Importantly, similar to the newly discovered genetic variants of large effects, most genetic disorders are associated with ASD only in a fraction of affected subjects, thus the defining variants in these disorders also display incomplete penetrance.
As is evident from the calculations, there is a wide range of estimates for the time necessary to generate the New World defining variants, i.e. averages range from ∼6,000 to ∼25,000 years.
In the absence of a biphasic skyline plot, we can calculate first approximations of the time necessary to generate the defining variants for the New World mithochondrial founding haplogroups.
Variability estimation reported in the human mitochondrial database and predictions of pathogenicity [ 20- 22] were also applied to non-haplogroup defining variants, revealing an intriguingly heterogeneous scenario among populations.
We used LDSelect version 1.0 (17) across 22 2 Mb windows (one per autosomal chromosome) to estimate the average number of independent variants (MAC ≥ 4) we would expect to observe, defining variants as independent if their pair-wise r cut-off <0.8.
This approach takes into consideration the limited ability of Affymetrix platform to precisely define variant breakpoints and the difference between the discovery and the validation platform probe length (25-mers versus ∼60).
We defined variant accuracy (VA) as the percentage of homoplasmic and heteroplasmic variant calls by Sanger that were concordant with 454 vs. total number of variants found by both technologies; we calculated variant accuracy as VA = (B2 + C3) / (A2 + A3 + B2 + B3 + C2 + C3).
In addition, the LD pattern in Africans is sufficiently different from Europeans so that LD relationships in African Americans may be substantially different with a trait-defining variant, thus obscuring the true relationship.
Variability scores contributed to the recognition of private variants or mutations with a potential pathogenic role: they ranged from 0 to 1, where low variability values may be suggestive of a novel haplogroup-defining variant or a rare disease-linked mutation, while high variability scores were owned by common alleles within genomes stored in HmtDB.
A non-skeptical reading of the literature would define variant SCN5A-G615E as a known pathogenic variant.
