Biology Reference
In-Depth Information
Generally, prior to identification of causal genes, we must first localize
a QTL to a restricted genomic region. In the absence of complete sequence
information for all study participants (which still lies in the future in
terms of technical and economic feasibility), gene localization depends
either on the random effect of known genetic markers assessed via
linkage, or the main effect of the markers via association.
In linkage analysis, we expand the standard variance component
model for a pedigree to also include an additional component that reflects
the chromosomal location-specific relatedness among individuals. This
new structuring matrix, the so-called IBD matrix (for identity by descent
probability matrix) must be calculated from genome-wide genetic marker
information such as highly polymorphic short tandem repeat (STR)
markers or, now more commonly, from high density SNP marker sets.
Allowing for location-specific QTL effects at location l in the genome, we
now write the covariance model as:
U ¼ð2Fh r þ P l h 2 Ql þ Ie 2 Þs p
(12.3)
where P l refers to the estimate of the IBD probability matrix at position l
in the genome, h 2 Ql is the heritability due to the QTL, and h r refers to the
remaining residual heritability after controlling for the QTL (and any
covariates). If h 2 Ql is significantly greater than zero (using the same like-
lihood ratio test for a single variance component as described above), then
there is evidence for a QTL at genomic position l that influences worm
burden. One quirk of the field must be noted here. Instead of using
a standard LRT statistic for tests of linkage hypotheses, we utilize the
statistic LOD
LRT/(2 ln(10)). The localization of a human QTL is typi-
cally imprecise. This precision is noted by the 1-LOD support interval
which is the region which captures a one-unit LOD score drop around
a given QTL peak. This area is typically 10
¼
15 cM in studies of humans.
e
Thus,
linkage-derived QTL regions typically involve approximately
10
15 Mb of human genome sequence.
Association methods can also be used to identify QTL regions using
genome-wide high density SNP arrays. This approach depends upon
alleles shared, not necessarily IBD, but identical by state (IBS). If a marker is
physically close enough to a functional variant, linkage between the
functional and marker alleles will not be disrupted by meiotic recombi-
nation: that is, the alleles are in linkage disequilibrium (LD 36 ). Association is
conceptually and mathematically simpler than linkage analysis: associa-
tion analysis is typically based on measured genotypes (MG) either for
individual markers (often diallelic single nucleotide polymorphisms,
SNPs, which are closely spaced throughout the human genome), or on
haplotype blocks of marker alleles in high LD. In family-based studies,
association may be measured as the main effect of the measured genotype
e
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