Cambridge,
England (Dec. 1, 1999)- As this century draws to a close, the first complete
sequencing of a human chromosome is likely to be a gift to researchers that
will keep on giving well into the next.
A large international team of researchers led by Dr. Ian Dunham of the Sanger
Centre in Cambridge, England has mapped virtually all of the genetic sequence
of chromosome 22. They describe a sequence of 12 contiguous segments spanning
33.4 megabases, contains at least 545 genes and 134 pseudogenes. This major
scientific accomplishment is an important step towards the mapping of the
entire human genome. The map will provide useful clues for many ongoing investigation
into the structure of the genome, genetics in general, the nature of certain
gene specific diseases, and the bigger questions of the origin and evolution
of life.
The public research consortium adopted a clone-by-clone sequencing strategy
to map the chromosome. This involves individual cloning of each DNA fragment,
which is then propagated in a library, by inserting it into the genome of
a bacterial artificial chromosome (BAC). The unordered set of BAC clones is
then rearranged into a 'physical map', using the polymerase chain reaction
(PCR) to identify overlapping fragments sharing short sequences of DNA. These
fragments are known as sequence tagged sites. Once BAC 'contigs' (clones representing
overlapping regions of the genome) spanning the entire genome have been constructed,
the BACs are sequenced. The tricky part then involves rearranging the fragments
in the order in which they occur on the chromosome. This painstaking process,
known as 'finishing' involves joining up raw DNA data to form contigs, fixing
sequence errors, and filling in gaps between contigs.
"The significance of this week's publication is that it shows you can get
very good finishing using the clone-by-clone approach," said Dr. Dunham.
While
chromosome 22 may be the second smallest of the 23 human chromosomes, it has
already been linked to a number of diseases. Previous studies suggest the
genes on this chromosome play a role in schizophrenia, chronic myeloid leukemia,
congenital heart disease, tumor progression and trisomy 22, the second most
common cause of miscarriages.
Although the sequenced portion contains at least 679 genes, there may be
200 to 300 additional genes on the functional portion of chromosome 22 that
have not yet been identified. Moreover, the actual functions of more than
half the identified genes are yet to be discovered.
right: (click
to enlarge) Sequence of events -- from Mendel's discovery of the existence
of genes, to 2002 and the projected date for completion of sequencing the
human genome. The first protein to be sequenced was insulin; the first genome,
that of the bacterium Haemophilus influenzae.
"The sequencing is a first step. As with genes on all the other chromosomes,
a great deal of further work needs to be done to use this genetic information
to develop better tools for diagnosing and improving outcomes for individuals
with genetic diseases," Dr. Beverly Emanuel, the chief of Human Genetics
and Molecular Biology at the Children's Hospital of Philadelphia, and leader
of one of the 200 teams involved in the project. .
The sequencing of chromosome 22 is considered to be the first chapter in
the book of the human genome. Spurred by this accomplishment, researchers
are expected to have a rough map of the full sequence of human DNA on all
of the chromosomes within three years. Then researchers will have to identify
the proteins, some 200,000 to 300,000 of them, that make up a human being.
The research appears in the Dec.2, 1999 issue of the journal Science
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