Genomic characterization of world’s longest selection experiment in mouse reveals the complexity of polygenic traits

Abstract

A unique set of mouse outbred lines has been generated through selective breeding in the longest selection experiment ever conducted on mice. Over the course of >140 generations, selection on the control line has given rise to two extremely fertile lines (>20 pups per litter each), two giant growth lines (one lean, one obese) and one long-distance running line. Genomic analysis revealed line-specific patterns of genetic variation among lines and high levels of homozygosity within lines as a result of long-term intensive selection, genetic drift and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits. We conclude that the genomes of these lines are rich in beneficial alleles for the respective selected traits and represent an invaluable resource for unraveling the polygenic basis of fertility, obesity, muscle growth and endurance fitness.

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

“…Based on the phenotypic analysis, we hypothesized that several genetic alterations in Titan mice would translate to the observed phenotype (metabolic regulation, weight and size). We first assessed the genetic differentiation associated with the Titan mouse, in comparison to the control unselected line but also to other Dummerstorf long-term selected mouse lines 9 . For this, we used the whole genome sequencing data recently generated from the 'Dummerstorf mouse lines' 9 .…”

“…We first assessed the genetic differentiation associated with the Titan mouse, in comparison to the control unselected line but also to other Dummerstorf long-term selected mouse lines 9 . For this, we used the whole genome sequencing data recently generated from the 'Dummerstorf mouse lines' 9 . We first re-analyzed regions of distinct genetic differentiation (RDD) unique to Titan mice and identified 84 genes (Table S1).…”

“…The initial population of mice was created in 1969/1970 by crossing four outbred and four inbred populations 6,7 creating a non-inbred mouse line (FZTDU) with a polygenetic background. Based on this polygenetic mouse line, the selection for high body mass started in 1975 with every generation consisted of 60-80 mating pairs 8,9 (see Methods). Importantly, an unselected population was maintained as a control group throughout the selection process 9 .…”

“…Based on this polygenetic mouse line, the selection for high body mass started in 1975 with every generation consisted of 60-80 mating pairs 8,9 (see Methods). Importantly, an unselected population was maintained as a control group throughout the selection process 9 .…”

“…Since body mass and lifespan are two traits known to be inversely correlated to each other 23 , we also assessed whether the lifespan of Titan mice was shortened compared to control mice. In addition, we used recently published genomic sequence data to link several phenotypic features of the mouse line to their specific genetic differentiation caused by the selection procedure 9 . Furthermore, since the liver is an organ central to lipid and carbohydrate metabolism, we evaluated possible molecular alterations in liver tissue.…”