They're Sequencing a What?

Genome scientists go out on a limb of the tree of life

11:31am, October 5, 2004
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Quick. Would you know a placozoan if it bit you? Not that it actually would attack, unless you were as small as a fleck of algae. And even then, it wouldn't bite but would instead clamp down and ooze digestive enzymes. Yet this summer, placozoans—the simplest of free-living multicellular animals—and some other, equally nonfamous creatures made the list of targets for the next wave of DNA

sequencing to be funded by the U.S. government. As genome science is expanding in scope, its targets have begun to span the tree of life.

Sequencing a genome, figuring out the order of bases of a creature's DNA molecules, often gets compared to reading the book of life. Tallies vary, but geneticists have the text for more than 100 species. These include laboratory stars such as the chimp, rat, and mouse. Others in the group, such as rice and honeybees, are important to agriculture and many are pathogens, such as the microbe behind Legionnaires' disease.

Yet biologists are calling for still more diversity. Panels advising the National Human Genome Research Institute (NHGRI) in Bethesda, Md., on selecting its targets frame the case in terms of understanding the human genome. Most of the human genome evolved long before humans themselves did, noted a panel report this summer. Parts of the human genome resemble bits of the simple organisms called prokaryotes, although their lineages split from ours more than a billion years ago. People also share genes with other, less remote cousins. Studying our genetic resemblances, or lack thereof, with various relatives should provide ideas about how we ended up as we are.

It's not just about us, though. Consideration of strategically chosen, very different lineages will permit scientists to "probe deeply the nature of genomes," says Laura F. Landweber of Princeton University, a co-chair of an NHGRI panel. "We will learn more about all genomes on Earth," she predicts.

Think of the diverse genomes as navigation beacons, says Brent Mishler of the University of California, Berkeley, who has championed a proposal submitted to the Department of Energy (DOE) for sequencing nonflowering plants. "You wouldn't want three [beacons] in Colorado and four in Texas and none anywhere else in the country," he says.

So, these are the glory days for placozoans, lesser hedgehog tenrecs, choanoflagellates, Oxytricha ciliates, and such. For readers who aren't on a first-name basis with these new genetic celebrities, here's a cheat sheet.

Disputed tenrec

Among the nine mammals added in August to the list of NHGRI sequencing targets, the least familiar is probably the lesser hedgehog tenrec (Echinops telfairi). It looks like a hedgehog and rolls into an impenetrable ball of prickles when threatened. Yet during the last decade, a growing number of mammalogists have argued that the tenrec is more closely related to the elephant than to the Mrs. Tiggywinkle–style of European hedgehog.

The main drive behind selecting the group of mammals that includes the tenrec comes from a plan to determine which parts of the human genome provide crucial functions and which don't, says Adam Felsenfeld, a program officer of NHGRI. Stretches of DNA that look similar among diverse groups might have been conserved through evolutionary time because organisms depend on them. The tenrecs won't be given the kind of detailed analysis that went into the mouse, for example, says Felsenfeld, but the results "ought to be sufficient for comparisons."

The tenrecs made the list as representatives of Afrotheria, which mammalogists suspect was the earliest of the four major lineages of placental mammals that are still around today. This grouping is the result of a recent rethinking of mammal history.

For decades, the 30-some species of the tenrec family, found mostly in Madagascar, were classified in the order now called Lipotyphla, with such animals as shrews, moles, Southern Africa's golden moles, and hedgehogs. In 1997, though, geneticists argued that their work justified shuffling mammals in the evolutionary tree to create a new superorder, Afrotheria (SN: 1/6/01, p. 4: Genes Seem to Link Unlikely Relatives). This superorder, made up of several African lineages, lumped tenrecs and golden moles with such groups as elephant shrews, aardvarks, hyraxes, elephants, and the slow, aquatic dugongs and manatees.

Wherever they sit on the evolutionary tree, tenrecs are "bizarre little animals," says Link Olson of the University of Alaska Museum of the North in Fairbanks. Living in Madagascar's desert, the lesser hedgehog tenrec is among the few mammals that fall into metabolic torpor during the day but snap out of it in the evening. This isn't typical mammalian post-lunch napping. These tenrecs drop their metabolic rate profoundly, as if compressing a cycle of winter hibernation and spring emergence into a single day.

The variable body temperature is one of several traits that the NHGRI panel notes as making the lesser hedgehog tenrec an interesting contrast to the other Afrotherian about to get sequenced, the elephant. These traits also include undescended testicles and a cloaca, a multitasking opening shared by the reproductive and excretory systems.

First settlers

Moss specialist Mishler points out that moss lineages arose during one of the most exciting eras in plant history, the move from nurturing water to dangerously dry land. Some mosses coped with the transition by becoming perennial green cushions, while others took up a style of living fast and dying young. In August, the DOE's Joint Genome Institute named one of the latter species, Physcomitrella patens, to be among the first nonflowering plants targeted for sequencing.

Mishler's lab mates have been visiting lakeshores in California to collect the moss, which spends most of the year as a spore. But when the dry season exposes muddy stretches along the receding waters' edge, the moss seizes the moment. The spores germinate in the mud, grow rapidly into green fuzz a few millimeters high, and then make new spores—all in a matter of weeks.

That breakneck life cycle proved a big selling point for Physcomitrella when the world's moss-genetics community got together last year to recommend a species for sequencing, says Mishler. Scientists can quickly grow Physcomitrella in a laboratory.

