Origins of albino and hooded rats: implications from molecular genetic analysis across modern laboratory rat strains - PubMed (original) (raw)

Origins of albino and hooded rats: implications from molecular genetic analysis across modern laboratory rat strains

Takashi Kuramoto et al. PLoS One. 2012.

Abstract

Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ∼460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (h(i)) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Linkage and haplotype mapping of the hooded (H) locus.

Left: Haplotypes of backcross progeny carrying the recombinant chromosome between D14Rat84 and D14Got40. The grey boxes represent rats homozygous for genetic markers, while the white boxes represent rats heterozygous for genetic markers. The coat pattern phenotypes of the progeny and the number of the progeny for each haplotype are described above and below the haplotypes, respectively. The H locus was narrowed down from D14Rat13 to D14Got40 (boxed with a solid line). Right: SNP haplotypes around the H locus in representative inbred rat strains. Two hooded rat strains and one Irish rat strain shared the identical haplotype of the genomic region between ENSRNOSNP2799338 and ENSRNOSNP2799342. The genomic region that was shared among the four self strains was narrowed down from ENSRNOSNP2799339 to ENSRNOSNP2799341 (boxed with a solid line). The linkage and haplotype analyses demonstrated that the hooded locus was mapped to the region defined by D14Rat13 and ENSRNOSNP2799341 (boxed with a dashed line).

Figure 2

Figure 2. Physical position of the hooded mutation.

The hooded mutation spanned to the 92 kb region defined by D14Rat13 and ENSRNOSNP2799341 (boxed in red). This region contains the upstream region and five exons of the rat Kit gene (black arrow). The hooded critical region was covered by BACs that contain F344/Stm, LE/Stm and ACI/NJcl genomic DNAs. Grey bars represent the regions covered by BACs. Grey squares represent positions of the SSLP or SNP makers examined.

Figure 3

Figure 3. Insertion of the ERV into intron 1 of the rat Kit gene.

A: Position and organization of the ERV insertion found in intron 1 of the rat Kit gene. The insertion was located 8,054 bp upstream of exon 2. The ERV sequence with 2 LTRs on both ends was found in the “hooded” strains. The solitary LTR sequence was found in the “Irish” strains. A set of primers (indicated by solid arrows) was designed to detect the absence of the ERV insertion and the presence of the solitary LTR sequence. A set of primers (indicated by dotted arrows) was designed to detect the presence of the ERV insertion. B (Left): PCR product obtained with the rKit-ERV-neg primer set (solid arrows). A 1,006 bp product was obtained from the BN (self) genome and a 1,590 pb product was obtained from the ACI (Irish) genome. Meanwhile, no products were obtained from the F344 (albino, hooded) genome and the LE (hooded) genome. (Right): PCR products obtained with the rKit-ERV-posi primer set (dotted arrows). Products 997 bp in size were obtained from the F344 genome and the LE genome, while no products were obtained from the BN genome and the ACI genome. M; 100-bp ladder molecular marker.

Figure 4

Figure 4. Possible scenarios for the establishment of the albino and hooded rat strains.

Scenario 1: The rat albino (299His) mutation occurred in a rat of the hooded (piebald) rat stock. From the stock, the albino stock was established. Then they were introduced into the Wistar Institute and some albino rats were used for the establishment of the Wistar-independent stocks. Scenario 2: The albino stock that can be traced back to an albino rat that carried the 299His mutation and the hooded (piebald) stock were independently established. Crossing occurred between the albino and the hooded stocks. In the resultant stocks of this cross, albino rats that carried either the hooded (h) or self (H) allele must be present. The albino rats with the particular genotype (h/h, c/c) were “by chance” selected and used to establish the albino rat stock. Such new-established albino stock was introduced into the Wistar Institute and some rats from it were used for the development of the Wistar-independent albino stocks.

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This work was supported in part by Grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science (21300153 to T. Kuramoto), a Grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare, and the Fujiwara Memorial Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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