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Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model.

Šedová L, Pravenec M, Křenová D, Kazdová L, Zídek V, Krupková M, Liška F, Křen V, Šeda O - PLoS ONE (2016)

Bottom Line: We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains.SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats.The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and the General Teaching Hospital, Prague, Czech Republic.

ABSTRACT
Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference) and diastolic (10-15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

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The rat chromosome 16 (RNO16) differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain.The RNO16 differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain compared with a previously published congenic strain carrying Brown-Norway-origin RNO16 (SHR.BN-(D16Rat87-D16Mgh1)/Jk) [13]. The RNO16 markers genotyped in this study to determine the differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain are shown to the right of the chromosome. Chromosomal regions of SHR origin are depicted by open bars; the BN-derived segment is shown as a solid bar. Genes with “probably damaging” nonsynonymous mutations distinguishing SHR from BN-Lx are shown in bold. Genes that are associated with features of metabolic syndrome in human genome-wide association studies and that show variance between SHR and BN-Lx (in silico comparison) are shown in italics. Asb14—ankyrin repeat and SOCS box-containing 14, Il17rd—interleukin 17 receptor D, Arhgef3—Rho guanine nucleotide exchange factor 3, Wnt5a - wingless-type MMTV integration site family, member 5A, Cacna2d3—calcium channel, voltage-dependent, alpha2/delta subunit 3, Cacna1d - calcium channel, voltage-dependent, L type, alpha 1D subunit, Sfmbt1—Scm-like with four mbt domains 1, Itih1—inter-alpha-trypsin inhibitor heavy chain 1, Pbrm1—polybromo 1, Stab1—stabilin 1, Nisch—nischarin, Btd—biotinidase, Syt15—synaptotagmin XV, Ercc6—excision repair cross-complementing rodent repair deficiency, complementation group 6, Arhgap22—Rho GTPase activating protein 22, Grid1—glutamate receptor, ionotropic, delta 1, Nrg3—neuregulin 3, RGD1564958—similar to glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) (EC 1.2.1.12), Myo9b (myosin IXb), Comp—cartilage oligomeric matrix protein, Tmem161a (transmembrane protein 161A), Gatad2a - GATA zinc finger domain containing 2A, Cilp2—cartilage intermediate layer protein 2, Pbx4—pre-B-cell leukemia homeobox 4, Lpar2—lysophosphatidic acid receptor 2, Slc18a1—solute carrier family 18 (vesicular monoamine transporter), member 1, Lpl—lipoprotein lipase.
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pone.0152708.g001: The rat chromosome 16 (RNO16) differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain.The RNO16 differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain compared with a previously published congenic strain carrying Brown-Norway-origin RNO16 (SHR.BN-(D16Rat87-D16Mgh1)/Jk) [13]. The RNO16 markers genotyped in this study to determine the differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain are shown to the right of the chromosome. Chromosomal regions of SHR origin are depicted by open bars; the BN-derived segment is shown as a solid bar. Genes with “probably damaging” nonsynonymous mutations distinguishing SHR from BN-Lx are shown in bold. Genes that are associated with features of metabolic syndrome in human genome-wide association studies and that show variance between SHR and BN-Lx (in silico comparison) are shown in italics. Asb14—ankyrin repeat and SOCS box-containing 14, Il17rd—interleukin 17 receptor D, Arhgef3—Rho guanine nucleotide exchange factor 3, Wnt5a - wingless-type MMTV integration site family, member 5A, Cacna2d3—calcium channel, voltage-dependent, alpha2/delta subunit 3, Cacna1d - calcium channel, voltage-dependent, L type, alpha 1D subunit, Sfmbt1—Scm-like with four mbt domains 1, Itih1—inter-alpha-trypsin inhibitor heavy chain 1, Pbrm1—polybromo 1, Stab1—stabilin 1, Nisch—nischarin, Btd—biotinidase, Syt15—synaptotagmin XV, Ercc6—excision repair cross-complementing rodent repair deficiency, complementation group 6, Arhgap22—Rho GTPase activating protein 22, Grid1—glutamate receptor, ionotropic, delta 1, Nrg3—neuregulin 3, RGD1564958—similar to glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) (EC 1.2.1.12), Myo9b (myosin IXb), Comp—cartilage oligomeric matrix protein, Tmem161a (transmembrane protein 161A), Gatad2a - GATA zinc finger domain containing 2A, Cilp2—cartilage intermediate layer protein 2, Pbx4—pre-B-cell leukemia homeobox 4, Lpar2—lysophosphatidic acid receptor 2, Slc18a1—solute carrier family 18 (vesicular monoamine transporter), member 1, Lpl—lipoprotein lipase.

Mentions: We used a genotyping scan with a set of 34 markers polymorphic between SHR and BN-Lx on chromosome 16 to reveal the extent of the BN-Lx-origin differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub congenic strain (SHR.BN16 hereafter). The differential segment spans about 22 Mb at the telomeric end of the RNO16 short arm (Fig 1). Several total genome scans conducted during derivation of the SHR.BN16 strain excluded the presence of non-SHR alleles other than those fixed on RNO16, confirming the congenic status of the new strain. The BN-Lx-derived RNO16 segment hence represents the only genomic difference between the SHR and SHR.BN16 strains.


Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model.

