Abstract
Over 500 strains of inbred brown rats (Rattus norvegicus) have been developed for use as a biomedical model organism. Most of these inbred lines were derived from the colony established at the Wistar Institute in 1906 or its descendants following worldwide distribution to research and breeding centers. The geographic source of the animals that founded the Wistar colony has been lost to history; thus, we compared 25 inbred rat strains to 326 wild rats from a global diversity dataset at 32 k SNPs, and 47 mitochondrial genomes to identify the source populations. We analyzed nuclear genomic data using principal component analyses and co‐ancestry heat maps, and mitogenomes using phylogenetic trees and networks. In the nuclear genome, inbred rats clustered together indicating a single geographic origin for the strains studied and showed admixed ancestral variation with wild rats in eastern Asia and western North America. The Sprague Dawley derived, Wistar derived, and Brown Norway strains each had mitogenomes from different clades which diverged between 13 and 139 kya. Thus, we posit that rats originally collected for captive breeding had high mitochondrial diversity that became fixed through genetic drift and/or artificial selection. Our results show that these important medical models share common genomic ancestry from a few source populations, and opportunities exist to create new strains with diverse genomic backgrounds to provide novel insight into the genomic basis of disease phenotypes.
Highlights
Brown rats (Rattus norvegicus) have been used as medical models for a diverse array of biomedical studies including those in physiology, neurology, behavior, nutrition, surgery, and toxicology
Within the 25 inbred rat strains that we investigated, the nuclear genomes formed a single genomic cluster of admixed Asian ancestry (Figure 2); neither of our hypotheses were supported
Posterior 1.00 0.58 1.00 1.00 0.76 0.72 1.00 0.90 0.99 1.00 1.00 1.00 first hypothesized that inbred rats would cluster with Western Europe genotypes due to an assumption that colonies were founded by wild rats closest to the researchers in Europe and the USA that initially developed experimental colonies
Summary
Brown rats (Rattus norvegicus) have been used as medical models for a diverse array of biomedical studies including those in physiology, neurology, behavior, nutrition, surgery, and toxicology. Not all rat strains have Wistar ancestry; for example, Maynie Rose Curtis produced several inbred lines including Fisher 344, Marshall 520, and August 7,322 from stocks she received from breeders, where the breeder’s name became the name of the line She produced the Avon and Copenhagen lines that were named for cities in Connecticut, USA, and Denmark, respectively (Lindsey & Baker, 2006). The history of the rat colony at the Wistar Institute suggests multiple putative origins of rats including countries in Western Europe where rat studies began in the mid-1800s, Chicago, USA, and/or Philadelphia, USA. Strains such as the Copenhagen were known to be sourced from Denmark; we hypothesize that inbred lines will share evolutionary similarity with multiple geographic locations
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