Extended regions of suspected mis-assembly in the rat reference genome

AbstractWe performed whole-genome sequencing for eight inbred rat strains commonly used in genetic mapping studies. They are the founders of the NIH heterogeneous stock (HS) outbred colony. We provide their sequences and variant calls to the rat genomics community. When analyzing the variant calls we identified regions with unusually high levels of heterozygosity. These regions are consistent across the eight inbred strains, including Brown Norway, which is the basis of the rat reference genome. These regions show higher read depths than other regions in the genome and contain higher rates of apparent tri-allelic variant sites. The evidence suggests that these regions may correspond to duplicated segments that were incorrectly overlaid as a single segment in the reference genome. We provide masks for these regions of suspected mis-assembly as a resource for the community to flag potentially false interpretations of mapping or functional results.

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Alcohol Preference and Voluntary Alcohol Intakes of Inbred Rat Strains and the National Institutes of Health Heterogeneous Stock of Rats

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.1984.tb05708.x ◽

1984 ◽

Vol 8 (5) ◽

pp. 485-486 ◽

Cited By ~ 152

Author(s):

U Ting-Kai ◽

Lawrence Lumeng

Keyword(s):

Alcohol Preference ◽

National Institutes Of Health ◽

Rat Strains ◽

Inbred Rat Strains ◽

Heterogeneous Stock ◽

Inbred Rat

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Characteristics of the aortic elastic network and related phenotypes in seven inbred rat strains

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00544.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H769-H777 ◽

Cited By ~ 28

Author(s):

Jacques Behmoaras ◽

Mary Osborne-Pellegrin ◽

Dominique Gauguier ◽

Marie-Paule Jacob

Keyword(s):

Growth Factor ◽

Vascular Function ◽

Transforming Growth Factor ◽

Brown Norway ◽

Internal Elastic Lamina ◽

Rat Strains ◽

Inbred Rat Strains ◽

Insulin Growth Factor ◽

Igf I ◽

Inbred Rat

Extracellular matrix (ECM) molecules such as elastin and collagen provide mechanical support to the vessel wall and are essential for vascular function. Evidence that genetic factors influence aortic ECM composition and organization was concluded from our previous studies showing that the inbred Brown Norway (BN) rat differs significantly from the outbred Long-Evans (LE) and the inbred LOU rat with respect to both thoracic aortic elastin content and internal elastic lamina (IEL) rupture in the abdominal aorta and iliac arteries. Here, we measured aortic elastin and collagen contents as well as factors that may modulate these parameters [insulin growth factor (IGF)-I, transforming growth factor (TGF)-β1, and matrix metalloproteinase (MMP)-2] in seven inbred rat strains, including BN and LOU. We also investigated whether IEL ruptures occur in strains other than BN. We showed that LOU, LE, BN, and Fischer 344 (F344) rats were significantly different for aortic elastin content and elastin-to-collagen ratio, whereas LE, Lewis, WAG, and Wistar-Furth (WF) were similar for these parameters. BN and F344 had the lowest values. BN was the only strain to present numerous IEL ruptures, whereas F344, LE, and WF presented a few and the other strains presented none. In addition, IGF-I and TGF-β1 levels in the plasma and aorta differed significantly between strains, suggesting genetic control of their production. Because inbred rat strains provide interesting models for quantitative trait locus analysis, our results concerning elastin, collagen, IEL ruptures, and cytokines may provide a basis for the search for candidate genes involved in the control of these phenotypes.

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Functional polymorphisms in inbred rat strains and their allele frequencies in commercially available outbred stocks

Physiological Genomics ◽

10.1152/physiolgenomics.00222.2007 ◽

2008 ◽

Vol 33 (2) ◽

pp. 205-211 ◽

Cited By ~ 5

Author(s):

Takashi Kuramoto ◽

Satoshi Nakanishi ◽

Tadao Serikawa

Keyword(s):

