It has long been assumed that most parts of a genome and most genetic variations or SNPs are non-functional with regard to reproductive fitness. However, the collective effects of SNPs have yet to be examined by experimental science. We here developed a novel approach to examine the relationship between traits and the total amount of SNPs in panels of genetic reference populations. We identified the minor alleles (MAs) in each panel and the MA content (MAC) that each inbred strain carried for a set of SNPs with genotypes determined in these panels. MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms, including life span, tumor susceptibility, learning and memory, sensitivity to alcohol and anti-psychotic drugs, and two correlated traits poor reproductive fitness and strong immunity. These results suggest that the collective effects of SNPs are functional and do affect reproductive fitness. collective effects, complex traits, minor alleles, SNPs, recombinant inbred lines, minor allele content (MAC) Citation:

We studied the collective effects of single nucleotide polymorphisms (SNPs) on transgenerational inheritance in Caenorhabditis elegans recombinant inbred advanced intercross lines (RIAILs) and yeast segregants. We divided the RIAILs and segregants into two groups of high and low minor allele content (MAC). RIAILs with higher MAC needed less generations of benzaldehyde training to gain a stable olfactory imprint and showed a greater change from normal after benzaldehyde training. Yeast segregants with higher MAC showed a more dramatic shortening of the lag phase length after ethanol exposure. The short lag phase as acquired by ethanol training was more dramatically lost after recovery in ethanol free medium for the high MAC group. We also found a preferential association between MAC and traits linked with higher number of additive QTLs. These results suggest a role for the collective effects of SNPs in transgenerational inheritance, and may help explain human variations in disease susceptibility.

Objective: The aim of this study was to investigate the shared molecular pathways of obesity and cancer by exploring the role of RIZ1 in obesity and the phospatidylinositol 3-kinase (PI3K)/V-Akt murine thymoma viral oncogene homolog (PKB) (AKT)/mechanistic target of rapamycin (mTOR) pathway. Methods: Male wild type (WT) and Riz1 2/2 mice (KO) were fed a standard diet (STD) or a high-fat (HF) diet for up to 8 months. These mice were studied for phenotypic and molecular changes. Results: Riz1 2/2 mice gained more weight on a HF diet compared to WT mice, with higher free fatty acid and increased visceral fat. Metabolic cage analysis of Riz1 2/2 mice showed lower oxygen consumption but no changes in food intake and ambulatory activity. Riz1 2/2 mice showed impaired glucose regulation but no change in insulin sensitivity. RNA-seq and quantitative RT-PCR analysis found altered expression in certain glycolysis and ATP production genes such as Ubiad1, Atp5g2, and Cyp4a12. The PI3K/AKT/mTOR pathway was activated in the Riz1 2/2 mice fed a HF diet with higher Akt3 mRNA levels and increased phosphorylation of AKT (Ser473), mTOR, and S6. Conclusions: The results identify RIZ1 as an important regulator of both Akt3 transcription and AKT phosphorylation and suggest a role for RIZ1 in HF-induced obesity and the AKT pathway.