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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.

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Related in: MedlinePlus

Analysis of GK/Slac specific protein affecting SNVs.(A) Variants were classified into five groups based on their genotypes in GK/Slac and Wistar/Slac. As shown in the bottom legend, circles stand for the original reference allele whereas stars and triangles represent two different mutant alleles. Taken group 1 as an example, variants is heterozygous in GK/Slac that have one mutant allele and one reference allele, while it is homozygous-reference in Wistar/Slac. Almost all variants are in group1, group2, and group3. (B) Genotype profiling for 1762 GK/Slac specific SNVs in 28 previous sequenced rat strains. GK/Ox and GK/Slac are GK strains which came from different geographical locations. BBDP is a type 1 diabetic model, another 11 Wistar derived rats are labeled by green. (C) T2D related prior genes. (D) Functional effect of nonsynonymous SNVs predicted by SIFT.
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pone.0141859.g004: Analysis of GK/Slac specific protein affecting SNVs.(A) Variants were classified into five groups based on their genotypes in GK/Slac and Wistar/Slac. As shown in the bottom legend, circles stand for the original reference allele whereas stars and triangles represent two different mutant alleles. Taken group 1 as an example, variants is heterozygous in GK/Slac that have one mutant allele and one reference allele, while it is homozygous-reference in Wistar/Slac. Almost all variants are in group1, group2, and group3. (B) Genotype profiling for 1762 GK/Slac specific SNVs in 28 previous sequenced rat strains. GK/Ox and GK/Slac are GK strains which came from different geographical locations. BBDP is a type 1 diabetic model, another 11 Wistar derived rats are labeled by green. (C) T2D related prior genes. (D) Functional effect of nonsynonymous SNVs predicted by SIFT.

Mentions: Next we investigated potential T2D candidate variants from GK/Slac-specific SNVs and indels. We divided SNP/indels into five groups to illustrate their genotype patterns in GK/Slac and Wistar/Slac (Fig 4A). Group1 (0/1, 0/0) contained sites that were heterozygous variant in GK/Slac and homozygous reference in Wistar/Slac; Group2 (1/1, 0/0) contained sites that were homozygous variant in GK/Slac and homozygous reference in Wistar/Slac; Group3 (1/1, 0/1) contained sites that were homozygous variant in GK/Slac and heterozygous variant in Wistar/Slac; Group4 (1/2, 0/0) was similar with Group2 and Group5 (1/2, 0/1) was similar with Group3, which were rare sites with two mutant alleles. Among 1,354,739 GK/Slac specific SNVs, group 1 to 3 accounted for the majority of SNVs with 3.6%, 92.9% and 3.5%, respectively (Table 1). Like SNVs, among 134,554 GK/Slac specific indels, proportion of group1 to group3 were 5.0%, 81.9% and 13.1%, respectively. In summary, most SNV and indel variants belonged to groups 1, 2 and 3, and only few allele sites had the complicated allele composition in group 4 and 5 which was consistent with the low probability of de novo production of two rare alleles in the lab inbreeding strain. Group 2 accounted for a large proportion that was concordant with the high homozygosity rate of inbred laboratory rat. Next we annotated the functional effect of GK/Slac specific SNVs/indels by ANNOVAR [45]. Table 2 showed the number of SNPs/indels in each genotype group and functional class. Variants had potential to interrupt the protein functions were called protein affecting variants (PAVs), including nonsynonymous, stopgain, stoploss, splicing, frameshift indels and exonic ncRNA. We detected 1796 PAVs, including 1762 SNVs and 34 indels (S7AB File).


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)

Analysis of GK/Slac specific protein affecting SNVs.(A) Variants were classified into five groups based on their genotypes in GK/Slac and Wistar/Slac. As shown in the bottom legend, circles stand for the original reference allele whereas stars and triangles represent two different mutant alleles. Taken group 1 as an example, variants is heterozygous in GK/Slac that have one mutant allele and one reference allele, while it is homozygous-reference in Wistar/Slac. Almost all variants are in group1, group2, and group3. (B) Genotype profiling for 1762 GK/Slac specific SNVs in 28 previous sequenced rat strains. GK/Ox and GK/Slac are GK strains which came from different geographical locations. BBDP is a type 1 diabetic model, another 11 Wistar derived rats are labeled by green. (C) T2D related prior genes. (D) Functional effect of nonsynonymous SNVs predicted by SIFT.
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pone.0141859.g004: Analysis of GK/Slac specific protein affecting SNVs.(A) Variants were classified into five groups based on their genotypes in GK/Slac and Wistar/Slac. As shown in the bottom legend, circles stand for the original reference allele whereas stars and triangles represent two different mutant alleles. Taken group 1 as an example, variants is heterozygous in GK/Slac that have one mutant allele and one reference allele, while it is homozygous-reference in Wistar/Slac. Almost all variants are in group1, group2, and group3. (B) Genotype profiling for 1762 GK/Slac specific SNVs in 28 previous sequenced rat strains. GK/Ox and GK/Slac are GK strains which came from different geographical locations. BBDP is a type 1 diabetic model, another 11 Wistar derived rats are labeled by green. (C) T2D related prior genes. (D) Functional effect of nonsynonymous SNVs predicted by SIFT.
Mentions: Next we investigated potential T2D candidate variants from GK/Slac-specific SNVs and indels. We divided SNP/indels into five groups to illustrate their genotype patterns in GK/Slac and Wistar/Slac (Fig 4A). Group1 (0/1, 0/0) contained sites that were heterozygous variant in GK/Slac and homozygous reference in Wistar/Slac; Group2 (1/1, 0/0) contained sites that were homozygous variant in GK/Slac and homozygous reference in Wistar/Slac; Group3 (1/1, 0/1) contained sites that were homozygous variant in GK/Slac and heterozygous variant in Wistar/Slac; Group4 (1/2, 0/0) was similar with Group2 and Group5 (1/2, 0/1) was similar with Group3, which were rare sites with two mutant alleles. Among 1,354,739 GK/Slac specific SNVs, group 1 to 3 accounted for the majority of SNVs with 3.6%, 92.9% and 3.5%, respectively (Table 1). Like SNVs, among 134,554 GK/Slac specific indels, proportion of group1 to group3 were 5.0%, 81.9% and 13.1%, respectively. In summary, most SNV and indel variants belonged to groups 1, 2 and 3, and only few allele sites had the complicated allele composition in group 4 and 5 which was consistent with the low probability of de novo production of two rare alleles in the lab inbreeding strain. Group 2 accounted for a large proportion that was concordant with the high homozygosity rate of inbred laboratory rat. Next we annotated the functional effect of GK/Slac specific SNVs/indels by ANNOVAR [45]. Table 2 showed the number of SNPs/indels in each genotype group and functional class. Variants had potential to interrupt the protein functions were called protein affecting variants (PAVs), including nonsynonymous, stopgain, stoploss, splicing, frameshift indels and exonic ncRNA. We detected 1796 PAVs, including 1762 SNVs and 34 indels (S7AB File).

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