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Comparative Genome of GK and Wistar Rats Reveals Genetic Basis of Type 2 Diabetes.

Liu T, Li H, Ding G, Wang Z, Chen Y, Liu L, Li Y, Li Y - PLoS ONE (2015)

Bottom Line: Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways.It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype.Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
The Goto-Kakizaki (GK) rat, which has been developed by repeated inbreeding of glucose-intolerant Wistar rats, is the most widely studied rat model for Type 2 diabetes (T2D). However, the detailed genetic background of T2D phenotype in GK rats is still largely unknown. We report a survey of T2D susceptible variations based on high-quality whole genome sequencing of GK and Wistar rats, which have generated a list of GK-specific variations (228 structural variations, 2660 CNV amplification and 2834 CNV deletion, 1796 protein affecting SNVs or indels) by comparative genome analysis and identified 192 potential T2D-associated genes. The genes with variants are further refined with prior knowledge and public resource including variant polymorphism of rat strains, protein-protein interactions and differential gene expression. Finally we have identified 15 genetic mutant genes which include seven known T2D related genes (Tnfrsf1b, Scg5, Fgb, Sell, Dpp4, Icam1, and Pkd2l1) and eight high-confidence new candidate genes (Ldlr, Ccl2, Erbb3, Akr1b1, Pik3c2a, Cd5, Eef2k, and Cpd). Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways. We present the genomic difference between two closely related rat strains (GK and Wistar) and narrow down the scope of susceptible loci. It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype. Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models.

No MeSH data available.


Related in: MedlinePlus

Density and distribution of SNVs and small indels.(A). Distribution of SNV density in 1Mb segments. (B) Distribution of small-indel density in 1Mb segments. (C) Correlation between the distribution of SNVs and small indels.
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pone.0141859.g003: Density and distribution of SNVs and small indels.(A). Distribution of SNV density in 1Mb segments. (B) Distribution of small-indel density in 1Mb segments. (C) Correlation between the distribution of SNVs and small indels.

Mentions: There were 1,354,739 GK/Slac specific SNVs and 134,554 GK/Slac specific indels. The density of GK/Slac specific SNV/indel was calculated in each 1Mb segment, and their distribution was plotted in Fig 3A and 3B. Most genomic regions were relatively conserved with extremely low SNV density (0–0.0001) and regions with median SNV density (0.0001–0.001) were evenly distributed. When the SNV density increased, the frequency decreased smoothly (0.001–0.002). A long tail indicated the existence of extremely high SNV density (>0.002) regions.


Comparative Genome of GK and Wistar Rats Reveals Genetic Basis of Type 2 Diabetes.

Liu T, Li H, Ding G, Wang Z, Chen Y, Liu L, Li Y, Li Y - PLoS ONE (2015)

Density and distribution of SNVs and small indels.(A). Distribution of SNV density in 1Mb segments. (B) Distribution of small-indel density in 1Mb segments. (C) Correlation between the distribution of SNVs and small indels.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631338&req=5

pone.0141859.g003: Density and distribution of SNVs and small indels.(A). Distribution of SNV density in 1Mb segments. (B) Distribution of small-indel density in 1Mb segments. (C) Correlation between the distribution of SNVs and small indels.
Mentions: There were 1,354,739 GK/Slac specific SNVs and 134,554 GK/Slac specific indels. The density of GK/Slac specific SNV/indel was calculated in each 1Mb segment, and their distribution was plotted in Fig 3A and 3B. Most genomic regions were relatively conserved with extremely low SNV density (0–0.0001) and regions with median SNV density (0.0001–0.001) were evenly distributed. When the SNV density increased, the frequency decreased smoothly (0.001–0.002). A long tail indicated the existence of extremely high SNV density (>0.002) regions.

Bottom Line: Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways.It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype.Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
The Goto-Kakizaki (GK) rat, which has been developed by repeated inbreeding of glucose-intolerant Wistar rats, is the most widely studied rat model for Type 2 diabetes (T2D). However, the detailed genetic background of T2D phenotype in GK rats is still largely unknown. We report a survey of T2D susceptible variations based on high-quality whole genome sequencing of GK and Wistar rats, which have generated a list of GK-specific variations (228 structural variations, 2660 CNV amplification and 2834 CNV deletion, 1796 protein affecting SNVs or indels) by comparative genome analysis and identified 192 potential T2D-associated genes. The genes with variants are further refined with prior knowledge and public resource including variant polymorphism of rat strains, protein-protein interactions and differential gene expression. Finally we have identified 15 genetic mutant genes which include seven known T2D related genes (Tnfrsf1b, Scg5, Fgb, Sell, Dpp4, Icam1, and Pkd2l1) and eight high-confidence new candidate genes (Ldlr, Ccl2, Erbb3, Akr1b1, Pik3c2a, Cd5, Eef2k, and Cpd). Our result reveals that the T2D phenotype may be caused by the accumulation of multiple variations in GK rat, and that the mutated genes may affect biological functions including adipocytokine signaling, glycerolipid metabolism, PPAR signaling, T cell receptor signaling and insulin signaling pathways. We present the genomic difference between two closely related rat strains (GK and Wistar) and narrow down the scope of susceptible loci. It also requires further experimental study to understand and validate the relationship between our candidate variants and T2D phenotype. Our findings highlight the importance of sequenced-based comparative genomics for investigating disease susceptibility loci in inbreeding animal models.

No MeSH data available.


Related in: MedlinePlus