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households (environments). Using genetic markers, we have localized
several QTL influencing Ascaris burden in this population including
a major one on chromosome 13. Using common SNP variants, we further
localize potential functional variants to the region including the
TNFSF13B and IRS2 genes, both of which represent reasonable biological
candidate genes. Initial classical sequencing of the TNFSF13B coding (and
promoter) regions has identified a rare variant that is correlated with both
Ascaris burden and TNFSF13B gene expression levels (in PBMCs). Thus,
TNFSF13B continues to be an excellent candidate for partial explanation
of our original chromosome 13 QTL. However, this region (and other
genome regions harboring additional QTLs) still requires exhaustive
evaluation. Next-generation sequencing is dramatically changing our
approach to sequence variant detection and typing. Our current goal is to
perform whole genome sequencing in this population to capture all
existing genetic variation, both common and rare. It is becoming clear in
these early days of large-scale sequencing that there is a vast amount of
rare functional variation segregating in the human genome.
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What is the best way to study rare functional variation influencing host
susceptibility? Studies of very large pedigrees, such as the Jirel study,
represent the most powerful design for the identification of rare func-
tional variants. In fact, pedigrees are the only appropriate design for
studying the many private (i.e. occurring in only one lineage) functional
variants that occur in humans. For such rare variants, the extended
pedigree design is powerful because Mendelian transmission leads to
numbers of potential allelic copies greatly in excess of those expected
from random selection of unrelated individuals. Alternatively, conven-
tional epidemiological studies of unrelated individuals can only capture
a single copy of such private variants by definition, a result that is not
amenable to statistical inference. We already have preliminary evidence
that such rare variants may be the underlying source of our chromosome
13 Ascaris burden QTL.
Figure 12.4
shows the results of lineage-specific quantitative trait linkage
analysis in the Jirel pedigree for chromosome 13. Such analyses (using
a standard pedigree-based association model in which the founder-specific
IBD probability vector is the focal covariate) examine the potential for
a given founder to have transmitted a unique rare variant to his descen-
dants that correlates with Ascaris burden. Examination of approximately
100 of the largest male founder lineage reveals that our original linkage
signal is driven by two such lineages. (The results for females are similar, as
=
FIGURE 12.4
Results of lineage-specific quantitative trait linkage analysis to search for
evidence of rare functional variants. Panel A shows the results for founder A90; panel B
shows the results for founder FD304. Both founders appear to be transmitting rare func-
tional variants near the previously identified chromosome 13 Ascaris burden QTL.
