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• W2975601983 abstract "EditorialWill the real Dahl S rat please stand up?John P. Rapp and Michael R. GarrettJohn P. RappDepartment of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio and Michael R. GarrettDepartment of Pharmacology, University of Mississippi Medical Center, Jackson, MississippiPublished Online:07 Nov 2019https://doi.org/10.1152/ajprenal.00359.2019This is the final version - click for previous versionMoreSectionsPDF (177 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat TO TELL THE TRUTH“To Tell the Truth” was a classic television game show that ran from 1956 to 1978 with the basic premise that three challengers were introduced, all claiming to be the “central character.” The announcer would ask the challengers, standing side by side, “What is your name, please?” Each challenger would answer, “My name is [central character's].” After questioning was completed by a celebrity panel, each member would vote on which of the challengers they believed to be the central character. Once votes were in, the host would ask, “Will the real [person's name] please stand up?” The central character would, usually with playful feigning among the challengers, stand. Interestingly, during this same period of time, the Dahl salt-sensitive (S) rat was being developed as a model of salt-sensitive hypertension by Lewis Dahl, and most relevant to this analogy is that there have been several other “Dahl S strain challengers” used and/or commercialized (SS/Jr, SS/Iwai, SS/JrHsd, SS/JrHsdEnv, SS/JrHsdMcwi, and SS/JrHsdMcwiCrl). Variability and inconsistency in blood pressure (BP) have been noted in commercially available Dahl S rats (62, 85), particularly related to salt sensitivity and susceptibility to kidney injury, with some claiming that the “Dahl S” rat is exhibiting a new and previously unobserved enhanced BP phenotype (SS/JrHsdEnv) (53). To look at this from a different perspective, are all these “Dahl S” models really the same, and, if so, how is it that the “same” model exhibits such significant variability from study to study or investigator to investigator? Aside from the direct impact on researchers that use the Dahl S model, these issues are highly relevant to biomedical research as animal models play a significant role in understanding human health and disease. This article will discuss how the various “Dahl S” strains are similar, why they may be different, and whether these factors can ultimately impact study conclusions.RIGOR AND REPRODUCIBILITYIn recent years, the National Institutes of Health (NIH) has placed significant emphasis on the concept of “Rigor and Reproducibility.” Rigor, as defined by the NIH, is the “strict application of the scientific method to ensure unbiased and well-controlled experimental design, methodology, analysis, interpretation and reporting of results” (https://grants.nih.gov/policy/reproducibility/index.htm). This concept is a cornerstone of research as it allows for research findings to be confirmed and extended by others to move scientific discovery forward. In particular, “Rigor and Reproducibility” has become a significant topic in research studies involving animals as they are overwhelmingly used to investigate diseases relevant to humans. In recent years, standards of reporting animal research as well as specific requirements for publication have been adopted to address these issues (41, 66, 80). In the United States, ~1 million animals [covered by the Animal Welfare Act (1)] are used for research annually, with estimates in the millions for mice and rats (31). Of all research published in 2018, ~14% involved animal research (based on PubMed), with almost 20% of funded NIH research involving animal models (NIH Reporter). With the issue of “Rigor and Reproducibility” in mind, it is vitally important that studies involving the Dahl S model and animal models in general are conducted with consideration of important factors, including strain fidelity/genetic purity, breeding paradigms, diet, and environment, as well as the reporting of these factors in grants and publications.ORIGIN OF THE DAHL S RAT MODEL BY SELECTIVE BREEDINGLewis K. Dahl was a physician whose first work was clinical in nature. One of Dahl’s earliest studies involving the association of salt (NaCl) and hypertension was conducted using groups of employees at Brookhaven National Laboratory in Long Island, NY. This work demonstrated that for employees classified on the basis of a survey of eating habits as low, intermediate, or high salt intake, the percentage of individuals with hypertension in each group was positively correlated with salt intake (15). A more dramatic correlation between actual average daily NaCl intake and the percentage of individuals with hypertension in five geographically defined populations from around the world [Inuit (termed “Eskimos” in the original publication) (Alaska), Marshall Islanders (Pacific), Americans (Northern United States), Japanese (Southern Japan), and Japanese (Northern Japan)] was reported by Dahl in 1960 (7, 8). [Note that reference (8) is a reprint from the original symposium.] These data produced the well-known graph showing a linear relationship between dietary salt and percentage of individuals with hypertension (7, 8).Armed with this epidemiological evidence and the wide variation in BP response of Sprague-Dawley rats to salt (47), Dahl began to selectively breed outbred Sprague-Dawley rats for their BP when fed a high-salt (8% NaCl) diet. After only three generations of selective breeding, there was a clear separation into two lines, one line selected for high BP (S rats) and one line selected for low BP [salt-resistant (R) rats] (10, 11). In the initial breeding experiment, brother-sister mating was practiced, but inbreeding was stopped and an extraneous undefined stock was introduced and selective breeding (without inbreeding) was practiced after three generations of selection (37). From 1962 to 1975, rats bred for experiments (without inbreeding) were produced without selection and only periodically selectively bred for salt sensitivity when the BP response to salt was observed to be reduced (L. K. Dahl, personal communication). This breeding paradigm has important theoretical consequences for the higher-order epistatic structure of inbred SS/Jr rats subsequently derived from the outbred S colony (discussed below in more detail).INBRED S RATS DERIVED FROM DAHL’S OUTBRED COLONYWhile Dahl’s selectively bred lines were informative for investigating the relationship between salt and BP, a limitation was that offspring at each generation exhibited a wide variation in BP among individual rats due to genetic heterogeneity from being outbred. Subsequently, both S and R rat lines were inbred (>20 generations of brother-sister mating) to ensure uniformity in the BP phenotype as well as for future utility in genetic studies. There were two independent derivations of inbred S and R rats, one derivation reported by Rapp and Dene (60) and the other derivation reported by Iwai and Heine (38). Inbred S and R rats reported by Rapp and Dene were produced by simply inbreeding (brother-sister mating) seven lines of S rats and five lines of R rats without any selection, starting with rats obtained from Dahl’s S and R outbred colonies. The rationale was that most of the high or low BP genetic factors were likely already fixed in the homozygous state or were at high frequency in the respective S and R stock as a result of the long, albeit intermittent, selection process and the finite size of Dahl’s colony. For R rats, at filial (F) generation 13 of inbreeding, all five lines were uniformly unresponsive to high-salt diet, so one line was chosen for completion of the inbreeding. S rats gave a somewhat more interesting result. At F8, the seven lines had differentiated clearly into two groups. Three lines had a BP response to high-salt diet in the range of 172–188 mmHg, and the other four lines had a BP response to high-salt diet in the range of 205–240 mmHg. One of the high-response S lines was selected for completion of inbreeding. These inbred rats were designated SS/Jr for the inbred Dahl S rat and SR/Jr for the inbred Dahl R rat.S and R rats independently inbred by Iwai and Heine (38) have been available only in Japan (79). SS/Iwai inbred rats are salt sensitive; however, in contrast to SS/Jr rats, SS/Iwai rats have been reported to remain normotensive on a low-salt diet (36, 38, 78). This could be the result of different selective breeding paradigms between Rapp and Dene and Iwai and Heine, although this is hard to determine because Iwai and Heine’s breeding protocol is not described (38).There are currently two colonies of authentic SS/Jr and SR/Jr rats at academic institutions in the United States and one colony in Canada, with animals from these colonies demonstrating consistent and reproducible phenotypes identical to the animals first inbred more than 30 yr ago. The term “authentic” is being used to denote the original strain as well as those directly established from the original colony [this term was previously used by others (75)]. These colonies belong to Bina Joe [Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences (UTCOM) (formerly the Medical College of Ohio), Toledo, OH] and Michael R. Garrett [Department of Pharmacology and Toxicology, University of Mississippi Medical Center (UMMC), Jackson, MS]. The UMMC colony was established in 2010. In addition, a third presumably authentic colony of SS/Jr rats is maintained by Alan Y. Deng (Departement de Medicine, Centre de Recherche, Centre Hospitalier de L’Universite deMontreal, Universite de Montreal, Montreal, QC, Canada). This colony was established from the UTCOM colony in 1998.CONSISTENT AND REPRODUCIBLE BP IN INBRED DAHL SS/JR RATSTo appreciate the properties of authentic SS/Jr rats, and to recognize when the original selected SS/Jr phenotype has been compromised, a brief description of the husbandry practices that have been successfully used for the past 34 yr to ensure a consistent phenotype will be discussed.In breeding SS/Jr rats to generate animals for subsequent experiments, the following protocol has been successful in eliciting a robust and consistent systolic BP response ranging from 180 to 200 mmHg without lethality. First, litters are culled to 8–10 pups at 3–4 days after birth to provide animals consistent in weight. Although weaning weight has only a small effect on BP (only in male rats), it does have a dramatic positive correlation to days survived on 8% NaCl diet in both male and female rats (16). That is, larger pups survive a salt challenge longer than smaller pups. Since the weight of pups at weaning is inversely proportional to litter size (16), it is important in many situations to control litter size. Additionally, breeder female SS/Jr rats are typically bred a single time because second-litter pups are smaller than first-litter pups due to hypertension and renal pathology (which may be related to less milk production) in breeder female rats despite their being maintained on a low-salt (0.2−0.4% NaCl) diet. Second, pups are weaned at 30 days of age (versus the typical 21 days) to ensure stronger animals more consistent in size and weight. Finally, to test salt sensitivity, experimental animals are provided an elevated but modest level of NaCl in their diet (2%) for 24 days starting at 45–48 days of age. While the percentage of salt in the diet can be altered (up to 8%) to elicit a more rapid BP response, for authentic SS/Jr rats a greater salt load significantly hastens morbidity and mortality (4, 5, 29, 63), which can impact experimental variability. For example, even though an 8% salt diet was used in the development of the model, an 8% salt diet is toxic to authentic inbred SS/Jr rats and all are dead before 8 wk on such a diet (60). Most importantly, the age at which a high-salt diet is started makes a difference in the BP response. Using the outbred S rats, Dahl showed very clearly that starting the high-salt diet at weaning resulted in a greater BP response than when it was started 3 or 6 mo after weaning (14). The phenomenon of increased response of young rats to various types of experimental insult is not unique to S rats or to salt-induced hypertension and has been reviewed in detail by Zicha et al. (83, 84). In addition to salt, there are other dietary factors that influence the BP response of S rats, including sources of protein, carbohydrates, and fat (26, 44, 45). It is therefore important to standardize diet, litter size, weaning age, and the age at which a diet is started in making strain comparisons and, most importantly, before comparing results between laboratories. Because all these variables influence the BP response to salt, it is critical that investigators only perform strain comparisons by studying the strains concomitantly in the same laboratory using a blinded protocol. It is also important to note that aside from these factors, there are other things that could impact comparison across studies, including differences in each strain’s microbiome (which could be animal facility specific and/or result from differences in diet) as well as likely epigenetic differences between strains (which could result due to shipping stress, multiple breeding, barrier versus conventional housing, or changes in diet from vendor vs. animal facility diet, among other factors).THE DAHL SS/JR MODEL, SPONTANEOUS/AGE-RELATED HYPERTENSION, AND RENAL INJURYAs noted above, authentic Dahl SS/Jr rats, even on a low-salt diet, develop spontaneous/age-related high BP. Thus, despite the Dahl SS/Jr model being selected for hypertension in response to a high-salt diet, genes/alleles that promote “spontaneous” or “aged” hypertension were also selected in the Dahl SS/Jr model. The major evidence for the development of hypertension on a low-salt diet is based on data from the initial characterization (60) and numerous studies that have investigated the progression of BP and kidney injury in the Dahl SS/Jr model on a 0.3% NaCl diet (21, 22, 27, 63, 71, 76, 82).In general, there is a well-established connection between hypertension and kidney injury. These two phenotypes are inextricably linked in the Dahl S model, such that increases in BP leads to kidney damage, but intrinsic genetic factors also alter kidney function leading to elevations in BP. The earliest work suggesting that the kidney itself in the Dahl S model was predominately responsible for hypertension were kidney cross-transplantation studies between S and R rats (9, 12, 13). All three studies conducted by Dahl using outbred S and R colonies reached the same conclusion: that genetically controlled factors functioning through the kidney are responsible for setting the BP level. For example, an S kidney transplanted into an R rat resulted in increased BP. Conversely, an R kidney transplanted into an S rat resulted in reduced BP. In general, clear results were obtained when rats were maintained on a low-salt diet. However, high-salt diet fed to kidney-transplanted rats tended to confound the above results. This was attributed to salt exacerbating ischemic renal damage, which presumably occurred during transplantation. This concept of kidney control of BP was supported by Author Guyton and coworkers in the 1970s, who promulgated the idea that the long-term level of BP is dependent on kidney function, specifically through resetting (rightward shifting) the pressure-natriuresis curve (30).Based on these concepts, two questions naturally arise: first, is the hypertension of the S rat due to genetic mechanisms operating de novo through the kidney? And, second, are the renal lesions that are always associated with hypertension in the S rat the cause of the hypertension or only the result of hypertension? These are complicated questions to answer and beyond the scope of this article. However, in the context of discussing the predisposition of authentic SS/Jr rats to develop hypertension with age on a low-salt diet, it is important to mention genetic studies as they are a critical part of understanding the SS/Jr phenotype as genetic analysis can provide some insight into cause-and-effect relationships (55–59, 61). It is important to note that the S rat is a genetic model in which susceptibility alleles for hypertension, salt sensitivity, and renal disease were selected for and concentrated into a single strain. In contrast, the SR/Jr rat was selected independently for alleles for resistance to salt sensitivity/hypertension. This means there never could be a control for drawing cause-and-effect relationships between BP and other physiological traits for either strain due to the polygenetic nature of BP regulation (for examples and further explanation, see Table 1 in Ref. 57). That is not to say that strain comparisons in physiological studies are not informative. For example, as pointed out above, comparing pressure-natriuresis curves between S and R strains yields data supporting the Guyton hypothesis (28, 46, 51, 64, 65, 72, 74). However, such studies provide zero information on the problem as to whether the right-shifted pressure natriuresis curves of S rats are the cause of the hypertension or the result of renal lesions caused by increased BP. This would require a genetic approach. In genetic analysis, strain controls are not needed because individual, contrasting alleles are compared or the control is built into the design, in the case of congenic strains (used in causative gene identification), transgenic models, or gene knockout done on the same genetic background. In some situations, the S rat serves as its own control, such as in studies on investigating the effects of drugs, dietary substances, or gonadectomy, etc.Previously, several genetic studies using a cross between the SS/Jr rat and the spontaneously hypertensive rat (SHR) were conducted to map loci involved in BP and kidney injury. Genetic studies involving SS/Jr and SHR models are particularly informative because, while both models are genetically susceptible to hypertension, the SHR is highly resistant to kidney injury, whereas the SS/Jr rat is very susceptible. The SHR model in itself provides strong evidence that hypertension and kidney injury can be decoupled and there must be some genes that provide kidney protection despite significant systemic hypertension. The first study using a segregating population derived from SS/Jr rats and SHRs raised on 8% NaCl diet identified only three genetic loci linked to BP with a single locus (on chromosome 9) accounting for 30% of the total variance in BP (25). While this study did not investigate kidney injury measures, it did provide some idea of loci that may confer salt sensitivity to the SS/Jr rat (at least compared with the SHR). A subsequent segregating population derived from SS/Jr and SHR rats raised on a low-salt (0.3% NaCl) diet did collect measures of kidney injury in addition to BP. The study identified multiple genomic loci associated with kidney injury (proteinuria and histological injury), predominately independent of loci for BP (21). These findings demonstrated that the Dahl S model, even without significant hypertension, is prone to develop kidney injury that is controlled genetically. A second genetic study was performed using the same cross fed a moderately high-salt (2% NaCl) diet. This study confirmed the loci controlling albuminuria observed on a low-salt diet (8 wk of age) but showed that some of the loci (on chromosomes 2, 11, and 19) are clearly influenced by salt loading 4 and 8 wk after 2% NaCl feeding (24). A subsequent study using a congenic strain that transferred the protective SHR quantitative trait locus allele on chromosome 2 into the SS/Jr background markedly reduced albuminuria without changing BP (22). Aside from one locus, BP did not colocalize with kidney injury measures, suggesting that the SS/Jr model