NEVER mind the hoopla surrounding this milestone in biology: the first draft
of the human genome will be full of holes. And no matter how hard sequencers try
over the next few years, many of these gaps will stubbornly refuse to reveal
their secrets.
About 3 per cent of the long arm of chromosome 22鈥攖he first chromosome
to be 鈥渃ompleted鈥濃�攑roved to be unreadable
(the gaps are marked in the diagram),
and the four chromosomes completed since then contain gaps as well. In addition,
about 10 per cent of the genome is virtually impossible to sequence because of
its repetitive nature, so it has been quietly omitted from all discussion of
progress鈥攅ven though it may contain important information. 鈥淚t would be
good to get at these gaps, because there might be genes in there,鈥� says Robert
Waterston, director of the Genome Sequencing Center at Washington
University.
Even when the public Human Genome Project completes its final draft in 2003,
gaps will remain鈥攁nd some genes might have been overlooked.
Advertisement
One source of gaps is the method used to sequence DNA. The reactions used to
read off the bases are stalled by some highly repetitive sequences. But such
gaps are unlikely to contain genes, says Elbert Branscomb, director of the Joint
Genome Institute in California. 鈥淭he stuff that defeats the chemistry of
sequencing is where the biology is least likely to lie,鈥� he says.
Another kind of gap is harder to dismiss as irrelevant. To be sequenced, a
chromosome must first be chopped into more manageable bits. Researchers 鈥渃lone鈥�
these bits by splicing them into artificial chromosomes that are inserted into
and copied by bacteria. But some DNA segments somehow prevent the artificial
chromosome replicating. As a result, these segments will be missing from the
final sequence.
Combining private results like Celera鈥檚 with public data could fill many of
the gaps, Branscomb says. 鈥淕aps in one might not be gaps in the other,鈥� he
says.
There is another sort of gap in the data that no one talks about,
however鈥攖he 10 per cent or so of human DNA that consists almost
exclusively of short repeated sequences. While the repeated sequence can be
read, one segment of repetitive DNA looks like every other, so there is no way
to pinpoint where in the mass of repeats it came from.鈥漌e can鈥檛 say for sure
there aren鈥檛 any nuggets buried in the midst of it,鈥� Waterston says.
But some researchers believe that by ignoring these regions the sequencers
are missing essential genes. Evan Eichler, a biologist at Case Western Reserve
University in Cleveland, Ohio, and his colleagues have discovered arrays of
genes on the edges of repetitive regions, interspersed with the short repeats.
鈥淚f we exclude these areas from sequencing, we could be missing a whole region
of the genome that is medically important,鈥� he says.