Genome-Wide Association Study of Piscine Myocarditis Virus (PMCV) Resistance in Atlantic Salmon (Salmo salar)

Cardiomyopathy syndrome is a severe, viral disease of Atlantic salmon that mostly affects farmed animals during their late production stage at sea. Caused by piscine myocarditis virus (PMCV), over the past few years outbreaks due to this disease have resulted in significant losses to the aquaculture industry. However, there is currently no vaccine that has proven effective against this virus. In this study, using a challenge model, we investigated the genetic variation for resistance to PMCV, by screening a large number of animals using a 55 K SNP array. In particular, we aimed to identify genetic markers that are tightly linked to higher disease resistance and can potentially be used in breeding programs. Using genomic information, we estimated a heritability of 0.51 ± 0.06, suggesting that resistance against this virus, to a great extent, is controlled by genetic factors. Through association analysis, we identified a significant quantitative trait locus (QTL) on chromosome 27, explaining approximately 57% of the total additive genetic variation. The region harboring this QTL contains various immune-related candidate genes, many of which have previously been shown to have a different expression profile between the naïve and infected animals. We also identified a suggestive association on chromosome 12, with the QTL linked markers located in 2 putatively immune-related genes. These results are of particular interest, as they can readily be implemented into breeding programs, can further assist in fine-mapping the causative mutations, and help in better understanding the biology of the disease and the immunological mechanisms underlying resistance against PMCV.

Genomic Locus Modulating IOP in the BXD RI Mouse Strains

PurposeIntraocular pressure (IOP) is the primary risk factor for developing glaucoma. The present study examines genomic contribution to the normal regulation of IOP in the mouse.MethodsThe BXD recombinant inbred (RI) strain set was used to identify genomic loci modulating IOP. We measured the IOP from 532 eyes from 34 different strains. The IOP data will be subjected to conventional quantitative trait analysis using simple and composite interval mapping along with epistatic interactions to define genomic loci modulating normal IOP.ResultsThe analysis defined one significant quantitative trait locus (QTL) on Chr.8 (100 to 106 Mb). The significant locus was further examined to define candidate genes that modulate normal IOP. There are only two good candidate genes within the 6 Mb over the peak, Cdh8 (Cadherin 8) and Cdh11 (Cadherin 11). Expression analysis on gene expression and immunohistochemistry indicate that Cdh11 is the best candidate for modulating the normal levels of IOP.ConclusionsWe have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL that are two potential candidates for modulating IOP with the most likely gene being Cdh11.

Genomic Locus Modulating IOP in the BXD RI Mouse Strains

PurposeIntraocular pressure (IOP) is the primary risk factor for developing glaucoma. The present study examines genomic contribution to the normal regulation of IOP in the mouse.MethodsThe BXD recombinant inbred (RI) strain set was used to identify genomic loci modulating IOP. We measured the IOP from 532 eyes from 33 different strains. The IOP data will be subjected to conventional quantitative trait analysis using simple and composite interval mapping along with epistatic interactions to define genomic loci modulating normal IOP.ResultsThe analysis defined one significant quantitative trait locus (QTL) on Chr.8 (100 to 106 Mb). The significant locus was further examined to define candidate genes that modulate normal IOP. There are only two good candidate genes within the 6 Mb over the peak, Cdh8 (Cadherin 8) and Cdh11 (Cadherin 11). Expression analysis on gene expression and immunohistochemistry indicate that Cdh11 is the best candidate for modulating the normal levels of IOP.ConclusionsWe have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL that are two potential candidates for modulating IOP with the most likely gene being Cdh11.

Dissection of Genetic Factors Modulating Fetal Growth in Cattle Indicates a Substantial Role of the Non-SMC Condensin I Complex, Subunit G (NCAPG) Gene

The increasing evidence of fetal developmental effects on postnatal life, the still unknown fetal growth mechanisms impairing offspring generated by somatic nuclear transfer techniques, and the impact on stillbirth and dystocia in conventional reproduction have generated increasing attention toward mammalian fetal growth. We identified a highly significant quantitative trait locus (QTL) affecting fetal growth on bovine chromosome 6 in a specific resource population, which was set up by consistent use of embryo transfer and foster mothers and, thus, enabled dissection of fetal-specific genetic components of fetal growth. Merging our data with results from other cattle populations differing in historical and geographical origin and with comparative data from human whole-genome association mapping suggests that a nonsynonymous polymorphism in the non-SMC condensin I complex, subunit G (NCAPG) gene, NCAPG c.1326T>G, is the potential cause of the identified QTL resulting in divergent bovine fetal growth. NCAPG gene expression data in fetal placentomes with different NCAPG c.1326T>G genotypes, which are in line with recent results about differential NCAPG expression in placentomes from studies on assisted reproduction techniques, indicate that the NCAPG locus may give valuable information on the specific mechanisms regulating fetal growth in mammals.