Also useful is the ease with which the moss accepts a gene inserted from other organisms. Mishler predicts that Physcomitrella could therefore be a model organism for a range of questions, including his favorite: How did some mosses evolve extreme adaptations, such as a tolerance for desiccation? Mishler's lab maintains a moss cam that enables Web surfers to watch a natural patch of another moss dry out and then come back to life when it rains (http://www.jamesreserve.edu/mosscam/mosscamView1.html).

The other nonflowering species selected for the DOE sequencing pipeline comes from an equally venerable lineage of the plant kingdom, the club mosses. Like the true mosses, they reproduce from spores instead of seeds, but the club mosses have what might be considered a vital improvement for life on land: decent plumbing.

The club mosses' internal hydraulic systems raise water centimeters above the roots and also distribute sugars produced in the sun-catching greenery. The new subject of sequencing, Selaginella moellendorffii, stretches above the forest floor only about as high as the top of a hiking boot, but it has the beginnings of the hydraulic system that has evolved to maintain all plants, including skyscraping redwoods.

Real simple

Placozoans are about as simple as you can get and still be multicellular. To the naked eye, these organisms look like specks in the water. Their flat bodies consist of two layers of just four types of cells. That's the fewest cell types known for a free-living animal.

In selecting the placozoan Trichoplax adhaerens for sequencing, the NHGRI panel noted that placozoans are simple in yet another way. They have the smallest genome of any animal yet measured. Not only will that make the sequencing quick, but it also will highlight the essentials of the animal lifestyle.

Placozoans resemble a microscopic version of a penny that's been run over by a train. Although they do have a topside and an underside, they don't have recognizable front or rear edges, or anything as fancy as a mouth. They eat by fitting themselves on top of, say, a bit of algae and then exuding digestive enzymes and absorbing the resulting soup.

Such simplicity is deceptive, says James W. Valentine of the University of California, Berkley, who studies ancient multicellular animals. It might be tempting to assume that placozoans are the most ancient of multicellular animals. However, although sponges have body plans of baroque complexity compared with the placozoans', genetic evidence so far suggests that the sponges appear to be the older group, Valentine says. Today's placozoans may have come from ancestors that had more complex bodies but then scaled back to the basics.

Almost animal?

The choanoflagellates have just one cell, but they're more closely related to people and other animals than are most single-celled organisms. Unlike bacteria and archaebacteria, the choanoflagellate cell has a clearly defined nucleus. That puts it among eukaryotes, which include the more-elaborate, single-celled organisms as well as animals, plants, and fungi.

One end of the choanoflagellate cell is adorned with a long whip, or flagellum. Some species move in the direction the whip points; some move in the opposite direction. Around the flagellum's base, a ring of hairlike projections forms the flared collar that distinguishes choanoflagellates from other flagellum-bearing cells.

Choanoflagellates rely on their collars to trap food, which usually snags on the outside. Then, a fingerlike projection, formed just for this task, arises from the body of the cell, extends to the food, and withdraws with it into the body.

The distinctive collar made scientists think that choanoflagellates were closely related to multicellular organisms. More than a century ago, microscopist Henry James Clark noticed that some of the cells in sponges grew collars and looked essentially like embedded choanoflagellates. He proposed that choanoflagellates therefore might be our unicellular sister group.

Since then, biologists have found other collared cells in animals, for instance, in mammalian skin.

Genetic evidence so far, says Nicole King of the University of California, Berkeley supports the idea that choanoflagellates are the single-cell lineage most similar to multicellular animals.

"So, if we want to understand the basic molecular components of what makes an animal cell, then we need to do a comparison to our closest relative—[and] here it is," says Peter Holland of the University of Oxford in England.

Monosiga ovata is the choanoflagellate species that's just been approved for NHGRI sequencing. A team is already sequencing another species, Monosiga brevicollis.

Nuclear synergy

Several research groups are sequencing members of a group of single-celled organisms that bristle with short hairlike projections called cilia. Thomas G. Doak of Princeton University and his colleagues have argued—successfully, as of August—for NHGRI-funded work to tackle the ciliate Oxytricha trifallax.

The Oxytricha, which are convex disks, grow their cilia on the underside. Although Oxytricha can swim, most of the time they move along a surface on their tufts. In Doak's words, "they scuttle." Oxytricha are formidable predators in their microscopic world. "They're the ones dashing around slurping up everybody," says Doak.

Ciliates show the rare characteristic of growing two types of nuclei in the same cell. A micronucleus contains the whole diploid genome of the organism. It gives rise to a workaday version of itself, a macronucleus, with just the animal's 27,000 or so genes and not the 95 percent of DNA that scientists typically call junk because it doesn't encode any proteins. In the macronucleus, almost every gene ends up as a separate minichromosome. Furthermore, each minichromosome gets copied into about a thousand replicas.

During most of a cell's existence, the micronucleus is inactive, and the macronucleus directs the business of making proteins. When it comes time to divide, the macro- and micronucleus simply copy themselves, and the cells just split into identical daughter cells.

When food becomes scarce and the organism becomes stressed, the micronucleus takes charge and trades genetic material with a mating partner. During this sexual encounter, a new micronucleus forms. It then creates a new macronucleus that takes over for the old one.

One of the marvels of O. trifallax is the still-unknown molecular machinery that precisely excises noncoding DNA to create the new macronucleus, explains Glenn Herrick of the University of Utah in Salt Lake City. Another mystery is the unscrambling for the macronucleus of genes that had been shattered into pieces and scattered out of order in the micronucleus.

The weird charms of this ciliate might be explained by a look at its genome, say Doak and Herrick. They and many other biologists are now eager to push genome research into less-than-familiar territory.

Says Doak, "The genomes that have been sequenced so far are painfully dull in some ways."

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