Coat Color ◽

Cholesterol Biosynthesis ◽

Inbred Strains ◽

Rat Strains ◽

Genetic Characteristics ◽

Genetic Profiling ◽

Prostate Tumorigenesis ◽

Inbred Rat Strains ◽

Functional Polymorphisms ◽

Inbred Rat

Polymorphisms that have been proven to influence gene functions are called functional polymorphisms. It is significant to know the distribution of functional polymorphisms in the rat, widely used in animal models for human diseases. In this study, we assessed 16 functional polymorphisms consisting of 3 coat color and 13 disease-associated genes in 136 rat strains, as a part of the genetic profiling program of the National Bio Resource Project for the Rat (NBRP-Rat). Polymorphisms of Cdkn1a, Fcgr3, Grp10, Lss, and Fdft1, which were proven to function in prostate tumorigenesis, glomerulonephritis, hyperphagia, and cholesterol biosynthesis, were shared among various inbred strains. These findings indicated that most rat strains harbored the disease-associated alleles and suggested that many unidentified functional polymorphisms might exist in inbred rat strains. The functional polymorphisms shared in inbred strains were also observed within outbred stocks available commercially. Therefore, this implies that experimental plans based on either rat inbred strains or outbred stocks need to be carefully designed with a full understanding of the genetic characteristics of the animals. To select the most suitable strains for experiments, the NBRP-Rat will periodically improve and update the genetic profiles of rat strains.

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Glucocorticoid negative feedback on the HPA axis in five inbred rat strains

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.2.r420 ◽

1998 ◽

Vol 274 (2) ◽

pp. R420-R427 ◽

Cited By ~ 12

Author(s):

Francisca Gómez ◽

E. Ronald De Kloet ◽

Antonio Armario

Keyword(s):

Hpa Axis ◽

Negative Feedback ◽

Acute Stress ◽

Suppressive Effect ◽

Brown Norway ◽

Shr Rats ◽

Rat Strains ◽

Inbred Rat Strains ◽

Interstrain Differences ◽

Inbred Rat

The aim of the present work was to study the influence of altering glucocorticoid negative feedback on both basal activity of the hypothalamic-pituitary-adrenal (HPA) axis and its response to acute stress (tail shock) in five inbred rat strains known to differ in some depression-like behaviors: Brown Norway (BN), Fischer 344 (F344), Lewis (Lew), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY) rats. Two complementary approaches were used: 1) enhancement of negative feedback by administration of 0.05 and 0.2 mg/kg dexamethasone (Dex) and 2) attenuation of negative feedback by pharmacological adrenalectomy (PhADX). The results indicate that 1) Lew rats consistently show adrenocorticotropic hormone (ACTH) and corticosterone hyporesponsiveness to stress, 2) interstrain differences in the effect of Dex on the HPA axis were very weak and not related apparently to differences in the metabolism of the steroid, 3) the suppressive effect of the highest dose of Dex on basal corticosterone levels was lower in BN rats than in the other strains, and 4) after PhADX, an increase in ACTH levels was observed in response to acute stress in BN, F344, and WKY but not in Lew and SHR rats, suggesting possible interstrain differences in pituitary sensitivity to neural stimuli induced by stress. In summary, our results indicate that there are differences among the strains with regard to both 1) the suppressive effect of Dex on the HPA axis, BN rats showing a certain degree of resistance, and 2) the capability of PhADX rats to respond to acute stress, which suggests a defective release of ACTH in Lew and SHR rats. The biological meaning of these alterations of corticosteroid negative feedback among the five inbred strains studied remains to be established.

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Genetic influences on survival time after severe hemorrhage in inbred rat strains

Physiological Genomics ◽

10.1152/physiolgenomics.00245.2010 ◽

2011 ◽

Vol 43 (12) ◽

pp. 758-765 ◽

Cited By ~ 8

Author(s):

Harold G. Klemcke ◽

Bina Joe ◽

Mariam L. Calderon ◽

Rajiv Rose ◽

Thomas Oh ◽

...

