Because of known population stratification between CEU and YRI, this is a reasonable rare variant burden test.
This assumption is reasonable unless the variant is, for example, part of a variable duplicated site, in which case an individual may actually carry three alleles.
This assumption may be reasonable for rare variants when the phenotype being studied reduces fitness.
Importantly, both g.-2945A>G g.-2945A>G7G>T reside within the proximandpromoter (PPR) and g.-1767G>T g.-1767G>Tthin the 3′-UTresidech makes each of these variants reasonable candidates for putatively regulatory hypomorphic mutations.
The exact role of TNF genetic variation on mammographic density is thus unclear, however, if inflammation is an important aspect of breast cancer development, then it seems reasonable that TNF variants may play a role.
We therefore propose that 3-fold increase in mutation rate over the wild-type is the reasonable threshold between harmless variants on one side, and the variants with reduced MMR activity that may contribute to cancer susceptibility on the other side of a threshold.
While this is an efficient method to rule out the vast majority of variants, and is reasonable in scenarios where the disease-causing variant is hypothesized to be novel, it may be overly restrictive.
Upon evaluating 2D7 recognition of the azF-CCR5 variants, we found reasonable binding of 2D7 to all azF variants, except those in positions 171 173 and 178.
50 52 Amyloid-β precursor protein and embryonic myosin variants showed reasonable q values between 20% and 40% (data not shown).
Although this assumption is reasonable for single-nucleotide variants (SNVs), a microsatellite targeted by selection will reliably violate this assumption due to high mutation rate.
In summary, our investigation indicates that merging the low heterogeneous duplicated WES data within each subject into a single sample and then conducting SNP calling are a reasonable strategy to discover variants from the next generation sequencing technology.
