biographies story podcast video

Fossils of Our Genetic Past

Like paleontologists working in miniature, scientists studying the human genome sift through our DNA to find relics of past viral invasions. John C. Cannon goes along for the dig. Illustrated by Emily Harrington and Kristy Whitehouse.


Illustration: Emily Harrington

Scientists who study how our genes evolved have no fossil record to explore. Helical bits of DNA dont leave discernible impressions in rock, as do the bones of dinosaurs. Instead, clues about how our genome has changed over time and how it functions today lie within the code itself. Some of the most telling recent evidence comes from the remnants of ancient invaders, called endogenous retroviruses. These bizarre viral vestiges now reside deep within our own genomemillions of years after they attacked the cells of our distant ancestors.

Termed endogenous because they are fully incorporated into DNA, these retroviruses remind scientists of fossils because the first ones penetrated our genome some 60 million years ago. Their descendants now make up a staggering 8 percent or more of our DNA. But the fossil analogy doesnt do justice to these retroviral foes since their invasions. Like the ancient coelacantha primordial fish that has existed for hundreds of millions of years and is similarly called a living fossilendogenous retroviruses have continued to evolve, sculpted by selective forces over the millennia. But theyve remained remarkably similar in form to their ancestors, just as the coelacanth has, and have changed little since entering our DNA.

It's a strange partnership. Imagine if the ancestors of animals alive today had plucked the bones of dead dinosaurs from the ground, inserted the bones into their own bodies and, with slight modifications, used them for some new internal function. Moreover, the animals then passed this new bone and the function to their young. In effect, thats one way endogenous retroviruses have interacted with our genome.

Its a window on evolution in action, says David Haussler, a genomicist at UC Santa Cruz. This is emblematic of the type of innovation that must have occurred in wave after wave over the evolution of vertebrate species.

Haussler and his colleagues at UCSC, including postdoctoral researcher Ting Wang, have discovered that endogenous retroviruses may have been critical to our development as a species. Itinerant by nature, retroviruses apparently helped copy and rapidly spread critical sequences that regulate when dozens of other genes turn on or off in our cells. Such a mechanism could explain the relative speed with which organisms diverged from each other to form new species. Its a symbiotic relationship because endogenous retroviruses offer the host a way to accelerate evolution, says Wang. Theyre evolutionary reservoirs.

Harboring the enemy

A lot of our DNA is derived from infection, says virologist Robin Weiss of University College London. Charles Darwin would have been amused to learn that were descended from viruses as well as apes.

Weiss was one of the first scientists to champion the existence of endogenous retroviruses. In 2006, he wrote a paper commissioned by the journal Retrovirology that reviewed major events in their discovery. The scientific community wasnt convinced until advanced molecular biology techniques like gene cloning and microarrays provided hard evidence for endogenous retroviruses, Weiss observes, though biologists first hypothesized their presence in the 1960s.

Vertebrates have been faced with these retroviruses ever since we came out of the waters, Weiss says. Their fate and their continuing influence today represent an ongoing interaction between genetic elements that invade us and how we handle them, he adds.

Like marauding aliens from science fiction, endogenous retroviruses initially infiltrated our genome by infecting reproductive cells. If the attack didnt kill the egg or sperm, the host passed the intruders genetic material from one generation to the next, unnoticed. To the viruss benefit, this absorption into the hosts genome ensured its DNA would survive under the management of the hosts cells.

The most notorious of todays retroviruses is human immunodeficiency virus (HIV), which causes AIDS. A retrovirus like HIV is exquisitely programmed for one mission: to slip past an organisms cellular defenses and use the machinery of its adversary to make identical copies of itself. Biologists think the precursors of endogenous retroviruses also were virulent pathogens when they first entered the genome.

Unlike other viruses, however, a retrovirus doesnt carry its own double-stranded DNA. In nearly all living things, DNA is the template used to make RNA, the messenger that tells a cell which proteins to make and how to stitch them together. This mosaic of proteins creates our individual traitsdifferences in eye and hair color, height and body type, and other genetically controlled physical characteristics. But a retrovirus packages genetic information in thrifty, single-stranded RNA and relies on a special molecule capable of reversing the process to make DNA. Hence, the prefix retro.

