Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources

Abstract

Zhang-James Y, Middleton FA, Faraone SV. Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources. Physiol Genomics 45: 528 -538, 2013. First published May 14, 2013 doi:10.1152/physiolgenomics.00002.2013.-The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders.WKY; SHR; autism; ADHD; inbred rat; animal models; SNP; behavior THE SPONTANEOUSLY HYPERTENSIVE rat (SHR) is an inbred strain established from outbred Wistar rats selected for high blood pressure (8a). Although the SHR develops hypertension spontaneously at the age of 7-15 wk (36), prior to this age they have been used and validated as a model for attention deficit/hyperactivity disorder (ADHD), demonstrating all three ADHD core symptoms: hyperactivity, impulsivity, and inattentiveness (25, 28). The Wistar-Kyoto (WKY) strain was established from the same parental Wistar stock as the SHR and as a result has been commonly used as a control strain for the SHR (8a). Notably, however, the sources of WKY rats often varies between studies, and significant variability in the comparative results that employed these substrains has been noted, probably because the WKY breeding stock was distributed to different breeders prior to being fully inbred (11,13,21). In addition, the littermate pairings that produced the inbred WKY from the Wistar rat were initiated Ͼ10 yr after the inbreeding for the SHR was initiated (13), thus increasing the heterogeneity between the WKY and SHR and leading some to question the validity of the WKY as a control strain for SHR (30). ...

Effect of variation in BDNF Val66Met polymorphism, smoking, and nicotine dependence on symptom severity of depressive and anxiety disorders

“…In a recent animal model of depression, nicotine administration exacerbated depressive-like behavior in inbred Wistar-Kyoto (WKY) rats, which had reduced hippocampal volume but not in the control Wistar rats with comparatively large hippocampal volume (Tizabi et al, 2010). Research has also shown greater genotypic variability among WKY rats compared to other inbred strains Zhang-James et al, 2013). It has been proposed that the differential responses of WKY and Wistar rats to nicotine may reflect genetic differences (Tizabi et al, 2010).…”

Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD

“…Of note, WKY from Charles River/GER, a model for the predominantly inattentive subtype of ADHD (Sagvolden, Dasbanerjee et al 2008), have a large number (35%) of discordant SNP genotypes relative to WKY from Harlan/UK, a well-recognized control for SHR (Sagvolden, Johansen et al 2009). In contrast, WKY from Charles River/US have a small number (2.5%) of discordant SNP genotypes relative to WKY from Harlan/UK (Zhang-James, Middleton et al 2013), and are not expected to differ from WKY from Harlan/UK. Thus, WKY from Charles River/US were used as the inbred control herein.…”

Autism-related behavioral phenotypes in an inbred rat substrain

“…In contrast, even other lines within the WKY and SHR lineages differed in more than 20–30% of the genome. In addition, we found that their genomic regions tagged by the small numbers of polymorphic SNPs were highly enriched for ASDs candidate genes and pathways involved in brain development and neuronal functions [12]. Although SNP-based analyses can only estimate the possible divergent genomic regions, and cannot reveal the actual causal genetic variants, our analysis suggests that there could be potential differences in genes related to ASDs, thus affecting brain functioning and behavior.…”

“…Although SNP-based analyses can only estimate the possible divergent genomic regions, and cannot reveal the actual causal genetic variants, our analysis suggests that there could be potential differences in genes related to ASDs, thus affecting brain functioning and behavior. Indeed, re-sequencing verified that two known risk genes for ASDs and ADHD in the estimated regions,SLC9A9 and SLC6A3, harbor genetic variants that could be functional [12]. Unfortunately, these two substrains have been used interchangeably in previous research and almost no study, except one examining stress-response[13], has directly compared the two.…”