A new technique successfully takes on a
longstanding challenge in DNA sequencing – determining whether a particular
genetic sequence comes from an individual's mother or father. The method,
described in a Ludwig Cancer Research study in Nature Biotechnology, promises
to accelerate studies of how genes contribute to disease, improve the process
of matching donors with organs and help scientists better understand human
"The technique will enable clinicians
to better assess a person's individual risk for disease. It is potentially
transformative for personalised medicine," says Bing Ren, Ludwig scientist
at the University of California, San Diego School of Medicine, who led the
research on the new technique, called "HaploSeq".
"Current sequencing technologies are
fast and rapidly getting cheaper – an individual's genome can now be sequenced
in about a week for $5000," says Ren. "In the not too distant future,
everyone's genome will be sequenced. That will become the standard of
care." But, he explains, "There has been a problem with this
scenario." Except for the sex chromosomes, everyone has two copies of each
chromosome. One copy comes from mom, and the other from dad.
cannot distinguish between the two copies of each gene and, therefore, are not
very good at determining whether particular genetic differences, such as a
single-letter change in the DNA, originate with an individual's mother or
father – muddying genetic analyses.
Profound effects on genetic research
Ren's new technique, a mixture of molecular
biology and computational biology approaches, bypasses this problem. The method
enables researchers to quickly determine which genetic variants occur together
on the same stretch of chromosome and, therefore, came from the same parent.
"This advance has direct implications for the utility of genomics in
clinical practice and will also have profound effects on genetic research and
discovery," says Ludwig scientist Siddarth Selvaraj, who contributed to
the study with Ren and fellow Ludwig researcher Jesse Dixon.
More immediately, the technique will enable
clinicians to better assess a person's individual risk for disease, a
cornerstone of personalised medicine. For instance, people at risk for a
disease such as cancer often have more than one DNA mutation. HaploSeq could
enable clinicians to determine if the two mutations are on the same chromosome
or on different chromosomes, which can help in risk assessment – for instance,
risk may be reduced if two mutations are on the same chromosome, since the
'good' chromosome can often compensate.
Similarly, the method, with further honing,
has the potential to refine the currently cumbersome process of determining
whether there is a genetic match between an organ donor and recipient. A large
number of genes contribute to compatibility between donor and recipient, but
there is a lot of genetic variability in these genes.
The new technique could
help determine whether DNA differences between donor and recipient are likely
to be a good match. "This will require more study," says Ren,
"but by creating a DNA database, it may be possible to more accurately and
expediently pair recipients and donors."
The new method will also help researchers
analyse human migration and determine ancestry from their DNA sequences.
"In principal," says Ren, "you could compare your genetic
sequence to your neighbour's and ask if you have any recent ancestors in
common. With our technique we can study each individual and how they relate to
other individuals. As we accumulate data from many individuals we can more
precisely determine their relationships." Such findings will also bolster
an ongoing international project to assess worldwide human genetic variation,
the HapMap project.
One advantage of the new technique is that
it builds on common sequencing technologies and should be easily adapted for
use by clinicians and researchers alike. Says Ren, "I anticipate that this
new method will be quite widely used."