JGI's pufferfish sequence offers in-depth look at human gene pool
An international research consortium led by the Joint Genome Institute
(JGI) reported Wednesday on the draft sequencing, assembly, and analysis
of the genome of the Japanese pufferfish Fugu rubripes.
The report was released on Science Magazine’s "Science Express"
Website (http://www.sciencemag.org/sciencexpress/recent.shtml).
Pufferfish have the smallest known genomes among vertebrates, the group
of animals with backbones that includes humans. The Fugu sequence contains
roughly the same number of genes as the much larger human genome, but
in a compact form streamlined by the relative scarcity of the "junk"
DNA that fills much of the human sequence.
Through comparison of the human and pufferfish genomes, the researchers
were able to predict the existence of nearly 1,000 previously unidentified
human genes. These additional hypothetical human genes are of largely
unknown function, but contribute to the complete catalog of human genes.
Determining the existence and location of genes helps enable scientists
to begin characterizing how they are regulated and function in the human
body.
"Comparative genomics programs like the Fugu project are key to understanding
the biology of the human genome," said JGI Interim Director Eddy
Rubin. "As historic and important as the Human Genome Project is,
it’s only the first step in determining how genes work – and
why they sometimes don’t work the way they should."
The draft sequencing and assembly of the Fugu genome, announced last October,
marked the first publicly released animal genome after the human sequence,
and the first vertebrate genome publicly sequenced and assembled using
the whole genome shotgun method. The Fugu genome sequence, along with
other information about the project, is available on the World Wide Web
at www.jgi.doe.gov/fugu and www.fugubase.org.
The JGI, one of the largest public genome sequencing centers in the world,
is operated jointly by three DOE national laboratories managed by the
University of California – Lawrence Berkeley and Lawrence Livermore
in California, and Los Alamos in New Mexico. In addition to the Fugu project,
the JGI has genomics programs focused on microbes, fungi, animals, and
plants.
Fugu is a delicacy in Japanese cuisine that can deliver a deadly neurotoxin
if improperly prepared. Its scientific value, however, is based on its
small genome size. According to Daniel Rokhsar, Associate Director for
Computational Genomics at the JGI, the compact structure of the Fugu genome
(only one-eighth the size of its human counterpart) made it possible to
identify genes that had been obscured by the many repetitive and non-coding
sequences that make up about 97 percent of human DNA.
Rokhsar noted that nearly three-fourths of the genes in the human genome
have identifiable counterparts in Fugu, highlighting the shared anatomy
and physiology common to all vertebrates.
"These similarities are recognizable in the two genome sequences
despite the 400 million years of evolution since the two species diverged
from their common ancestor," he said. "Proteins found in humans
but not in pufferfish, and vice versa, help define the sets of genes at
the core of differences between four-limbed animals (reptiles, amphibians,
birds, and mammals, including humans) and finned fish."
"For the first time we are seeing the overall differences as well
as the similarities in the protein parts that make up fish and man,"
said Dr. Samuel Aparicio, Principal Investigator at the Wellcome Trust
Centre for Molecular Mechanisms in Disease at the Department of Oncology,
Cambridge University, England. "When we matched the predicted Fugu
proteins directly against the human genome sequence, for 961 cases we
found that there was a match in human which didn’t overlap an already
predicted or known human gene.
"This flags up for human geneticists the position of potentially
novel human genes in the human genome. In addition, direct comparisons
of the fish DNA with the human DNA show that more human genes will be
found by comparing fish with man. In this way, the pufferfish sequence
is helping to find previously undiscovered features in the human genome
sequence – a process often compared to the decipherment of the Rosetta
stone."
The study also revealed how the ordering of genes in genomes can be shuffled
over time. Many small groups of genes are found in the same order in man
and fish, but over longer distances, the ordering of genes becomes scrambled.
The rearrangements found by the researchers shed light on the processes
that drive genome evolution.
The International Fugu Genome Consortium was formed in November 2000 by
the JGI and the Singapore Biomedical Research Council’s Institute
for Molecular and Cell Biology. Other members of the consortium are the
UK Medical Research Council’s Human Genome Mapping Resource Centre
in Cambridge, England, the Cambridge University Department of Oncology
and the Institute for Systems Biology in Seattle. Two U.S. companies,
Celera Genomics of Rockville, Md. and Myriad Genetics, Inc., of Salt Lake
City, contributed to the consortium’s efforts.
More information about JGI can be found at
www.jgi.doe.gov
.