A module is a group of closely related proteins that act in concert to perform specific biological functions through protein–protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.

An elevated plasma apolipoprotein B (apoB) level is a strong predictor of atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F 2 and N 2 (backcrossed) offspring (n ‫؍‬ 572) derived from crosses between the B6 and 129 mouse strains. These loci were designated ApoB regulator genes ( Abrg ), because the gene products are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, designated Abrg1 , was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker ( ϳ 45.9 cM). Abrg1 contributed approximately 35% of the genetic variance. The second locus, designated Abrg2 , was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker ( ϳ 35 cM). Abrg2 contributed approximately 26% of the genetic variance. Epistasis between Abrg1 and Abrg2 was detected and accounted for approximately 12% of the genetic variance. The combination of these two QTL has major effects ( Ͼ 70%) on the regulation of plasma human apoB levels in the tested population. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candidates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia.