An international team that includes biologists at UCSD has determined the complete genetic blueprint of Dictyostelium discoideum, a simple social amoeba long used by researchers as a model genetic system, much like fruit flies and laboratory mice, to gain a better understanding of human diseases.
The scientific details of this seven-yearlong genetic sequencing effort, which involved 97 scientists from 22 institutions in five countries, are contained in a paper featured on the cover of the May 5 issue of the journal Nature.
The international team’s achievement will have an immediate application for biomedical researchers, who can now mine the Dictyostelium genome for a host of genes that cause human disease, thus gaining a new and efficient way to study those human diseases with a simple organism in their laboratories.
For evolutionary biologists, the genetic blueprint of Dictyostelium, the first amoeba genome to be sequenced, has clarified the place that Dictyostelium occupies in the hierarchy of life.
“It is more closely related to fungi and animals than we had previously thought,” says Adam Kuspa, a professor of biochemistry and molecular biology at Baylor College of Medicine in Houston and a senior author of the Nature paper.
The discovery will also improve geneticists’ understanding of how the genes from Dictyostelium and other genetic model organisms have been conserved or adapted through evolution in humans and other organisms.
“The cells which gave rise to plants and animals had more types of genes available to them than are presently found in either plants or animals,” explains William Loomis, a professor of biology at UCSD and one of the key members of the international sequencing effort. “Specialization appears to lead to loss of genes as well as the modification of copies of old genes. As each new genome is sequenced, we learn more about the history and physiology of the progenitors and gain insight into the function of human genes.”
In 1989, Loomis and Kuspa, then a postdoctoral fellow in Loomis’ laboratory, initiated a critical portion of the effort when they began the arduous task of constructing a physical map of the genes located on the six chromosomes of Dictyostelium.
The scientists mapped the location of several hundred genes on those chromosomes based on landmarks that had been discovered over the years, then created a set of 5,000 large DNA clones, each about 200,000 nucleotide bases long, that proved useful for other researchers in assembling the genetic sequences of Dictyostelium’s genome. Another UCSD biologist involved in the genome effort, Christophe Anjard, an assistant project scientist in Loomis’ laboratory, analyzed families of Dictyostelium genes and uncovered relationships with these genes in both animals and plants.
Dictyostelium is used as a model organism for studying cell polarity, how cells move and the differentiation of tissues. It also exhibits many of the properties of white blood cells.
Three years ago, another team of UCSD biologists discovered that two genes that are used by Dictyostelium to guide the organism to food sources are also used to guide human white blood cells to the sites of infections and play a role in the spread of cancer. (see: http://ucsdnews.ucsd.edu/newsrel/science/mcchemo.htm )
Dictyostelium usually exists as a single cell organism that inhabits forest soil, consuming bacteria and yeast. When starved, however, the single cells come together, differentiate into tissues and become a true multicellular organism with a fruiting body composed of a stalk with spores poised on top. This increases its utility in a variety of studies.
“An organism’s relationship to humans depends on how related the proteins are that are found in the two cell types,” says Kuspa. “You can make direct analogies, or you could learn general principles about how cells regulate their behavior. Both things will apply in the studies we do.”
He and the other members of the international sequencing team found that there are more protein coding genes in the organism than they had thought and nearly twice as many as there are in fungi. Their unraveling of the genome also allowed Rolf Olsen, a postdoctoral fellow working in Loomis’ laboratory, to generate a tree of life and show that amoebozoa, the group to which Dictyostelium belongs, evolved from the common ancestor of eukaryotes (the group of organisms that contain all animals, plants, algae, protozoa, slime mold and fungi) before fungi. Dictyostelium has about 12,000 genes that produce a greater variety of proteins than the approximately 6,000 found in fungi. And its genes are more closely related to human genes than are the genes from fungi.
“That really speaks to how much we will relate the gene function information we find to humans,” Kuspa says. "It makes Dictyostelium a better model for looking for targets against which drugs can act.”
Key collaborators in the project at Baylor included Richard Gibbs and George Weinstock, co-directors of Baylor’s Human Genome Sequencing Center, and Richard Sucgang, an assistant professor of biochemistry. Baylor performed about one half of the sequencing work.
The project was funded by grants from the National Institute for Child Health and Development, Deutsche Forschungsgemeinschaft, the Medical Research Council and the European Union.