When the burden of the copying invaders begins to take its toll on the host cell, a retrovirus has no qualms abandoning the cell for dead to find a new genetic proxy. And it leaves behind a path of destruction that can give us a cold, a flu, orin the case of HIVa ravaged, nonfunctioning immune system.

Most retroviruses attack ordinary body cells, like the ones that form lung tissue or the living layers of skin. Such assaults endanger the host and are likely to harm the body. But the host wouldnt pass the infection onto their offspring unless the retroviruses managed to break into germ cellsthe sperm cells and eggs involved in reproduction.

The first retroviruses that eventually became endogenous happened upon some of those germ cells, bursting with their own genetic heritage for the next generation. After such an infection, the cells duplicated the foreign DNA. As they divided to form new organisms, virtually identical copies ended up in every cell in the newly developing body, including the germ cells. And so the cycle continued.

The strategy was marvelous, if completely accidental, as in all evolutionary changeeven though one might think the retroviruses had that intent all along. Remember, its the blind watchmaker here, Haussler says. The endogenous retroviruses had no clue as to where [they] should go. Regardless, the retroviruses ensured the survival of their genetic information.

But an overzealous virus can overwhelm its host, killing it and leaving the virus once again with the predicament of finding another genetic copy machine. It makes sense that viruses would evolve to allow their host to survive while still churning out hereditary facsimiles. Absorption into the hosts genome was one way to negotiate that treaty.

Once protected inside the hosts cells, the retroviruses no longer needed to waste resources building new protective coats of protein around themselves, which all other viruses need. Nor would they have to search for other hapless hosts when the original cells wore outa dangerous undertaking that invites counterattack from an organisms immune system.

Saddled with these imposters, the hosts adapted in a bizarre and seemingly risky way. If they couldnt rid themselves of the deadly bugs, at least the organisms could relegate them to a harmless statusor so the evolutionary strategy worked out. This development benefited the retroviruses as well, as the hosts stayed alive and healthy.

At some point, however, the hosts stopped merely controlling the retroviral DNA. New evidence shows that host cells co-opted these relics and used their nimble mobility to increase the power of certain molecules that dictate the actions of hundreds of our genes.

The whole idea that genomes of infectious agents can be adopted by the host theyve invaded and put to use is a curiosity, says Weiss. Many endogenous retroviruses are highly mobile pieces of DNA called transposons, which Nobel laureate Barbara McClintock discovered more than 50 years ago. She contended that transposons have far-reaching effects on how genes behave, a fact only later confirmed by advances in molecular biology at the end of the 20th century.

By turning the tables, cells took advantage of the jumping bean nature of endogenous retroviruses. Consider a graphic designer, who might use a template for a webpage to create the same basic design from scratch over and over. In the end, she produces a variety of websites that resemble each other only slightly. In the same way, cells may have pounced on the opportunity to copy a desirable sequence contained in a stretch of retroviral DNA and then distribute it throughout the genome, resulting in myriad uses. In some areas, that splice fell into obscurity. But in others, particularly near active genes, the sequence developed a role in gene behavior.

Many of these transposons dont code for genetic traits, but they are excellent places for certain molecules to attach and manipulate the functions of other genes. These proteins control how genetic instructions contained within DNA are transcribed onto RNA molecules.

One of the key players among these proteins is p53, a master regulator of the human genome. According to Ting Wang, p53 is the most important molecule for humans. It's akin to a cellular mechanic charged with repairing damaged DNAso important that if it malfunctions, cancer commonly results. But it took detective work by Wang to recognize that leaping retroviruses had anything to do with this crucial genetic kingpin.

The interlopers influence

Wang doesnt study viruses by trade. He doesnt work with highly infectious diseases on a daily basis, and there are no white contamination suits in his closet. But four years of bench research after college gave him intimate knowledge of wet genomic research. In graduate school, Wang traded his pipettes for computers, completing his doctorate in bioinformatics.

Now a Helen Hay Whitney Fellow, he spends much of his time in a tiny partitioned cubicle, surrounded by computer screens. There, as a crack bioinformaticist, he develops new algorithms to comb the human genome for new information. Although Hausslers researchers are known internationally as intrepid explorers of the genome, the work with p53 is their first foray into the world of retroviral invaders.

