Featured Interview | September 2014
‘We’re Going to Find the Keys’
Dan Geraghty Discusses an Approach to
Understanding Causal Genetic Variation
Dan Geraghty, a researcher at Fred Hutchinson Cancer
Research Center and CEO of Scisco Genetics, has
spent much of his career focused on the genetics of
immune response. Recently he talked to Mendelspod
host Theral Timpson as part of a series of podcasts on
the rise of long-read sequencing.
Geraghty explained that while there have been
decades’ worth of studies associating the genetics
of the major histocompatibility complex (MHC), and
the highly polymorphic HLA class 1 and 2 genes, we
still haven’t found the key mutations for a variety
of different autoimmune diseases such as type 1
diabetes, rheumatoid arthritis, multiple sclerosis, and
others.
Enormous amounts of linkage disequilibrium in these
regions are one factor, as is getting information in
phase, so larger stretches of sequence are needed.
Recently Geraghty has begun using Single Molecule,
Real-Time (SMRT®) Technology with hopes of drilling
down to the causal genetics.
Should PacBio Be Used For All Major
Sequencing Projects?
Geraghty explained that sequencing fosmids with
short-read technology is cumbersome when it comes
to stitching together the reads. Data analysis and
finishing “became a roadblock that the Illumina shortread technology wouldn’t let us get beyond,” he said,
noting that the finishing process takes 30 minutes to
an hour per fosmid, prohibitive for any modest-scale
effort. Geraghty marveled that he has received 40 kb
reads from PacBio® sequencing – meaning a whole
fosmid can be sequenced in one piece.
Geraghty thinks so, noting that a resource such as the
1000 Genomes Project would be upgraded significantly
with PacBio data for complex regions such as MHC
and KIR. He said that if you look at these regions in the
1000 Genomes data you will find “a mass of confusion”
because those regions are highly repetitive and contain
a large amount of copy number and allelic variation,
making it difficult or impossible to assemble the data
correctly with short reads.
“Any large human genome sequencing projects using
only short-read technology are not going to acquire
usable data for these complex regions, it’s as simple
as that,” he said. For complex regions, “you’ll need
long-read data,” he said, “The long-read data will give
you really what everybody has been after all along
without realizing it. It will give you the phase and
all the detail on the polymorphism in these highly
polymorphic regions.”
PacBio Is Ready to Handle the Challenge
The Future Is Bright
Geraghty said that with recent technology
improvements, PacBio data is “really high quality” and
“as good or better than Illumina and Sanger,” noting
that his group has compared all three technologies
with the same sequences. “It opens up a whole new
possibility,” he said, because previously “you simply
weren’t getting all of the data. People were using
statistics to impute missing data and so on, and it
simply hasn’t worked.”
Geraghty expressed his excitement about the future
using long-read sequencing this way: “We’re hot on
the trail. We basically see the entire picture; we are
not looking under a lamp post for the keys. It’s daylight
and we can see the whole neighborhood. So we’re
going to find the keys.”
The Challenge With Short Reads
The full interview can be found at www.Mendelspod.com
www.pacb.com/hla
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