Epistasis, Not Numbers, Regulates Functions of Clustered Dahl Rat Quantitative Trait Loci Applicable to Human Hypertension

Charron, Sophie; Duong, Chenda; Ménard, Annie; Roy, Julie; Eliopoulos, Vasiliki; Lambert, Raphaëlle; Deng, Alan Y.

doi:10.1161/01.hyp.0000192024.72367.c3

Cited by 41 publications

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“…Interestingly, ϳ15% of known human diseases related to mutations in the mitochondria are found within the tRNA genes (http://www.mitomap.org). Because of its extensive physiological characterization along with the ability to be genetically manipulated (1,12,13,51,71), the rat is a useful model for many different complex diseases. However, only three complete mtDNA genome sequences are available: the Wistar strain, a wild rat from Copenhagen, and a Brown Norway strain (AC_000022; see Refs.…”

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confidence: 99%

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Schlick

Jensen‐Seaman²,

Orlebeke³

et al. 2006

American Journal of Physiology-Cell Physiology

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quence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains. Am J Physiol Cell Physiol 291: C1183-C1192, 2006. First published July 19, 2006 doi:10.1152/ajpcell.00234.2006.-Rat remains a major biomedical model system for common, complex diseases. The rat continues to gain importance as a model system with the completion of its full genomic sequence. Although the genomic sequence has generated much interest, only three complete sequences of the rat mitochondria exist. Therefore, to increase the knowledge of the rat genome, the entire mitochondrial genomes (16,307-16,315 bp) from 10 inbred rat strains (that are standard laboratory models around the world) and 2 wild rat strains were sequenced. We observed a total of 195 polymorphisms, 32 of which created an amino acid change (nonsynonymous substitutions) in 12 of the 13 protein coding genes within the mitochondrial genome. There were 11 single nucleotide polymorphisms within the tRNA genes, six in the 12S rRNA, and 12 in the 16S rRNA including 3 insertions/deletions. We found 14 single nucleotide polymorphisms and 2 insertion/deletion polymorphisms in the D-loop. The inbred rat strains cluster phylogenetically into three distinct groups. The wild rat from Tokyo grouped closely with five inbred strains in the phylogeny, whereas the wild rat from Milwaukee was not closely related to any inbred strain. These data will enable investigators to rapidly assess the potential impact of the mitochondria in these rats on the physiology and the pathophysiology of phenotypes studied in these strains. Moreover, these data provide information that may be useful as new animal models, which result in novel combinations of nuclear and mitochondrial genomes, are developed. genome; mitochondria MITOCHONDRIA ARE THE ONLY organelles (other than the nucleus) with their own DNA, which is maternally inherited (31, 36). The mammalian mitochondrial DNA (mtDNA) is a circular, double-stranded DNA that lacks introns and has only ϳ7% noncoding sequences (23) in contrast to the genomic DNA. The mtDNA encodes 37 genes, including 13 protein-coding genes that, in conjunction with subunits encoded by the nuclear genome, form the electron transport chain, the primary ATP producer for the cell. Also included within these 37 coding genes are 22 tRNA genes whose function is to transport amino acids to the ribosome and match them to the codons of the mRNAs thus facilitating incorporation of amino acids into the growing polypeptide during translation. The final 2 genes are rRNA genes. The D-loop or control region, although noncoding, contains binding sites for two transcription factors, three conserved sequence blocks (CSBs) associated with initiation of replication and the loop strand termination associated sequences (9,21,23,61

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mentioning

confidence: 99%

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Schlick

Jensen‐Seaman²,

Orlebeke³

et al. 2006

American Journal of Physiology-Cell Physiology

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“…The remaining five (Table 2) have been resolved only by congenic fine mapping (Charron et al, 2005a;Dutil et al, 2005). C1QTL, C16QTL, C10QTL and C2QTL showed partial dominance in linkage analyses, that is the BP of the heterozygotes fell between the two homozygotes.…”

Section: Linkage Versus Congenic Resultsmentioning

confidence: 99%

“…DSS, LEW and MNS rats have previously been described (Palijan et al, 2003a, b;Ariyarajah et al, 2004;Moujahidine et al, 2004;Charron et al, 2005a, b;Dutil et al, 2005;Eliopoulos et al, 2005;Grondin et al, 2005). Nine congenic strains had trapped BP QTLs and were largely based on those isolated previously (Palijan et al, 2003b;Ariyarajah et al, 2004;Moujahidine et al, 2004;Charron et al, 2005a;Dutil et al, 2005;Grondin et al, 2005).…”

Section: Animalsmentioning

confidence: 99%

“…For example, our previous work revealed the presence of a QTL in a 46-cM region on rat Chr 10 (Deng and Rapp, 1995;Garrett et al, 1998), whereas, in fact, there are four QTLs in this segment. Three of them are clustered within a section of less than 15 cM (Palijan et al, 2003b;Charron et al, 2005a). Second, false negatives or false positives can appear.…”

Section: Introductionmentioning

confidence: 99%

“…Two novel functional aspects of BP QTLs have become apparent from the analyses of congenic strains. First, each of them accounts for at least 33 mm Hg/ 88 mm Hg ¼ 38% of the total BP difference between DSS and LEW parental strains, as measured directly by telemetry (Moujahidine et al, 2004;Dutil et al, 2005;Grondin et al, 2005;Charron et al, 2005a), exhibiting the status of a major QTL. Second, each QTL appears have an individual influence on BP: no combination seems to be necessary for any one of them to affect BP, despite QTLQTL epistatic interactions (Deng and Rapp, 1992;Rapp et al, 1998;Palijan et al, 2003a;Charron et al, 2005a, b;Dutil et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Duong

Charron

Deng³

et al. 2006

Heredity

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We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.

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Molecular Genetics of Polygenic Hypertension

Deng

2017

Encyclopedia of Life Sciences

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Essential hypertension is one of the most damaging health risk factors; however, its underlying mechanisms of pathogeneses continue to be undeciphered. To assist this endeavour, investigations utilising human populations and rodent models have revealed numerous genetic building blocks known as quantitative trait loci (QTLs) for blood pressure (BP). Although BP is a quantitatively measured trait manifesting in a continuous variation in heterogeneous populations, each QTL governing it appears to functionally behave as an independent and ‘monogenic’ Mendelian determinant. Mechanistically, multiple QTLs are functionally modularised by epistasis that implies a common pathway or cascade among them, whereas others belong to parallel epistatic modules/pathways. These insights suggest that similar genetic mechanisms probably shepherd the genetic architectures in physiological functions for essential hypertension. Translations of gene discovery to therapeutic targets and diagnostic tools will require biology‐based function validations of specific genes constituting BP QTLs in appropriate animal models. Key Concepts There is a regulatory hierarchy in the genetic architecture governing the functional biology of BP determination. When a master control is removed, modularity and epistatic hierarchy, not a cumulation of minuscule effects, determine the functionality of multiple QTLs on BP. Mechanistically, separate epistatic modules integrating BP QTLs are best explained by independent pathways, each consisting of multiple components that act in sequential cascades in a pathway. As there are fewer pathways than the components comprising them, a defective protein product per se encoded by a mutated QTL, either qualitatively or quantitatively, can lead to a deficient BP‐regulating pathway of pathogenesis and does not have to directly act on BP as a physiological agent.

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Epistasis, Not Numbers, Regulates Functions of Clustered Dahl Rat Quantitative Trait Loci Applicable to Human Hypertension

Cited by 41 publications

References 39 publications

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Molecular Genetics of Polygenic Hypertension

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