Quantitative trait loci associated with maximal exercise endurance in mice

The role of genetics in the determination of maximal exercise endurance is unclear. Six- to nine-week-old F2 mice ( n = 99; 60 female, 39 male), derived from an intercross of two inbred strains that had previously been phenotyped as having high maximal exercise endurance (Balb/cJ) and low maximal exercise endurance (DBA/2J), were treadmill tested to estimate exercise endurance. Selective genotyping of the F2 cohort ( n = 12 high exercise endurance; n = 12 low exercise endurance) identified a significant quantitative trait locus (QTL) on chromosome X (53.7 cM, DXMit121) in the entire cohort and a suggestive QTL on chromosome 8 (36.1 cM, D8Mit359) in the female mice. Fine mapping with the entire F2 cohort and additional informative markers confirmed and narrowed the QTLs. The chromosome 8 QTL ( EE8 F) is homologous with two suggestive human QTLs and one significant rat QTL previously linked with exercise endurance. No effect of sex ( P = 0.33) or body weight ( P = 0.79) on exercise endurance was found in the F2 cohort. These data indicate that genetic factors in distinct chromosomal regions may affect maximal exercise endurance in the inbred mouse. Whereas multiple genes are located in the identified QTL that could functionally affect exercise endurance, this study serves as a foundation for further investigations delineating the identity of genetic factors influencing maximum exercise endurance.

Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats

The present study evaluated whether the impairment in autoregulation of renal blood flow (RBF) in the fawn-hooded Hypertensive (FHH) rat colocalizes with the Rf-1 region on chromosome 1 that has been previously linked to the development of proteinuria in this strain. Autoregulation of RBF was measured in FHH and a consomic strain (FHH.1BN) in which chromosome 1 from the Brown-Norway (BN) rat was introgressed into the FHH genetic background. The autoregulation indexes (AI) averaged 0.80 ± 0.08 in the FHH and 0.19 ± 0.05 in the FHH.1BN rats. We next performed a genetic linkage analysis for autoregulation of RBF in 85 F2 rats generated from a backcross of FHH.1BN consomic and FHH rats. The results revealed a significant quantitative trait locus (QTL) with a peak logarithm of the odds score of 6.3 near marker D1Rat376. To confirm the existence of this QTL, five overlapping congenic strains were created that spanned the region from markers D1Rat234 to D1Mit14. Transfer of a region of BN chromosome 1 from markers D1Mgh13 to D1Rat89 into the FHH genetic background improved autoregulation of RBF (AI = 0.23 ± 0.04) and reduced protein excretion. In contrast, RBF was poorly autoregulated and the rats were not protected from proteinuria in congenic strains in which other regions of chromosome 1 that exclude the D1Rat376 marker were transferred. These results indicate that there is a gene(s) that influences autoregulation of RBF and proteinuria between markers D1Mgh13 and D1Rat89 on chromosome 1 that lies within the confidence interval of the Rf-1 QTL previously linked to the development of proteinuria in FHH rats.

Influence of Slc11a1 on the Outcome of Salmonella enterica Serovar Enteritidis Infection in Mice Is Associated with Th Polarization