possesses genetic factors that predispose to kidney injury independent of BP and salt sensitivity, but there are likely distinct loci that regulate BP alone and/or through salt (24).ORIGINS OF OTHER DAHL S STRAINS: FROM ACADEMIA TO COMMERCIAL SUPPLIERSFigure 1 shows an overview of the various Dahl S strains that will be discussed in detail below. Specifically, the diagram shows the relationship between authentic SS/Jr rats and other academic or commercialized strains (SS/Iwai, SS/JrHsd, SS/JrHsdEnv, SS/JrHsdMcwi, and SS/JrHsdMcwiCrl) used in research. What is clear from the diagram and the details below is that today only genetically compromised versions of SS/Jr rats are available commercially. This is the result, unfortunately, of both commercial suppliers contaminating the SS/Jr strain and of academics developing a genetically contaminated version of SS/Jr rats and then making them commercially available as an inbred strain (Charles River Laboratories, SS/JrHsdMcwiCrl).Fig. 1.Diagram showing the historical relationships and properties among the various substrains of Dahl rats. Note that there are currently no intact, authentic strains of inbred SS/Jr rats commercially available in the United States. Abbreviations in the diagram are as follows: Lewis K. Dahl (Dahl), Dahl salt-sensitive rats (SS or S), Dahl salt-resistant rats (SR or R), Junichi Iwai (Iwai), John Rapp (Jr), University of Toledo College of Medicine and Life Sciences (UTCOM), University of Mississippi Medical Center (UMMC), Harlan Sprague Dawley (HSD), Medical College of Wisconsin (Mcwi), Charles River Laboratories (Crl), and Envigo (Env). The word “authentic” is used to refer to colonies that we can verify have the blood pressure phenotype originally reported by Rapp and Dene (60). An academic colony of SS/Jr, which is not shown, was derived from the UTCOM colony in 1998 and is maintained by Alan Y. Deng at the University of Montreal. The red color indicates commercially available models, and the green indicates authentic academic colonies.Download figureDownload PowerPointInitial Commercial Availability of SS/Jr Rats and Subsequent ContaminationIn 1985, shortly after the development of inbred SS/Jr and SR/Jr rats, the models were made available to the commercial breeders Harlan Sprague Dawley (Indianapolis, IN) and Molellegaard Breeding Center (Ejby, Denmark). In 1994, St. Lezin et al. (67) reported that the SS/Jr rats obtained from Harlan (SS/JrHsd) did not have the expected BP phenotype. Testing of genetic markers showed that the rats were genetically contaminated, probably by Lewis rats. This had immediate financial and research repercussions (1a). The commercial breeding operation at Harlan consisted of a foundation colony (10 breeder pairs), a pedigree expansion colony (20 male and 40 female rats), and a production colony (200 breeding pairs). The genetic contamination was traced to the pedigree expansion colony (42). Since the foundation colony at Harlan was a self-propagating colony maintained in a barrier pathogen-free facility, accidental genetic contamination in that environment would seem to be basically impossible (assuming there were no other strains within the same barrier facility). Unfortunately, contamination of an animal model is not unique to the Dahl S rat, and there are several documented examples of other research strains becoming contaminated by commercial suppliers (20, 40, 50).In 1996, Walder et al. (75) compared the S rats supplied by Harlan (SS/JrHsd) to authentic SS/Jr rats obtained from Rapp’s colony at the Medical College of Ohio (now UTCOM) in Toledo, OH. At this time, the ability to perform a comprehensive genome comparison was limited; however, all of the 22 markers tested (across 14 chromosomes) yielded the expected S rat allele. The authors concluded the following:“…phenotypic characteristics such as body weight, salt-induced hypertension, and mortality were significantly different in SS/JrHsd compared with authentic SS/Jr. This may reflect genetic differences between these two strains or differences in environmental factors and suggests that the SS/JrHsd and authentic SS/Jr may now constitute distinct substrains of Dahl SS/Jr.”There are two caveats to their conclusion. The first caveat is that rats obtained from the two sources were 6 mo apart and were not raised and studied concomitantly, which is an absolute requirement for rigorous strain comparisons, as discussed above. The second caveat is that short of whole genome sequencing, it is impossible to find all contaminating DNA no matter how many markers are used (that in itself is reason enough to avoid contamination in the first place and to discard any contaminated stocks once contamination is known).As a point of interest, authentic SS/Jr rats sent to Harlan by Rapp during this period were not used as intended to start a new colony to replace the contaminated strain. Instead, the rats were euthanized, and DNA was collected for genotyping (R. J. Russell, Harlan Sprague