To enter this arena, the team had to go beyond microarray technology, the standard genomic research tool of today. In these experiments, tiny magnetic particles carry highly specific probes to seek out and signal the presence of specific genes in long strands of DNA. Its a technique Wang often used during his bench research.

But because microarrays explore only certain areas of the genome, this search method is limited. Genes that carry instructions for proteins only make up a small fraction of human DNA. Most of the rest90% or morehas been denigrated as junk DNA. Before searching for a gene of interest, biologists use a chemical treatment to mask stretches of repeated sequences of DNA, which are thought to contain few genes or other segments of interest. If those segments arent masked, the microarrays probes could be swamped by hits that biologists have often presumed to be meaningless.

Click image above to play video. (May take a moment to download.)

VIDEO: Author John Cannon enlists biologist Ting Wang to explain endogenous retroviruses. Requires QuickTime Player


What is all this junk? Its a hotly debated subject in genetics today. Keith Garrison, postdoctoral researcher in immunology at UC San Francisco, says scientists are just beginning to comprehend what lies in the stuff between our genes. The assumption has been that its junk DNA, but I think thats an assumption you make at the peril of misunderstanding what a large proportion of the genome is doing at any given time, Garrison says. He and his colleagues are trying to develop an HIV treatment by tapping into part of that vast, unknown reservoir (see sidebar).

Theres always treasure in junk, Wang agrees. These sequences are there for a reason.

The treasure within

The connection between certain portions of junk DNA and the master regulators of our genome began to crystallize for Wang in 2006. A rival team from Singapore detailed the locations on the genome where p53 can bind to strands of DNA and exert its controlchemical landing pads that scientists call binding sites. But in their efforts to determine exactly how p53 behaves, the Singaporean scientists ignored the sites buried deep within the repetitive junk sequences.

Wang read the paper in the esteemed journal Cell. Something just hit me, he says. I thought, What if this is something biologically meaningful?

Applying the data from the Cell paper, Wang examined the occurrence of p53 sites using the Haussler labs powerful genomic browserscomputer programs designed to find specific bits of DNA among billions of possible matches. He then compared what he found to the sequences of known endogenous retroviruses. To his astonishment, one-third of p53s binding areas sat squarely within patterns of retroviral DNA. That many binding sites associated with such an important molecule suggests these fossils arent just remnants of past infections. Rather, they are more important players in the genome than anyone imagined. The team published its findings in the Proceedings of the National Academy of Sciences.

We have many genes in the genome that are master regulators like p53, where one gene controls a lot of other genes, Haussler says. So how did they establish their empires? The answer, he believes, is the curious penchant of endogenous retroviruses to travel and spread within the genome. The alternativethat these binding sites for gene regulators arose by chance in many different places in the genomestrikes Haussler as implausible. That would take an enormous amount of evolutionary time, he says, too much to explain the colorful diaspora of living things we see today.

That puzzle catalyzed Hausslers lab. We just launched a whole bunch of computational work to pinpoint: What kind of endogenous retroviruses are they? How old are they? And when did they enter the ancestral genome? Wang says.

All mammals have p53, from mice to humans, but, mysteriously, the molecule can act differently from one individual species to the next. The evidence from Wang and his team points to the entry of endogenous retroviruses as one reason for this variation. Two families of endogenous retroviruses where p53 is particularly active entrenched themselves in our ancestors genetic makeup some 25-40 million years ago, around the time when primates started to split into two groups. Some of the retroviral families found in humans arent found in New World Monkeys, such as marmosets. Predecessors of the apes, including humans, were Old World Monkeys, so Haussler and his team knew the retroviruses must have made their attack after these primate lineages split.

Ironically, the intrusion of these simple viral packages of hereditary information could explain why we are so different from our primate cousins. With their contribution to the influence of molecules like p53, our fates are so entwined that we as a species wouldnt be the advanced organisms we are today if it werent for these ancient invaders. Our DNA is the very instruction book that separates us from other species. Yet nearly one-tenth of it comes from retroviruses, some of the simplest beings on the planet.

Ultimately, says Wang, that shouldn't surprise us. Look at the human body. How much is human? he says, his arms outstretched. There are 10 times more bacteria [than human cells] if you just count the cells in our gut. Its hard to say which part is foreign and which part is human.


