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Hello, everybody.
My name is Nicholas Katsanis.
I am the director for the Center
for Human Disease Modeling at Duke
University and I am a
professor in the Department
of Cell Biology and Pediatrics.
My interests focus on how does
the genotype match the phenotype
in humans and how can you use
a mixture of technologies,
such as sequencing and
implementation of model organisms,
to understand causality
in human genetic disease
and complex genetic interactions?
Today, I will be giving a lecture
that is focused on ciliopathies
and the lessons that we've
learned in oligogenic phenomena
during our journey.
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Before I begin, I really thought
I should highlight some questions
that have really persisted
during the last hundred years,
truly since the discovery
of Mendel's laws.
If we think fundamentally
about the types of questions
that we're all trying to
investigate, while in the old days,
we used to use things like
karyotyping, in the modern days,
we try to address these
problems with next generation
sequencing and tools of that sort.
Nonetheless, the questions have
remained fundamentally the same.
The first question is what
variants cause disease?
And of course, we're
dealing with humans,
but the question naturally applies
to all model organisms as well.
It is fair to say that we
have made significant, rather
impressive progress in that regard.
We have identified thousands of
alleles in thousands of genes that
are associated causally with both
common and rare genetic disorders.
However, there's a
second question here,
and this question is,
what variants might
be associated with
disease modulation?
That question is both
harder and has proven
to be more difficult
to track experimentally
for a number of
reasons, some of which
I will highlight later in my talk.
And of course, the
subtext of all this
is, is there a difference
between alleles that appear
to be genetically sufficient
to cause a disease
and alleles that appear
to confer susceptibility,
or interaction, or epistasis,
or some of these perhaps used
to be exotic phenomena
in human genetics?
So the fundamental question
underneath all of this
is, we have always tried
to understand the effect
of a single allele on a
single gene in a vacuum.
However, it is important that
we remember that the presence
of rare alleles highly
directly resembles,
and the context, of course,
is going to be important,
but everything occurs in the
context and in the backdrop
of the entire genome, the epigenome,
and of course the environment.
Indeed, one of the greatest
difficulties that we have
at the moment is we cannot
really discern context-dependent
effect of alleles on the phenotype.