Keyword(s):

Survival Time ◽

Blood Volume ◽

Brown Norway ◽

Survival Times ◽

Rat Strains ◽

Inbred Rat Strains ◽

Percent Survival ◽

Severe Hemorrhage ◽

Inbred Rat ◽

Blood Volumes

To find a genetic basis for differential ability to survive severe hemorrhage, we previously showed eightfold differences in survival times among inbred rat strains. We assumed that rat strains had similar normalized blood volumes (NBV; ml/100 g body wt). As NBV might vary among strains and constitute one genetic variable affecting survival time to hemorrhage, in experiment 1 of the current studies we first measured total blood volumes and calculated NBV in specific inbred rat strains (Brown Norway/Medical College of Wisconsin, BN; Dark Agouti, DA; Fawn Hooded Hypertensive, FHH; Lewis, LEW; and Dahl Salt-Sensitive, SS) previously found to be divergent in survival time. NBV differed by 20% ( P < 0.01; BN > SS > FHH = LEW = DA) and had a heritability (h2) of 0.56. Hence, differential survival times in our previously published study might reflect strain-dependent differences in NBV. Then studies were conducted wherein rats were catheterized and, ∼24 h later, 47% of their blood volume was removed; these rats were observed for a maximum of 4 h. In experiment 2, blood volumes were measured the day prior to hemorrhage. Percent survival and survival time did not differ among strains. To obviate possible confounding effects of blood volume determination, in experiment 3 the average NBV for each strain was used to determine hemorrhage volumes. Percent survival ( P < 0.01) and survival times ( P < 0.001) were different with DA demonstrating the best (62.5%, 190 ± 29 min) and BN the worst (0%, 52 ± 5 min) survival responses. These data indicate that both blood volume and survival time after hemorrhage in rats are heritable quantitative traits, and continue to suggest that genetic assessment of these phenotypes might lead to novel therapeutics to improve survival to hemorrhage.

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Cardiac mitochondrial proteomic expression in inbred rat strains divergent in survival time after hemorrhage

Physiological Genomics ◽

10.1152/physiolgenomics.00118.2012 ◽

2013 ◽

Vol 45 (7) ◽

pp. 243-255 ◽

Cited By ~ 3

Author(s):

Harold G. Klemcke ◽

Robert M. DeKroon ◽

Mihaela Mocanu ◽

Jennifer B. Robinette ◽

Oscar Alzate

Keyword(s):

Survival Time ◽

Atp Synthesis ◽

Mitochondrial Proteins ◽

Brown Norway ◽

Dark Agouti ◽

Rat Strains ◽

Cellular Mechanisms ◽

Inbred Rat Strains ◽

Mercaptopyruvate Sulfurtransferase ◽

Inbred Rat

We have previously identified inbred rat strains differing in survival time to a severe controlled hemorrhage (StaH). In efforts to identify cellular mechanisms and ultimately genes that are important contributors to enhanced STaH, we conducted a study to characterize potential differences in cardiac mitochondrial proteins in these rats. Inbred rats from three strains [Brown Norway/Medical College of Wisconsin (BN); Dark Agouti (DA), and Fawn Hooded Hypertensive (FHH)] with different StaH (DA = FHH > BN) were assigned to one of three treatment groups ( n = 4/strain): nonoperated controls, surgically catheterized rats, or rats surgically catheterized and hemorrhaged 24 h postsurgery. Rats were euthanized 30 min after handling or 30 min after initiation of a 26 min hemorrhage. After euthanasia, hearts were removed and mitochondria isolated. Differential protein expression was determined using 2D DIGE-based Quantitative Intact Proteomics and proteins identified by MALDI/TOF mass spectrometry. Hundreds of proteins (791) differed among inbred rat strains ( P ≤ 0.038), and of these 81 were identified. Thirty-eight were unique proteins and 43 were apparent isoforms. For DA rats (longest STaH), 36 proteins increased and 30 decreased compared with BN (shortest STaH). These 81 proteins were associated with lipid (e.g., acyl CoA dehydrogenase) and carbohydrate (e.g., fumarase) metabolism, oxidative phosphorylation (e.g., ubiquinol-cytochrome C reductase), ATP synthesis (F1ATPase), and H2S synthesis (3-mercaptopyruvate sulfurtransferase). Although we cannot make associations between these identified mitochondrial proteins and StaH, our data do provide evidence for future candidate proteins with which to consider such associations.

