Description
The phastBias gBGC tracks show regions predicted to be influenced by GC-biased gene conversion
(gBGC). gBGC is a process in which GC/AT (strong/weak) heterozygotes are preferentially resolved
to the strong allele during gene conversion. This confers an advantage to G and C alleles that
mimics positive selection, without conferring any known functional advantage. Therefore, some
regions of the genome identified to be under positive selection may be better explained by gBGC.
gBGC has also been hypothesized to be an important contributor to variation in GC content and the
fixation of deleterious mutations.
PhastBias is a prediction method that captures gBGC's signature in multiple-genome alignments:
clusters of weak-to-strong substitutions amidst a deficit of strong-to-weak substitutions. Due
to the short life of recombination hotspots, phastBias searches for gBGC tracts on a single
foreground branch. PhastBias is designed to pick up gBGC tracts of arbitrary length and to be
robust to variations in local mutation rate and GC content. It uses a hidden Markov model (HMM)
that can be thought of as an extension to the phastCons model. Whereas phastCons predicts
conserved elements using an HMM with two states (conserved and neutral), phastBias predicts gBGC
tracts using a four-state HMM (conserved, neutral, conserved with gBGC, neutral with gBGC).
One of the main parameters of the phastBias model is B, which represents the strength of
gBGC and the degree to which weak-to-strong and strong-to-weak substitution rates are skewed on
the foreground branch. The tracks presented here were created with B=3, which was chosen
for being sensitive while still having a low false positive rate. Simulation experiments suggest
that phastBias has reasonable power to pick up tracts with length > 1000bp, and very good
power for tracts > 2000bp. Nonetheless, other lines of evidence suggest that phastBias only
identifies approximately 25-50% of bases influenced by gBGC, so the tract predictions should not
be considered exhaustive.
Display Conventions
The phastBias tracks display separate predictions for both human and chimp lineages of the
phylogenetic tree (from the human-chimp ancestor). For each lineage, two tracks are available: a
wiggle showing raw posterior probabilities, and a BED track showing regions predicted to be
affected by gBGC.
The posterior probability track shows the probability that each base is assigned to either of the
gBGC states under the phastBias HMM.
The phastBias tracts show regions predicted to be affected by gBGC on a particular lineage. These
are simply defined as all regions with posterior probability > 0.5.
Methods
The phastBias tracks were predicted using the phastBias program, available as part of the
PHAST software package.
The phastBias tracks represent two separate result sets; one predicting gBGC on the branch
leading from the human-chimp ancestor to human, and the other on the opposite branch leading
to chimp. The software was run on human-referenced alignments of hg18, panTro2, ponAbe2, and
rheMac2, which were extracted from the hg18 44-way multiple alignment. Details are available in
Capra et al., 2013 (cited below). Briefly, the gBGC bias parameter B was
set to 3, the mean expected tract length was set to 1/1000, and the transition rate into gBGC
states was estimated by expectation-maximization. Most other parameter settings were set to the
same values used for UCSC's mammalian conservation tracts. Relative branch lengths came from this
placental mammal tree model,
the conservation scale factor was set to 0.31, expected length of conserved elements to 45, and
expected coverage of conserved elements to 0.3. The alignment was split into 10 Mb chunks; for
each chunk, a scaling factor for the neutral tree, the transition/transversion rate ratio, and
the background base frequencies were re-estimated using the PHAST program phyloFit. The final
tracts were filtered to remove elements with length ≥ 5000bp, as these are likely due to
artifacts unrelated to gBGC (repeats, alignment error).
The method was re-run on hg19 data, extracting hg19, panTro2, rheMac2, and ponAbe2 from the
46-way alignments. The chimp tracks were not re-created for hg19, since interest in them is lower.
References
Capra JA, Hubisz MJ, Kostka D, Pollard KS, Siepel A.
A model-based analysis of GC-biased gene conversion in the human and chimpanzee
genomes. PLoS Genet. 2013 Aug;9(8):e1003684.
PMID: 23966869; PMC: PMC3744432
Hubisz MJ, Pollard KS, Siepel A.
PHAST and RPHAST: phylogenetic analysis with space/time models.
Brief Bioinform. 2011 Jan;12(1):41-51.
PMID: 21278375; PMC: PMC3030812
Duret L, Galtier N.
Biased gene conversion and the evolution of mammalian genomic landscapes.
Annu Rev Genomics Hum Genet. 2009;10:285-311.
PMID: 19630562
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