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is expected in a largely monogamous population.) These two lineages, A90
and FD304, are the only ones that show genome-wide significant linkage to
this region. Founder A90 has nine measured descendants that when
transmitted a hypothetical variant in this genome region exhibit substan-
tially higher Ascaris burdens (p
10
5
). Similarly, founder FD304 has
21 measured descendants that also exhibit significantly higher Ascaris
burdens (p
¼
2.8
10
4
) when transmitted such a variant in this region.
This result suggests that at least two rare functional variants are segre-
gating through the pedigree. These variants may or may not be in the same
gene. Such rare variants are generally not in linkage disequilibrium with
other sequence variants and therefore need to be directly identified and
genotyped. Only through whole genome sequencing will we be able to
identify such functional variants contributing to our existing (and still to be
found) QTLs influencing Ascaris burden.
The field of human complex disease genetics is rapidly moving
towards the measurement of comprehensive genetic information that is
only possible with whole genome sequencing. The coming availability of
such important data will mean that we no longer have to rely upon signals
resulting from correlated surrogate non-functional genetic variation to
find regions likely to harbor genes influencing disease susceptibility. Our
future challenge will be to separate the functional wheat from the chaff in
as efficient a manner as possible. For diseases as complex as Ascaris
infection which involves host genetic, worm genetic, and environmental
factors, we believe that our focus on very large human pedigrees will offer
a good natural study design for identifying both common and rare
functional variants playing a role in disease burden.
¼
3.7
Acknowledgments
We gratefully acknowledge the Jirel people for their participation in our studies of
helminthic infection. The new data reported in this chapter were generated under protocols
approved by the University of Texas Health Science Center at San Antonio Institutional
Review Board and the Nepal Health Research Council. This work was supported by
National Institutes of Health grants AI44406, AI37091, HL045522, and MH59490. The
lymphocyte expression profiling was supported by a generous donation from the Azar/
Shepperd families with additional funds from ChemGenex Pharmaceuticals, Ltd. The work
presented in this chapter was conducted in facilities that were constructed with partial
support from NIH grants C06 RR017515 and C06 RR013556.
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