medical school colleagues, is studying genetic links to hypertension in African-Americans and a genetic mutation that protects some people from acquiring HIV.

African-Americans are 25-30 percent more likely to develop high blood pressure than other Americans. This propensity may trace back to when the first humans fought to survive in the hot climes of Africa, according to Jorde. Heat sweats salt from the human body, and it’s possible the first people in Africa evolved a gene to help their bodies retain salt. If that gene was passed through thousands of generations, it may make African-Americans retain more salt and explain their tendency today for high blood pressure.

Jorde is collaborating with Jean-Marc LaLouel, M.D., D.Sci., U professor of human genetics and an investigator with the Howard Hughes Medical Institute, to study whether African-Americans have a genetic link to high blood pressure. The two are seeking a grant from the National Institutes of Health to fund more research.

In another project, Jorde has joined U geneticist Bamshad to research a gene in which a rare mutation makes about 1 percent of the population resistant to infection with HIV. The mutation, in a gene called CCR5, effectively shuts the “doorway” that allows HIV to enter a cell, according to Jorde. He and Bamshad are looking for evidence of natural selection in the variation that occurs within CCR5. Ultimately, that may shed light on why some people do not acquire HIV, or why some people with HIV live years without acquiring AIDS, Bamshad said.

As researchers look for ways to prevent and cure disease, they also are investigating how to help control disease through the use of therapeutic drugs. And that will be a major focus of future genetic research, Jorde believes.

A drug’s efficacy in treating disease can vary from person to person. A medication to control high blood pressure, for example, may work well for one person, but not another. But as more is revealed about individual genetic variation, Jorde foresees the day when people will undergo a simple genetic test to help determine which drugs will work best for each person.

He tells his medical students that, within their lifetimes, a person’s entire genetic makeup will be available on a computer chip.

Besides trying to crack the code of genetic evolution and disease, Jorde also appears as a forensic genetics expert witness and instructor for members of the judiciary. DNA evidence now is used in 50,000 court cases a year and probably will only grow in the scope of its importance, he said.

When he entered the field of genetics, Jorde did not imagine he’d branch out into forensics. But neither did he imagine the breakthroughs in knowledge that would evolve in the first decades of his career.

The future has arrived sooner than he or anyone foresaw. But that’s part of what drew him to his work.

“That’s what’s fun about genetics,” he said. “We get surprised a lot.”

Pullout/figures

“He’s a superb teacher,” said Gesteland, who described Jorde as a “stoic Scandinavian” with tremendous talent in mathematics and computers.

Jorde’s contributions to population genetics have earned him national and international reputations. His EIHG laboratory is engaged in two primary avenues of research: gene mapping to understand limb malformations and evolutionary genetics.

(A) A depiction of the multiregional hypothesis, in which archaic humans evolve in situ into modern humans in Africa, Asia, and Europe. Gene flow, shown by black arrows, maintains genetic similarities between populations.

(B) A depiction of the African replacement hypothesis, in which modern humans evolve from archaic forms only in Africa. Archaic humans living in Asia and Europe are replaced by modern humans migrating out of Africa.

A diagram of the coalescent model, in which all current mtDNA or Y chromosome lineages are traced back to a founder lineage. All lineages but the one shown in brown have become extinct.

Mismatch distributions for African, Asian and European populations. These estimates are based on 630 bp of hypervariable sequences 1 and 2 in the mtDNA control region. Applying the estimated mutation rates for these regions, each nucleotide difference corresponds to a time interval of approximately 5,800 years. Although the African peaks occur at 17 nucleotide differences, a curve fitted to the African data by using the method of moments yields a peak at 12 nucleotide differences, corresponding to an African expansion date of 70,000 years ago.

We always welcome your comments about the magazine. Address letters to: Editor, Health Sciences Report, Office of Public Affairs, University of Utah Health Sciences Center, 50 North Medical Drive, Salt Lake City, UT 84132. FAX: (801) 585-5188. E-mail: Susan.Sample@hsc.utah.edu.

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