Whole genome sequencing and novel candidate genes for CAKUT and altered nephrogenesis in the HSRA rat

Showmaker, Kurt C.; Cobb, Meredith; Johnson, Ashley; Yang, Wenyu; Garrett, Michael R.

doi:10.1152/physiolgenomics.00112.2019

Cited by 5 publications

(6 citation statements)

References 90 publications

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“…The ACI haplotype is barely distinct from BUF, F344, M520, MR, and WN. HS founders MT phylogeny has been reported previously (Showmaker et al 2020). However, their data (Ramdas et al 2018) swapped WN and WKY.…”

Section: Two Versions Of Mt Are Present In Modern Hs Ratsmentioning

confidence: 85%

Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population

Okamoto,

Chitre,

Sanches

et al. 2023

Preprint

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Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial Chromosomes. We genotyped the Y and mitochondrial chromosomes in heterogeneous stock rats (Rattus norvegicus), which were created in 1984 by intercrossing eight inbred strains and have subsequently been maintained as an outbred population for 100 generations. As the Y and mitochondrial Chromosomes do not recombine, we determined which founder had contributed these chromosomes for each rat, and then performed association analysis for all complex traits (n=12,055; intersection of 12,116 phenotyped and 15,042 haplotyped rats).We found the eight founders had 8 distinct Y and 4 distinct mitochondrial Chromosomes, however only two of each were observed in our modern heterogeneous stock rat population (Generations 81-97). Despite the unusually large sample size, the p-value distribution did not deviate from expectations; there were no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and mitochondrial Chromosomes were strongly associated with expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern heterogeneous stock rats there are no Y and mitochondrial Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and mitochondrial Chromosomes that do not appear in modern heterogeneous stock rats, nor do they address effects that may exist in other rat populations, or in other species.Article SummaryHeterogeneous stock rats were created in 1984 by intercrossing eight inbred strains. This genetically and phenotypically diverse population has been used for numerous genetic studies. We developed a method (leveraging existing data) to identify the founder strain origin of Y and mitochondrial Chromosomes in modern heterogeneous stock rats. We examined effects of these chromosomes’ genotype on behavioral, physiological, and gene expression traits among 12,055 rats. We found no significant associations, except for expression of genes located on these chromosomes.

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Section: Two Versions Of Mt Are Present In Modern Hs Ratsmentioning

confidence: 85%

Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population

Okamoto,

Chitre,

Sanches

et al. 2023

Preprint

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“…A sequence similarity analysis was performed, including the HSRA strain as the reference sequence, since it was inbred for URA and was selected from the same HS population (Showmaker et al, 2020). HSRA is a valuable reference to look for sequence similarity to uncover potential penetrance modifiers involved in increasing susceptibility to URA.…”

Section: Similarity Analysismentioning

confidence: 99%

“…As part of a large multi-center study of drug abuse-related behavioral traits (www.ratgenes.org). Showmaker et al (2020) used a model of congenital abnormalities of the kidney and urogenital tract or CAKUT named HSRA. This inbred strain was generated by phenotypic selection from a high URA incidence HS family from the same population used in the present analysis.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study and sequence similarity analysis for unilateral renal agenesis using heterogeneous stock rats undercovers theKITgene andAHR,ATF3,GATA3,HNF1B,POU2F2, andTFCP2transcription factors as potential candidates to explain incomplete penetrance

Leal-Gutiérrez,

Munro,

Chen

et al. 2023

Preprint

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Human unilateral renal agenesis is a congenital urinary tract malformation. Affected individuals have only one kidney, which is often an asymptomatic developmental defect. A total of 5,585 male and female HS rats were assessed for unilateral renal agenesis and genotyped for 3,513,321 markers. The R package SAIGEgds was used for the association analysis. The adjusted p-value threshold for the association analysis determined by permutation was equal to 5.6 (-log10). Two additional datasets were used as validation tests. Population two included 1,577 rats genotyped for 7,425,889 markers and a case-control imbalance equal to 1:174; population three included 1,407 rats, genotyped for 254,932 markers and case-control ratio equal to 1:38. The python package GxTheta was used to perform a polygenic epistasis analysis for the analyzed HS rat population. A founder haplotype mosaic determination was performed using the R package QTL2. Associated regions were selected for further analysis, including long-read PacBio sequencing for founder individuals and a founder haplotype prediction test. A similarity analysis at a genomic level and for loci encoding transcription factors predicted to interact with selected sequences inside the associated loci were accomplished. A total of 1,181 polymorphisms were associated with URA. All associated polymorphisms were located on chromosome 14 between 32.9 and 36.6 Mb. The most significant polymorphism was chr14:36,411,266, a G/T transversion. The same associated region was identified in population three. Polygenic epistasis was determined as not predominant for the presentation of URA. Based on the haplotype mosaic probability estimation, cases display a higher probability of inheriting the ACI allele. The long-read sequencing analysis showed the presence of an Erv insertion inside the intron one of the KIT gene located inside the associated region. The Erv insertion comprises one Erv sequence and two Ltr sequences located downstream and upstream of the former. No Erv insertion was identified for the founder strain BN. For ACI and HSRA, only one Ltr sequence was identified. One hundred and seven genes encoding TFs that recognize binding sites on the Erv insertion were analyzed for sequence similarity against the reference HSRA. The TF similarity score analysis for the interaction genotype and phenotype showed significance after FDR correction for 20 TFs, including AHR, HNF1B, JUNB, RARG, and RXRA. A mechanism identifying URA as a threshold phenotype is suggested in HS rats. It implies the existence of a minimum threshold for the final number of nephrons and kidney associated structures required for stalling the apoptotic process of the metanephric rudiments. Animals exhibiting a quantitative cumulative defect would express URA, being this malformation identified as a phenotype with decreased penetrance in the assessed population of HS rats. All these processes are described as mediated by KIT and TFs able to interact with sequences of the Erv insertion.

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“…Therefore, 29 rat stains, including ACI/EurMcwi, BBDP/Wor, F344/NCrl, FHH/EurMcwi, FHL/EurMcwi, GK/Ox, LE/Stm, LEW/Crl, LEW/NCrl, LH/MavRrrc, LL/MavRrrc, LN/MavRrrc, MHS/Gib, MNS/Gib, SBH/Ygl, SBN/Ygl, SHR/NHsd, SHRSP/Gla, SR/Jr, SS/Jr, SS/JrHsdMcwi, WAG/Rij, WKY/Gla, WKY/NCrl, WKY/NHsd, BN-Lx/CubPrin, SHR/NCrlPrin, SHR/OlaIpcvPrin and SUO_F344 were sequenced to screen the artificial selective sweeps associated with cardiovascular and metabolic phenotypes [26,31]. In addition, WGS was also performed on 7 strains: DA/BklArbNsi, F344/NHsd, DA/hanKini, DA/OlaHsd, E3/han, PVG/1AV1.Kini and HSRA to understand the differences in susceptibilities to arthritis, autoimmunity, inflammation, cancer and congenital abnormalities of the kidney and urogenital tracts [32][33][34].…”

Section: Strain Selectionmentioning

confidence: 99%

“…As illustrated in Figure 1 , 45 of 47 rat strains had whole genomes sequenced from 2010 - 2015, making this the most prolific period in rat genome sequencing history. Among these 47 rat strains, only the BN/SsNHsd rats were sequenced using the Sanger method 11 , while the remaining 46 rat strains were sequenced on either SOLiD 28 - 29 , 33 or Illumina platforms 26 - 27 , 30 - 32 , 34 . In terms of sequencing depth, the lowest genome coverage was 7× for the BN/SsNHsd rat, followed by ~10× for BBDP/Wor and ~12× for WKY/NHsd.…”

Section: Genome Sequencing In Ratsmentioning

confidence: 99%

Genome-to-phenome research in rats: progress and perspectives

et al. 2021

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Because of their relatively short lifespan (<4 years), rats have become the second most used model organism to study health and diseases in humans who may live for up to 120 years. First-, second- and third-generation sequencing technologies and platforms have produced increasingly greater sequencing depth and accurate reads, leading to significant advancements in the rat genome assembly during the last 20 years. In fact, whole genome sequencing (WGS) of 47 strains have been completed. This has led to the discovery of genome variants in rats, which have been widely used to detect quantitative trait loci underlying complex phenotypes based on gene, haplotype, and sweep association analyses. DNA variants can also reveal strain, chromosome and gene functional evolutions. In parallel, phenome programs have advanced significantly in rats during the last 15 years and more than 10 databases host genome and/or phenome information. In order to discover the bridges between genome and phenome, systems genetics and integrative genomics approaches have been developed. On the other hand, multiple level information transfers from genome to phenome are executed by differential usage of alternative transcriptional start (ATS) and polyadenylation (APA) sites per gene. We used our own experiments to demonstrate how alternative transcriptome analysis can lead to enrichment of phenome-related causal pathways in rats. Development of advanced genome-to-phenome assays will certainly enhance rats as models for human biomedical research.

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Whole genome sequencing and novel candidate genes for CAKUT and altered nephrogenesis in the HSRA rat

Cited by 5 publications

References 90 publications

Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population

Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population

Genome-wide association study and sequence similarity analysis for unilateral renal agenesis using heterogeneous stock rats undercovers theKITgene andAHR,ATF3,GATA3,HNF1B,POU2F2, andTFCP2transcription factors as potential candidates to explain incomplete penetrance

Genome-to-phenome research in rats: progress and perspectives

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