We hypothesize that these mutations gradually accumulated via multiple pathways, with variants containing all five hotspot mutations (U25A+C26A+G54A+U193C+U281A), or 4 of the 5 mutations (U25A+C26A+G54A+U281A), eventually becoming predominant in the population.
The observed redundancy in sugar-specific TFs is explained by (i) non-orthologous replacements of TFs for the same pathway in different genomes, and (ii) existence of alternative pathway variants and multiple paralogs regulated by different TFs in the same genome.
Finally, as discussed in Section 3.2.2, it is possible to examine genetic confounding through pleiotropy (i.e. variants influencing multiple pathways) or LD (i.e. variants being co-inherited) in more detail, using multiple combinations of genetic variants in different IV specifications.
For example, the tricarboxylic acid cycle (TCA) cycle has at least eight pathway variants associated with different taxonomic groups and several incomplete or reversible forms that share multiple reactions steps.
Moreover, a fine-grain functional annotation of all protein families (including those with multiple branches and paralogs) that comprise carbohydrate utilization machinery in complete genomes will enable accurate recognition of the corresponding functions and pathway variants in metagenomic samples.
Cytoskeletal functions were also highlighted with DISC1 'cis' variants, 'all DISC1 pathway variants' and 'all associated variants'.
Further characterization of the observed associations has enabled us to infer that SLI represents a qualitatively distinct disorder caused by a combination of genetic variants that disrupt multiple pathways important to the development of language.
We divide the possible mechanisms into 2 cases: 1) vertical pleiotropy, where a variant is associated with multiple risk factors due to the causal effect of the primary risk factor on a secondary trait, and 2) functional pleiotropy, where the genetic variant is associated with multiple pathways.
Queries requesting the reactions and pathways associated with kinases harboring RD pocket variants reveal that CHEK2 controls multiple pathways associated with cell cycle control and DNA damage repair upon activation loop phosphorylation [Xu et al., 2002] (Table 1).
In particular, the H1/H2 genotype is weakly associated with type 1 diabetes and Crohn's disease risk (14) which indicates that variants on this large haplotype may affect multiple pathways.
