The world's longest selection experiment on mice provides unique animal models for exploring the architecture of polygenic traits


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

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.

At the Research Institute for Farm Animal Biology (FBN) in Dummerstorf, Germany, a unique set mouse lines were generated over the course of more than 50 years of artificial selection. These lines have evolved impressive phenotypes of high fertility, body size and endurance fitness. To our knowledge, this is the longest selection experiment ever conducted on mice and we were keen on peering into the genomes of these unique animals, in order to uncover known and new loci associated to the traits under selection.

The traits litters size (mouse lines DUK and DUC), body mass (DU6), protein mass (DU6P) and running distance (DUhLB) have increased consistently since the beginning of the selection experiment. Most traits were also measured in the control line FZTDU, but for some lines, other comparable un-selected lines were employed (Duks, DUKB). Figure adapted from [1].

As a population adapts to a selective pressure, the alleles responsible for adaptation become more and more frequent over time. To identify the subtle allele frequency changes underlying complex traits, neutral evolution needs to be rigorously modelled, requiring genetic information not only from the present population but also from ancestral populations, ideally the founders. 
Despite the fact that the Dummerstorf mouse lines are outbred mouse populations, we found high levels of inbreeding within each line, resulting from genetic drift after a severe population bottleneck in 2011. Consequently, selected mice are highly homozygous, while at the same time, lines are genetically uniform and distinct from each other. 

Proportion of the genome in homozygosity (left), averaging more than 60% for the selected lines and almost 50% for the control line FZTDU. Selected lines have also become highly divergent from each other (right). This genetic divergence stems from artificial selection, but also from genetic drift. Figure adapted from [1].

Since genetic information from ancestral generations was not available (this experiment was started in 1969, before the genomic era) and pedigrees were incomplete, detection of signatures of selection was practically impossible. It was also unfeasible to know if response to selection resulted from large- or small-effect alleles, though the complex nature of the selected traits led us to infer that the former is rather unlikely.
The historical resources at our disposal were thus limited, so we tried to come up with an alternative approach that would at least give us an idea of which genes could be involved in the evolution of the selected traits. First, we obtained the genomewide genetic differentiation of each selected line relative to the control line (the control line as a proxy of the founder population, exposed only to genetic drift). We then looked for regions of line-specific high genetic differentiation, each one corresponding to a genomic location in which only the target line is highly differentiated from the control line, while all remaining lines are undifferentiated. This approach revealed a number of candidate genes, some of which are already known to be relevant in the biology of fertility, body mass, muscle growth, and endurance.

For each selected line, there are specific regions of extreme genetic differentiation relative to the control line FZTDU (encircled data points). For the rest of the lines (bottom of the plot), these same regions show almost no genetic differentiation (compared to FZTDU). This approach allowed the detection of multiple genes with known functions affecting the selected traits, some of which are shown in the figure. Figure adapted from [1].

Though we understand that the lack of a proper neutral model prevents us from taking these results as final, these are promising discoveries awaiting validation. We hope that within the next years, the hidden trait-associated alleles within the genomes of these unique mouse models can be uncovered.

1.     Palma-Vera SE, Reyer H, Langhammer M, Reinsch N, Derezanin L, Fickel J, et al. Genomic characterization of the world’s longest selection experiment in mouse reveals the complexity of polygenic traits. BMC Biol. 2022;20:52. 

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