ABSTRACT Genetic analyses identified Ses1 as a significant quantitative trait locus influencing the carrier state of 129S6 mice following a sublethal challenge with Salmonella enterica serovar Enteritidis. Previous studies have determined that Slc11a1 was an excellent candidate gene for Ses1. Kinetics of infection in 129S6 mice and Slc11a1-deficient (129S6-Slc11a1 tm1Mcg ) mice demonstrated that the wild-type allele of Slc11a1 contributed to the S. enterica serovar Enteritidis carrier state as early as 7 days postinfection. Gene expression profiling demonstrated that 129S6 mice had a significant up-regulation of proinflammatory genes associated with macrophage activation at day 10 postinfection, followed by a gradual increase in immunoglobulin transcripts, whereas 129S6-Slc11a1 tm1Mcg mice had higher levels of immunoglobulins earlier in the infection. Quantitative reverse transcription-PCR revealed an increase in Th1 cytokine (Ifng and Il12) and Th1-specific transcription factor Tbx21 expression during infection in both the 129S6 and 129S6-Slc11a1 tm1Mcg strains. However, the expression of Gata3, a transcription factor involved in Th2 polarization, Cd28, and Il4 was markedly increased in Slc11a1-deficient mice during infection, suggesting a predominant Th2 phenotype in 129S6-Slc11a1 tm1Mcg animals following S. enterica serovar Enteritidis infection. A strong immunoglobulin G2a response, reflecting Th1 activity, was observed only in 129S6 mice. All together, these results are consistent with an impact of Slc11a1 on Th cell differentiation during chronic S. enterica serovar Enteritidis infection. The presence of a Th2 bias in Slc11a1-deficient mice is associated with improved bacterial clearance.

Identification of Neuronal Enhancers of the Proopiomelanocortin Gene by Transgenic Mouse Analysis and Phylogenetic Footprinting

ABSTRACT The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-of-function mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a highly significant quantitative trait locus on chromosome 2 associated with obesity traits in several human populations. Here, we identify two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of mammalian POMC transcriptional units. We show that mouse or human genomic regions containing these enhancers are able to direct reporter gene expression to POMC hypothalamic neurons, but not the pituitary of transgenic mice. Conversely, deletion of nPE1 and nPE2 in the context of the entire transcriptional unit of POMC abolishes transgene expression in the hypothalamus without affecting pituitary expression. Our results indicate that the nPEs are necessary and sufficient for hypothalamic POMC expression and that POMC expression in the brain and pituitary is controlled by independent sets of enhancers. Our study advances the understanding of the molecular nature of hypothalamic POMC neurons and will be useful to determine whether polymorphisms in POMC regulatory regions play a role in the predisposition to obesity.

Corrigendum to: Genetic mapping of commercially significant starch characteristics in wheat crosses

Starch properties were measured on the doubled haploid progeny of 2 crosses, one between Cranbrook and Halberd and the other between CD87 and Katepwa. Properties studied included starch peak and final viscosity measured by Rapid Visco Analyser, starch granule size distribution measured by laser light scattering, starch gelatinisation temperature by differential scanning calorimetry, and flour swelling volume. In the Cranbrook Halberd cross (samples from 2 environments), a highly significant quantitative trait locus (QTL) was located on chromosome 4A for both starch peak viscosity and starch/flour swelling volume, centred around the Wx-B1 locus. In previous studies, this locus has been found to be linked to Japanese noodle quality. The increases in starch peak viscosity and flour swelling volume are derived from the Halberd parent, consistent with the fact that Halberd is null for the Wx-B1 locus on chromosome 4A and is missing the respective granule-bound starch synthase protein, whereas Cranbrook is a wheat line carrying the normal 3 Wx loci. The final starch viscosity also showed an association with the Wx-B1 locus. In the CD87 Katepwa cross, the progeny showed an association between peak viscosity and a marker on chromosome 7A. This appeared to be near the Wx-A1 locus. In some experiments, flour viscosity showed a highly significant QTL on chromosome 7B, apparently at the same locus as the late maturity - amylase derived from the Cranbrook parent. Starch gelatinisation onset temperature indicated a significant QTL on chromosomes 2B and 7A (LOD = 2.58 and 3.66, respectively, in interval analyses). Starch gelatinisation peak temperatures indicated a QTL on chromosome 7A, which, although not in the significant (P = 0.05) class based on regression analyses, indicated a LOD score of 3.06 in interval analyses. Heat of gelatinisation (H) indicated a suggestive QTL (LRS = 14.5 with a threshold of 14.7 for P < 0.05, LOD = 2.65 for interval analysis), on chromosome 4A, at the Wx-B1 locus with an increased effect coming from the Halberd parent. The A:B granule ratio analysis indicated a significant QTL on chromosome 4B, but this was not observed in all environments and may be due to the fact that the QTL corresponded to the position of a major QTL controlling plant growth.