Sidebar: Virus vs. Virus

Illustration: Kristy Whitehouse

T cells constantly patrol the body for dangerous invaders. These highly specialized guardians of the immune system target specific pathogens. They even attack endogenous retroviruses, the remnants of ancient infection that survive within our genome, if the retroviruses spring into action. Often, these usually dormant fossils alongside our genes will take advantage of a suppressed immune system when an HIV infection takes hold. A team of immunologists at UC San Francisco, now believes that by exploiting the T cell response to this awakening, they may be able to hone in on HIV itself.

T cells attack HIV just as they would any other virus. But one of the problems they run into is that HIV changes, or mutates, so quickly. By the time the body develops specific T cells to fight a particular strain, the viruss minions have changed, making them unrecognizable and thus impossible for the T cell to destroy. The immune system is always playing catch up, says Keith Garrison, lead author of the teams latest paper, published in PLoS Pathogens.

If the T cells had a steadier target, Garrison and his colleagues hypothesized, they would form a more effective battle line against HIV. T cells respond to proteins called antigens on the surface of passing cells that indicate when a cell is infected. A weakened, HIV-infected cell also is more likely to contain reactivated endogenous retroviruses. While a T cell might not recognize the antigen of shape-shifting HIV, an antigen prompted by an endogenous retrovirus could prod other T cells into attack mode. Healthy cells wouldnt show such activity, so T cells would spare them. But T cells aimed at endogenous retroviruses would destroy any cell with HIV.

To test this hypothesis, the group took blood samples from patients diagnosed with HIV. They compared the number of T cells aimed at attacking endogenous retroviruses with the amount of HIVwhat doctors viral load. Individuals with more of that specific kind of T cell had significantly less HIV present in their blood.

The findings suggest that rousing brigades of these targeted T cells into action may slow the progression of HIV. To determine whether T cell amplification could become a treatment option for the futureone that could affect the design of a vaccinethe team is now searching for the genetic factors that dictate whether an individuals cells can control internal outbreaks of endogenous retroviruses.

A self-described retro-element biologist, Garrison believes were only beginning to understand how big a role endogenous retroviruses play. These fossils from within could provide a weapon in the arsenal against HIV, but the research pathway to get there will be long and challenging, he says.



John C. Cannon
B.S. (biology) The Ohio State University
Internship: Los Alamos National Laboratory news office

Communication is essential in the natural world, as I've seen throughout my research and global travels. Cells fired cytokines back and forth to one another when I removed them from their comfortable organ capsules in my immunology lab. Humpback whales hung suspended in the Indian Ocean, catatonic save for hour-long arias sung to woo potential mates hundreds of miles away, as I listened from the deck of a scientific ship above them. A mother cooed to soothe her colicky baby under a baobab tree on the African Sahel, where I shared so many dinners during my Peace Corps work.

The science behind these stories is captivating, and now its my turn to communicate. My challenge is to transfer my excitement to readers, showing them thatas Kerouac wrotethe circumstances of existence are pretty glorious.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Emily Harrington
B.S. (biology) Colorado College

After graduating with my biology degree in 1998, I traveled and taught troubled youth in the remote Utah wilderness. From this, I concluded that carrying heavy packs, eating Top Ramen and sleeping on punctured Therma-rests should only be done for pleasure, not for work. And so, I turned my back briefly on science and ventured into art and graphic design. I have now added a science illustration certificate to my suite of skills and will be returning to my native Montana this summer to sleep on Therma-rests, hike through the Rocky Mountains, and work with the Biomimicry Institute in Missoula.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Kristy Whitehouse
B.S. (biology, cellular/molecular concentration) Humboldt State University

Drawing has been a lifelong joy, but always as a hobby. In school I was attracted to science, to learning how things work and the processes that are used. Molecular biology is especially interesting to me because proteins are mind-blowing little organic machines. Visualizing how they behave instantly takes me into a fascinating world of outer space mixed with deep sea and a little physics. My constant drawing and proficiency in science led others to bring the field of Science Illustration to my attention, and I was hooked! Not only am I able to combine my passions, I can also share this world with others and help them understand what is going on in the often mysterious and complex fields of genetics and proteomics.




  Virus vs. Virus