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Differences in response to anaesthetics and analgesics between inbred rat strains

Laboratory Animals ◽

10.1258/002367707781282811 ◽

2007 ◽

Vol 41 (3) ◽

pp. 337-344 ◽

Cited By ~ 24

Author(s):

H Avsaroglu ◽

A S van der Sar ◽

H A van Lith ◽

L F M van Zutphen ◽

L J Hellebrekers

Keyword(s):

Inbred Strains ◽

Sleep Time ◽

Albino Rats ◽

Rat Strains ◽

Inbred Rat Strains ◽

Future Studies ◽

Analgesic Effects ◽

Loss Of Righting Reflex ◽

Righting Reflex ◽

Inbred Rat

Differences in response to analgesic and anaesthetic drugs can partly be attributed to variations in the genetic background of experimental animals. This study was carried out to determine differences in the response of inbred rat strains to a selection of analgesics and drugs used in anaesthetic protocols. A cross between the most contrasting strains can then be phenotyped in future studies in order to localize quantitative trait loci (QTLs) involved in analgesic/anaesthetic drug sensitivity. Eight inbred strains ( n = 6 rats/strain) were selected for the study: the pigmented ACI, BN and COP strains and the albino F344, LEW, SHR, WAG and WKY strains. Each rat was injected intravenously with two analgesics (buprenorphine 0.05 mg/kg and nalbuphine 1 mg/kg) and three drugs used in anaesthetic protocols (propofol 25 mg/kg, medetomidine 50 μg/kg and ketamine 10 mg/kg), respectively, using a crossover design. Analgesic responses were assessed using an analgesiometric procedure. The sleep time of the rat and, where applicable, the interval between injection and loss of righting reflex were used to determine the anaesthetic response. Six out of eight strains responded significantly different from each other to the analgesic effect of buprenorphine with the ACI strain as hyper-responder. The tail withdrawal latency at 55°C of the F344 and WKY rats using buprenorphine was not significantly different from baseline tail withdrawal latencies. In this study, all strains were non-responsive to the analgesic effects of nalbuphine. The response to all three drugs used in anaesthetic protocols differed significantly among the strains. The F344 and BN strains were relatively resistant to the sedative effects of medetomidine. Use of ketamine was abandoned in the ACI and BN strains when the first two animals of both strains died soon after induction. With all three drugs the sleep time of albino rats was significantly longer compared with that of the pigmented ones. We conclude that the results from this study can be used in future studies where QTLs for the sensitivity to anaesthetic/analgesic drugs are localized.

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Short photoperiod inhibition of growth in body mass and reproduction in ACI, BUF, and PVG inbred rats

Reproduction ◽

10.1530/rep.1.00390 ◽

2004 ◽

Vol 128 (6) ◽

pp. 857-862 ◽

Cited By ~ 7

Author(s):

Nicole R Francisco ◽

Christen M Raymond ◽

Paul D Heideman

Keyword(s):

Body Mass ◽

Food Restriction ◽

Inbred Strains ◽

Brown Norway ◽

Sprague Dawley ◽

Rat Strains ◽

Young Males ◽

Laboratory Rats ◽

Photoperiodic Responses ◽

Inbred Rat

Laboratory rats have been generally considered non-photoresponsive, but strains of laboratory rats have been found to be variable for this trait. Young males of both the Fischer (F344) and Brown Norway strains (BN) suppress reproductive development, food intake and body mass in short winter photoperiod (short days (SD); 8 h light:16 h darkness), and food restriction interacts with SD to enhance the effect of SD alone. Conversely, young male Harlan Sprague Dawley outbred rats, along with other outbred laboratory rats tested, have little or no response to SD except when unmasked by food restriction or other treatments, and have generally been considered nonphotoperiodic. In order to assess how widespread this trait might be among rat strains, and to test for uncoupling of reproductive and nonreproductive responses, we tested 3 additional inbred strains, including ACI, PVG and BUF rats, for photoresponsiveness and for unmasking of photoperiodic responses by food restriction. Young males of all three inbred strains exhibited photoresponsiveness in testis mass (5–20% lower in SD), seminal vesicle mass (20–50% lower in SD), and body mass (5–10% lower in SD). Food restriction also suppressed reproduction, but there was little or no interaction with the effects of photoperiod. The results are consistent with the hypothesis that laboratory rats are genetically variable for photoperiodism, and that photoresponsiveness may be widespread among inbred rat strains, as all five inbred strains tested have shown photoperiodic responses. The results are particularly important because standard research protocols may unknowingly manipulate this pathway in rats, causing unsuspected variability among or within studies.

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