Dawley, personal communication). Nevertheless, the net result of this confusing history was that in 1996, Harlan resumed production of intact SS/Jr rats because the foundation colony of S rats in the barrier facility was, as far as we know, never actually compromised. The work of Walder et al. (75) quoted above regarding the phenotyping differences between SS/JrHsd and SS/Jr rats does not necessarily refute this possibility because comparisons were not made concomitantly. The authors can, however, be lauded for meticulously documenting that the phenotyping studies were not concomitantly performed.Origins of the SS/JrHsdMcwi (a.k.a. SS/Mcwi) StrainA substrain of Dahl S rats developed at the Medical College of Wisconsin (MCW) in the early 1990s from SS/JrHsd rats (designated as SS/JrHsdMcwi) has gained significant use in research. The SS/JrHsdMcwi designation is often shortened to SS/Mcw or SS/Mcwi in the literature. The strain has been mainly used by researchers at MCW and has been the basis of substantial NIH funding, including large-scale genetic studies (43, 48), effects of dietary constituents other than salt (44, 45), causative gene identification (6), and genetically modified models (49a, 49b). The strain designation SS/JrHsdMcwi belies a convoluted origin as the animals were not simply the result of a transfer of SS/Jr rats from one facility to another. The description of the SS/JrHsdMcwi strain from the Rat Genome Database provides only limited insights into their origin:“Inbred from a congenic control group of Dahl S rats (SS/Ren) obtained from Dr. Theodore Kurtz (UCSF, CA) which were originally derived from the Harlan SS/Jr colony. Maintained at the Medical College of Wisconsin since 1991, this strain has undergone considerable marker-selected breeding to eliminate residual heterozygosity and genetic contamination. To confirm homozygosity, the strain was tested with 200 microsatellite markers (genome-wide scan at 20cM) all of which were homozygous for all regions tested [Cowley et al. 2000, Physiol. Genomics. 2:107-115].”This description is incomplete because it omits the actual reference to the strain’s origin as given by Jiang et al. (39). Additionally, the SS/JrHsdMcwi strain was not established until after 1997, so what was likely maintained since 1991 were the contaminated SS/JrHsd rats obtained from Harlan by Kurtz. Although MCW researchers attempted to remove genetic contamination introduced by Harlan, they introduced genetic contamination from Dahl R rats. In the description provided by Jiang et al. (39), it is evident that the origin of SS/JrHsdMcwi rats resulted from the byproduct of an experiment to move the SR/JrHsd (donor strain) renin allele onto the background of SS/JrHsd (recipient strain). That is, the primary goal was to establish a congenic strain around the renin locus on the SS/JrHsd background. The experiment began by crossing S and R rats (SS/JrHsd and SR/JrHsd) to produce an F1 population followed by repeatedly backcrossing rats heterozygous (SR) at the renin locus to the SS/JrHsd strain. This effectively retained the R renin allele at each generation with the remainder of the R genome being diluted at each generation. The early steps in this process were done by Kurtz in California and then transferred to MCW as part of a collaboration to produce reciprocal congenic strains for the renin locus. It is noteworthy that St. Lezin et al. (68), in their paper reporting the congenic strain placing the S renin allele on the R background, stated that “subsequent transfer of the Dahl R renin allele onto the S genetic background had to be aborted because of genetic contamination of Dahl S rats supplied by Harlan Sprague Dawley.” It was not aborted, but, as stated explicitly by Jiang et al. (39), it was shipped to MCW and served as progenitor of the SS/JrHsdMcwi strain.The last step to produce the “SS/Ren” congenic strain was to cross rats heterozygous at the renin locus to produce a population segregating at the renin locus 1RR:2SR:1SS. Renin locus RR female rats were bred to renin locus RR male rats to produce the desired congenic strain. The standard procedure would be to use the recipient strain (SS/JrHsd, in this case) as the control against which the congenic strain was compared. Instead, Jiang et al. (39) did not use SS/JrHsd rats as the control but, in its place, produced a “control” by crossing renin locus homozygous SS female rats to renin locus homozygous SS male rats from the above segregating population. Regardless of the rationale for generating this “control,” the untoward result was that it served as the progenitor of the SS/JrHsdMcwi strain after subsequent extensive brother-sister mating with the net effect of fixing random segments of the R genome throughout the strain.Thus, the SS/JrHsdMcwi st" @default.
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• W2975601983 doi "https://doi.org/10.1152/ajprenal.00359.2019" @default.
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