Šedová L, Pravenec M, Křenová D, Kazdová L, Zídek V, Krupková M, Liška F, Křen V, Šeda O - PLoS ONE (2016)

The rat chromosome 16 (RNO16) differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain.The RNO16 differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain compared with a previously published congenic strain carrying Brown-Norway-origin RNO16 (SHR.BN-(D16Rat87-D16Mgh1)/Jk) [13]. The RNO16 markers genotyped in this study to determine the differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain are shown to the right of the chromosome. Chromosomal regions of SHR origin are depicted by open bars; the BN-derived segment is shown as a solid bar. Genes with “probably damaging” nonsynonymous mutations distinguishing SHR from BN-Lx are shown in bold. Genes that are associated with features of metabolic syndrome in human genome-wide association studies and that show variance between SHR and BN-Lx (in silico comparison) are shown in italics. Asb14—ankyrin repeat and SOCS box-containing 14, Il17rd—interleukin 17 receptor D, Arhgef3—Rho guanine nucleotide exchange factor 3, Wnt5a - wingless-type MMTV integration site family, member 5A, Cacna2d3—calcium channel, voltage-dependent, alpha2/delta subunit 3, Cacna1d - calcium channel, voltage-dependent, L type, alpha 1D subunit, Sfmbt1—Scm-like with four mbt domains 1, Itih1—inter-alpha-trypsin inhibitor heavy chain 1, Pbrm1—polybromo 1, Stab1—stabilin 1, Nisch—nischarin, Btd—biotinidase, Syt15—synaptotagmin XV, Ercc6—excision repair cross-complementing rodent repair deficiency, complementation group 6, Arhgap22—Rho GTPase activating protein 22, Grid1—glutamate receptor, ionotropic, delta 1, Nrg3—neuregulin 3, RGD1564958—similar to glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) (EC 1.2.1.12), Myo9b (myosin IXb), Comp—cartilage oligomeric matrix protein, Tmem161a (transmembrane protein 161A), Gatad2a - GATA zinc finger domain containing 2A, Cilp2—cartilage intermediate layer protein 2, Pbx4—pre-B-cell leukemia homeobox 4, Lpar2—lysophosphatidic acid receptor 2, Slc18a1—solute carrier family 18 (vesicular monoamine transporter), member 1, Lpl—lipoprotein lipase.
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getmorefigures.php?uid=PMC4816345&req=5

pone.0152708.g001: The rat chromosome 16 (RNO16) differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain.The RNO16 differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain compared with a previously published congenic strain carrying Brown-Norway-origin RNO16 (SHR.BN-(D16Rat87-D16Mgh1)/Jk) [13]. The RNO16 markers genotyped in this study to determine the differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub strain are shown to the right of the chromosome. Chromosomal regions of SHR origin are depicted by open bars; the BN-derived segment is shown as a solid bar. Genes with “probably damaging” nonsynonymous mutations distinguishing SHR from BN-Lx are shown in bold. Genes that are associated with features of metabolic syndrome in human genome-wide association studies and that show variance between SHR and BN-Lx (in silico comparison) are shown in italics. Asb14—ankyrin repeat and SOCS box-containing 14, Il17rd—interleukin 17 receptor D, Arhgef3—Rho guanine nucleotide exchange factor 3, Wnt5a - wingless-type MMTV integration site family, member 5A, Cacna2d3—calcium channel, voltage-dependent, alpha2/delta subunit 3, Cacna1d - calcium channel, voltage-dependent, L type, alpha 1D subunit, Sfmbt1—Scm-like with four mbt domains 1, Itih1—inter-alpha-trypsin inhibitor heavy chain 1, Pbrm1—polybromo 1, Stab1—stabilin 1, Nisch—nischarin, Btd—biotinidase, Syt15—synaptotagmin XV, Ercc6—excision repair cross-complementing rodent repair deficiency, complementation group 6, Arhgap22—Rho GTPase activating protein 22, Grid1—glutamate receptor, ionotropic, delta 1, Nrg3—neuregulin 3, RGD1564958—similar to glyceraldehyde-3-phosphate dehydrogenase (phosphorylating) (EC 1.2.1.12), Myo9b (myosin IXb), Comp—cartilage oligomeric matrix protein, Tmem161a (transmembrane protein 161A), Gatad2a - GATA zinc finger domain containing 2A, Cilp2—cartilage intermediate layer protein 2, Pbx4—pre-B-cell leukemia homeobox 4, Lpar2—lysophosphatidic acid receptor 2, Slc18a1—solute carrier family 18 (vesicular monoamine transporter), member 1, Lpl—lipoprotein lipase.
Mentions: We used a genotyping scan with a set of 34 markers polymorphic between SHR and BN-Lx on chromosome 16 to reveal the extent of the BN-Lx-origin differential segment in the SHR.BN-(D16Rat88-D16Rat9)/Cub congenic strain (SHR.BN16 hereafter). The differential segment spans about 22 Mb at the telomeric end of the RNO16 short arm (Fig 1). Several total genome scans conducted during derivation of the SHR.BN16 strain excluded the presence of non-SHR alleles other than those fixed on RNO16, confirming the congenic status of the new strain. The BN-Lx-derived RNO16 segment hence represents the only genomic difference between the SHR and SHR.BN16 strains.

Bottom Line: We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains.SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats.The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and the General Teaching Hospital, Prague, Czech Republic.

ABSTRACT
Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference) and diastolic (10-15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

Show MeSH
Related in: MedlinePlus