What is the Fugu Genome Project?
The Fugu Genome Project is an international program
aimed at determining the complete DNA sequence of the genome of
the Japanese pufferfish, Fugu rubripes. Despite the obvious differences
between fish and humans, it is expected that comparisons of the
human genome with that of Fugu will shed light on the common genetic
systems shared by these two species, and help us understand the
information encoded in the human genome.
What is Fugu?
Fugu is a teleost fish belonging to the order
Tetraodontiformes (four toothed puffers) and a member of the rayfinned
fish family (Actinopterygians). The other major branch of vertebrates
comprises of lobefinned fishes (Sarcopterygians), which includes
the Coelacanth, lungfishes and tetrapods (fourlegged animals including
humans). There are over 100 species of pufferfish with diverse salt
water and fresh water habitats.
Is Fugu not a poisonous fish?
Some organs of the Fugu, particularly the liver
and ovary, are highly toxic. They contain a potential neurotoxin,
Tetrotoxin, which is produced by a symbiotic bacterium (Pseudoalteromonas
haloplanktis tetraodonis) that lives in the Fugu. The toxin acts
by blocking the voltage-gated sodium channels on the surface of
nerve membranes. Needless to say, Fugu itself is immune to this
toxin. It is believed that most of the Fugu grown in fish farms
are free from these bacteria and the toxin.
What was actually accomplished?
Today's announcement marks the completion of
the draft sequence of the Fugu genome. Over the past year, the Fugu
Genome Consortium determined nearly four million pieces of Fugu
genome sequence. These genomic fragments, averaging around 600 DNA
bases in length, overlap each other, which allows them to be reassembled
computationally to reconstruct long stretches of the Fugu genome,
spanning tens of thousands of DNA bases in length. Fugu is the first
animal genome to be sequenced and assembled in the public sector
using this "whole genome shotgun" sequencing approach.
Why is this sequencing achievement important?
The Fugu genome is the first vertebrate genome
to be draft sequenced after human. Its compact form and similarity
to the human genome will make it an important tool for getting at
the information encoded in the human sequence. We now have in hand
the basic gene-level description of two vertebrates. Comparing and
contrasting them will allow us to discover new human genes and importantly,
elements that control or regulate the activity of genes. Using genomes
in this way has been compared to the way in which ancient languages
were decoded using the Rosetta stone-one common text translated
side-by-side into different languages.
But I thought all of the human genes were
identified by now?
No. The computational methods for predicting
genes are imperfect and we know that a significant number of human
genes remain to be discovered in the human genome sequence. Comparison
between genomes is a powerful way to find such genes. More significantly,
there are no good computational methods for reliably finding the
elements which surround genes and control their expression, that
is, determine when and where a gene will be turned on or off, and
how much protein should be made. For example, genes that are used
in the kidney may not be used in the brain. We are still learning
to detect these genomic signals. This is an important missing piece
of the human genome puzzle.
So what makes Fugu such a good choice for
comparison with human?
Firstly, Fugu is a vertebrate-despite their apparent
differences, fish have nearly all of the same organ systems and
physiology as humans, in contrast to the more distantly related
invertebrate animals already sequence, like flies and worms. Just
as importantly, however, is that the Fugu genome is unusually small
for a vertebrate. The pioneering work on Fugu, published in the
journal Nature in 1993, showed that despite a similar gene content,
the entire Fugu genome is only 1/8th the size of the human. Even
among fish, Fugu is special: most fish genomes are several times
longer than Fugu's.
How big is the Fugu genome?
Pufferfish have the smallest known vertebrate
genomes, around 350-400 million bases long, or 350-400 megabases.
(These bases are denoted by letters - A, C, T, or G - which represent
the chemical units that are strung together to make genes and chromosomes.)
Fugu has 22 pairs of chromosomes, though these have no direct correspondence
with the 23 pairs of human chromosomes. For comparison, the human
genome is about three billion bases long. Despite this size difference,
however, both Fugu and human are expected to have a similar repertoire
of genes
How can fish and humans have the same set
of genes? Aren't they very different?
It depends on what you mean by "the same."
It has been amply demonstrated that many human genes including,
for example, "disease genes" like dystrophin, whose mutation
causes muscular dystrophy-have close relatives in Fugu. These related
genomic features can be detected computationally by comparing the
two genomes and looking for similar sequences. The Fugu and human
genomes are similar by virtue of their shared vertebrate heritage.
Of course, humans (and Fugu) will have their own unique genes that
are special for human-ness and fish-ness that the genome comparisons
will also bring to light. But even these fish- and human-specific
genes are likely to share a common genetic heritage.
If they have similar gene content, why is
the Fugu genome so much smaller than the human genome?
Genomes contain more than just genes. In fact,
only a few percent of the human genome actually represents "coding
sequence," the functional parts of genes. The rest of the human
sequence is dominated by highly repetitive non-gene DNA-for example,
regions that read "ACACACAC …" for hundreds of bases,
or have longer sequences that are scattered throughout the human
genome hundreds of thousands of times. While these repeats make
up 40% of the human sequence, the Fugu genome has much less repetitive
content-for mysterious reasons that should be illuminated by the
genomic sequence now in hand. But its not only the relative lack
of repeats that makes Fugu special-Fugu genes themselves are more
compact than human genes, and packed more tightly on the genome.
This is the main reason Fugu was chosen for sequencing-as a cost-effective,
more-genes-for-the-buck shortcut to a vertebrate gene set, the gene
rich Fugu can't be beat.
Why sequence Fugu rather than another mammal
like mouse and rat?
Genome sequencing shouldn't be thought of as
an either-or proposition. It is essential that a broad range of
animal genomes be sequenced, to shed light on the underlying similarities
and essential differences between species. Fugu is just the beginning.
The ongoing mouse and rat genome projects are critical for biomedicine,
and will be particularly powerful tools because these animals are
mammals (more closely related to human) and can be bred and studied
more easily than Fugu. The Fugu genome provides a more distant evolutionary
comparison (400 million years, versus 100 million years for mouse
and rat) that permits a more accurate triangulation of genome function
than mouse or rat alone. Genomic features that are common to Fugu,
rodents, and human will focus our attention on the essential core
genes that define being a vertebrate.
How are fugu and humans related by evolution?
About 450 to 500 million years ago, the first
vertebrates (animals with segmented backbones made of cartilage
or bone) appeared in the early oceans. Their descendents split into
two main groups: the ray-finned fishes-which include Fugu and most
fish familiar to us from the dinner table-and the lobe-finned fishes,
a more obscure group with fleshy paddle-like appendages in place
of the paper-thin fins of the ray-finned fish. Over millions of
years, these lobefins evolved into the limbs possessed by all four-limbed
creatures (the tetrapods, including reptiles, amphibians, birds,
and mammals). So Fugu are our very distant cousins, sharing a common
ancestor with us nearly half a billion years ago. Remarkably, this
common ancestry is still recorded in our genes.
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