A new locus for resistance to γ-radiation-induced thymic lymphoma identified using inter-specific consomic and inter-specific recombinant congenic strains of mice
Javíer SantosXavier MontagutelliAbraham Acevedo‐ArozenaPilar LópezConcepción VaqueroMónica FernándezMaría Rosa ArnauMarek SzatanikEduardo SalidoJean‐Louis GuénetJosé Fernández‐Piqueras
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EL/Sea mice have 100% incidence of the absence of third molars (M3). Our previous linkage analysis using EL/Sea and MSM/Msf mouse strains provides statistical evidence of a major locus for the absence of M3, designated am3, of EL/Sea at the middle region of chromosome 3. To obtain independent evidence for linkage and more precisely determine the location of the am3 locus, we generated EL/Sea congenic strains for am3 in which the restricted interval of chromosome 3 of EL/Sea was replaced by an MSM/Msf-derived homologue. EL/Sea congenic mice that were either heterozygous or homozygous for the MSM/Msf-derived interval exhibited a significant decrease in the incidence of the absence of third molars, confirming previous genome scan results. These results confine the am3 locus to an approximately 4.4-cM region, and demonstrate that other unmapped genes are also involved in the absence of M3 in EL/Sea mice.
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A congenic rat has a small genomic fragment transferred from a donor strain into a recipient strain. It is therefore possible to make a hypertensive congenic strain with a single unknown hypertensive gene originating from a genetic hypertensive model rat such as SHR. Such a congenic strain is useful in the search for hypertension genes in rats. It can be applied (1) to further dissection of QTL regions, (2) to determination of the boundaries of QTL regions, which is necessary for selection of positional candidate genes, and (3) to physiological and biochemical studies to get intermediate phenotypes.
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Mammalian complex traits are little studied for combinatorial gene‐gene interactions. To study epistasis among blood pressure (BP) quantitative trait loci (QTLs) we developed bi‐and tri‐congenic strains that introgress R‐rat congenic regions containing RNO3, RNO7, and RNO9 low BP alleles into S rats. S rats, RNO3+RNO7+RNO9 tri‐congenic, and RNO3+RNO7, RNO3+RNO9, and RNO7+RNO9 bi–congenic rats (n=16) were concomitantly raised on a low (0.4% NaCl) salt diet until 6 weeks‐old, fed a higher (2% NaCl) salt diet for 24 days, after which tail‐cuff BP, body weight (BW), and heart weight (HW) were measured. While all bi‐ and tri‐congenic strains had lower BP (P<0.0001) compared to the parental, S, strain, BP differences were not observed among the bi‐ and tri‐congenic strains. Thus, low BP alleles in the congenic regions were non‐additive under this salt‐loading condition. While bi‐ and tri‐congenic strains had significantly lower HW (P<0.0001) compared to S rats, only RNO3+RNO7+RNO9 and RNO3+RNO7 rats had lower BW‐adjusted HW (1201.8 and 1128.0 mg, respectively) compared to S rats (1267.2 mg; P=0.004 and P<0.0001, respectively). Thus, low BP QTL‐containing alleles showed non‐additive effects, while RNO3+RNO7 bicongenic rats having lower BW‐adjusted HW compared with RNO3+RNO7+RNO9 rats (P<0.002). These results provide evidence for strong interactions between previously identified BP QTLs.
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SUMMARY 1. Linkage studies have revealed quantitative trait loci (QTL) for blood pressure in the rat genome using genetic hypertensive rat models. To identify the genes responsible for hypertension, the construction of congenic rats is essential. 2. To date, several congenic strains have been obtained from spontaneously hypertensive or Dahl salt‐sensitive rats. The results of these studies should be interpreted according to whether the rats carry the whole QTL region or not. 3. After establishing congenic strains, three strategies are possible: (i) an orthodox positional cloning in which, using subcongenic strains, the QTL region is cut down to smaller fragments suitable for physical mapping; (ii) a positional candidate strategy in which candidate genes in the QTL regions are studied; or (iii) physiological studies in which intermediate phenotypes directly associated with the hypertension gene are explored. Several other experimental strategies are also available using congenic strains as new animal models for hypertension. 4. To make the most of advances in DNA technology, the precise evaluation of the phenotypic difference between congenic strains carrying different QTL or between a congenic and parental strain is critical.
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A major advance has been made towards the positional cloning of char2 (a quantitative trait locus encoding resistance to Plasmodium chabaudi malaria). Mice congenic for the locus have been used to fine map the gene and to prove that char2 plays a significant role in the outcome of malarial infection, independently of other resistance loci.
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