Culminating a three-year research project, 115 scientists from around the world report in the Oct. 12 issue of the journal Science a "gold mine" of data on a tiny green alga called Chlamydomonas, with implications for human diseases.

The single-celled Chlamydomonas, a slimy organism that grows in soil and ponds, has approximately 15,000 genes, and scientists now know 95 percent of the sequence of its genome. Several years ago, they knew less than 2 percent.

"It's like having a dictionary of genes," said lead author Sabeeha Merchant, professor of biochemistry and associate director of UCLA's Molecular Biology Institute, who has studied the green alga for 20 years. "We know the words and now we want to learn to talk. Without the dictionary, you would be stuck and couldn't learn how to speak or write. We went from having a 200-word vocabulary to a 14,250-word vocabulary. Each of us is trying to learn how to put the words and sentences together in our own research programs.

"Having the genome sequence available fast-forwards our research by 10 or 20 years and allows us to make progress by leaps and bounds," she said. "The genome sequence opens the door for us to access all the genes and target our research on subsets of genes. What was just a dream 10 years ago, we have now accomplished."

Chlamydomonas' genes are likely to contain a wealth of data about the common ancestry of plants and animals, according to the international teams of scientists who compared its genes to those of plants and humans and other animals. The scientists report that the alga has maintained many genes that were lost during the evolution of land plants, has others associated with functions in humans and has numerous genes whose functions are unknown but which are associated with critical metabolic processes.

The alga turns out to be remarkably complex.

"Its single cell does much of the biochemistry that more complex organisms do," Merchant said. "It has to swim, find food, do photosynthesis and respiration, and it mates.”

Chlamydomonas performs photosynthesis like plants, by converting carbon dioxide, water and the energy of sunlight into oxygen and sugars. Indeed, much of what is known about photosynthesis was learned from Chlamydomonas.

"Now we have learned that we don't know everything about photosynthesis and that there are still many unknown proteins," Merchant said. "We found many proteins involved in antioxidant function. Photosynthesis generates the most powerful oxidants known in biology; there has to be a protection mechanism because oxidation causes aging. In Chlamydomonas, proteins and lipids can get oxidized if reactions of photosynthesis are not properly controlled. We discovered a number of proteins that may be important for protection against oxidative damage."

The scientists identified 349 genes that are present in algae and plants but not in humans and other animals. More than 200 of these genes have unknown functions, a fact that surprises the researchers.

"It's exciting that most of these genes are unknown," Merchant said, adding that the scientists suspect that many of these genes are involved in photosynthesis.

"We don't know what they do yet; we hope to learn what they do," she said.

The scientists identified many new proteins that are likely associated with cilia — thin organelles that allow a cell to sense its environment and tell where it is — and they differentiated proteins that are critical for movement from those associated with sensory functions. The cilia provide locomotion and act as a cellular antenna.

Humans also have cilia — in the brain, lungs and kidneys. The cilia are required for brain function in animals, and for metabolism. The loss of cilia leads to serious diseases, although scientists do not yet know why, Merchant said. Cilia perform key functions for a large number of organs, and the consequences of mutations can be severe. Embryos that lack cilia die very early in development. Model organisms like Chlamydomonas are ideal for discovering how cilia work and what goes wrong when they do not function properly.

The researchers have gleaned new insights about human diseases associated with dysfunction in human cilia, including diseases of the kidney and the eye.

The scientists — from the United States, France, China, Japan, Germany, Australia and elsewhere — can now predict what many of Chlamydomonas' genes do.

Co-authors on the paper include Simon Prochnik and Daniel Rokhsar of the U.S. Department of Energy's Joint Genome Institute and Arthur Grossman of the Carnegie Institution of Washington.

"We curate and catalog genes like an art curator curates works of art," Merchant said.

"An organism is more than the sum of its parts, but historically we've been able to look at only the little parts," she said. "In the genome age of biology, we can now analyze the whole organism. Now we can look at the whole organism and can figure out how the parts are linked. As a result of this project, we understand the organism much more and have a much better understanding of the connections, and we have tools to learn even more."

The Joint Genome Institute determined the genome sequence to discover what Chlamydomonas' DNA encodes.

While not the common ancestor of plants and animals, Chlamydomonas retains genes and proteins from the common ancestor, Merchant said.

The researchers performed a comparative gene analysis across species to explore the evolutionary history of Chlamydomonas and its relationship to other organisms. Of the 6,968 protein families that have so-called "homologs" — proteins that have similar amino acid sequences, often reflecting a similar or related function among the species — they found that Chlamydomonas shares 35 percent with both flowering plants and humans and an additional 10 percent with humans but not with flowering plants.

Chlamydomonas has many proteins that make it well-suited to living in the soil, including large families of specific transporters — proteins that help move material across cell membranes — which enable it to scavenge nutrients from soil. While some of these transporters have an affiliation with transporters in plants, others are more closely related to those in animals. There are also numerous genes and gene families that relate to making sugars and polysaccharides, to using the sugars and polysaccharides to produce energy, and to building a highly structured and efficient chloroplast, the factory where the cell harnesses the energy of sunlight.

The scientists identified protein families that are shared by Chlamydomonas, flowering plants and other algae but are not present in nonphotosynthetic organisms. This research led them to identify photosynthesis-related proteins conserved across the plant kingdom, with many even conserved in ancient cyanobacteria. The majority of the identified proteins have unknown functions but are probably critical since they have been exclusively maintained in photosynthetic organisms over nearly the entire period that life has existed on Earth.

Mechanisms that apply in algae also apply in many other forms of life and in other kinds of cells, including those of plants and mammals.

"We study algae to understand how cells work," Merchant said. "It's easier to conduct research with a microorganism."

Merchant was honored with the Gilbert Morgan Smith Medal for her exceptional scientific research by the National Academy of Sciences at the academy's annual meeting last year. The prestigious award is given only once every three years.
Merchant joined the UCLA faculty in 1987. She has been awarded research grants from the National Institutes of Health, the U.S. Energy Department and the U.S. Department of Agriculture.

For the Science paper, most of the sequence analysis was supported by U.S. Energy Department and the Joint Genome Institute; some aspects of the research were federally funded by the National Science Foundation through a grant to Grossman of the Carnegie Institution Department of Plant Biology.

In addition to Merchant, Prochnik, Rokhsar and Grossman, authors on the paper include Olivier Vallon of CNRS at Universit Paris 6, Elizabeth Harris of Duke University, Steven Karpowicz of UCLA, George Witman of the University of Massachusetts Medical School, Astrid Terry of the Joint Genome Institute; Asaf Salamov of the Joint Genome Institute, Lillian Fritz-Laylin of UC Berkeley, Laurence Marechal-Drouard of the Institut de Bioloigie Molculaire des Plantes, Wallace Marshall of UC San Francisco, Liang-Hu Qu of Zhongshan University in China; David Nelson of the University of Tennessee, Anton Sanderfoot of the University of Minnesota, Martin Spalding of Iowa State University, Vladimir Kapitonov of the Genetic Information Research Institute, Qinghu Ren of the Institute for Genome Research, Patrick Ferris of the Salk Institute, Erika Lindquist of the Joint Genome Institute, Harris Shapiro of the Joint Genome Institute, Susan Lucas of the Joint Genome Institute, Jane Grimwood of Stanford University School of Medicine, Jeremy Schmutz of Stanford University School of Medicine, Igor Grigoriev of the Joint Genome Institute, the Chlamydomonas Annotation Team and the Joint Genome Institute Annotation Team.

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