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

Abstract

Background Long-term selection experiments are a powerful tool to understand the genetic background of complex traits. The longest of such experiments has been conducted in the Research Institute for Farm Animal Biology (FBN), generating extreme mouse lines with increased fertility, body mass, protein mass and endurance. For >140 generations, these lines have been maintained alongside an unselected control line, representing a valuable resource for understanding the genetic basis of polygenic traits. However, their history and genomes have not been reported in a comprehensive manner yet. Therefore, the aim of this study is to provide a summary of the breeding history and phenotypic traits of these lines along with their genomic characteristics. We further attempt to decipher the effects of the observed line-specific patterns of genetic variation on each of the selected traits. Results 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. Whole genome sequencing analysis on 25 animals per line revealed line-specific patterns of genetic variation among lines, as well as high levels of homozygosity within lines. This high degree of distinctiveness results from the combined effects of long-term continuous selection, genetic drift, population bottleneck and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits. Conclusions The genomes of the Dummerstorf trait-selected mouse lines display distinct patterns of genomic variation harbouring multiple trait-relevant genes. Low levels of within-line genetic diversity indicate that many of the beneficial alleles have arrived to fixation alongside with neutral alleles. This study represents the first step in deciphering the influence of selection and neutral evolutionary forces on the genomes of these extreme mouse lines and depicts the genetic complexity underlying polygenic traits.

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

“…1186/ s12915-022-01248-9. *Correspondence: serpalma.v@gmail.com 1 Institute of Reproductive Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany Full list of author information is available at the end of the article • fast, convenient online submission • thorough peer review by experienced researchers in your field…”

Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes

“…However, the latter strains, have no lean counterparts derived from the same base population. Prolonged selective breeding of inbred mice for desired divergent phenotypes produces novel, polygenic, and reproducible models of disease (Saul et al 2019 ; Palma-Vera et al 2022 ).…”

Alterations in gonadotropin, apoptotic and metabolic pathways in granulosa cells warrant superior fertility of the Dummerstorf high fertility mouse line 1

“…FL1 mice are neither transgenic nor knockout mice, but are selected for increased litter size and total birth weight of the litters for more than 200 generations. During the selection process, FL1 mice almost doubled the number of pups per litter compared to the unselected control line (ctrl) with no signs of growth retardation in the offspring [17][18][19]. FL1 mice ovulate approximately twice as many oocytes compared to ctrl mice [20,21].…”