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- Original Research ARTICLE
- dachshund comprehensive owners guide Manual
- Dachshund Dog Characteristics
This comprehensive guide answers every question you may have including: Is a Miniature Dachshund right for me? What do I do now that I've brought home my new dog?
How can I best train my Mini Dachshund? What common mistakes should I avoid? How to Find a Reputable Breeder. Preparing an Indoor Space. The First Few Weeks. Rewarding Positive Behavior. The Benefits of Socialization. Fighting Between Your Dogs. A Primer on Operant Conditioning. Using the NimbleGen Sequence Capture technology and the Illumina platform we enriched and sequenced the target region in one affected and one unaffected dog of wire-hair.
A summary of the statistics describing the resequencing data is given in Table 1. Enrichment of the selected genomic region resulted in and fold enrichment for the affected and unaffected sample, respectively, compared to the non-enriched library. Using the MAQ software Li et al. These three variants where selected for genotyping in 56 unaffected and 28 affected wire-haired dogs of standard size.
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A list of the predicted functional effect on disk calcification for SNPs identified during resequencing can be found in Table A1 in Appendix. By genotyping the three SNPs in a sample of long- and smooth-haired Dachshund, we found no association to disk calcification, data not shown. Instead dogs of these two hair-varieties seem to be fixed for the genotype of affected wire-haired dogs. Table 2. Table 3. Test of association between SNPs and disc calcification. The LD blocks range from 20 to kb in size and all blocks include one or more markers significantly associating with disk calcification on a genome-wide level.
Original Research ARTICLE
Detailed view of the CFA12 genomic region associating with disk calcification in wire-haired Dachshunds. The x -axis show the position on CFA12 in mega bases Mb and the p -values on the y -axis correspond to the p -values from the GWAS in wire-haired dogs corrected for multiple testing Mogensen et al. The horizontal dotted line represents the threshold of genome-wide significance. The graphical representation of the LD pattern across the region is generated in Haploview 4.
The black horizontal lines in the Manhatten plot correspond to the position of the LD blocks defined in Haploview. Linear and logistic regression analyses were performed to investigate the effect of the haplotypes within each window on disk calcification. The maximal number of haplotypes is 2 n , where n is the number of SNPs in a window, which mean that 16 haplotypes could be expected in a four-SNP window. However, with the dataset available and the high extent of LD the observed haplotypes for each of the nine haplotype windows ranged from two to four.
In generalized linear model GLM , residual mean deviance RMD was used as an indicator for variance explained by the haplotype window and thus the lower the RMD the better is the model fit. Looking at both the linear model and GLM all haplotype windows are significantly associated with disk calcification; see Table 4.
Of the nine haplotype windows, we have identified haplotype window 3 as explaining the highest proportion of variance in the disk calcification dataset followed by haplotype window 1 and 2. Test of association with disk calcification for particular haplotypes within the different haplotype windows, based on both the linear model and GLM are given in Table A2 in Appendix. Table 4. We have previously shown that the CFA 36,,—38,, genomic region associates with disk calcification in wire-haired Dachshund on a genome-wide level Mogensen et al.
However, a comprehensive study of sequence variation within the region is required to identify the causal variant s that might explain the association signal. In this study we have investigated genetic variation within the target region through targeted resequencing in order to identify potential risk variants and validate original GWAS findings. To further investigate the locus we have identified LD block pattern across the disease-associated region and estimated the genetic variation explained by the different haplotype windows. Finally, we have developed a risk prediction model for wire-haired Dachshunds, using the disk calcification and haplotype dataset.
Functional SNPs may have variable effect on protein sequence, transcriptional regulation, splicing, microRNA- and transcription factor binding sites depending on their position and flanking sequences. By targeted resequencing we have made a comprehensive list of potential causal variants that could explain the association signal. A ranking of these SNPs is necessary for follow-up studies to be possible.
Numerous SNPs, identified in this study, are predicted to be located within transcription factor binding sites or microRNA-binding sites. Due to the high number of cases sharing the same haplotype we have focused on variants within protein coding regions or UTRs for which the case is homozygous. We have validated the association of one variant in the UTR of KCNQ5 and two synonymous variants in MB21D1 in an independent sample of wire-haired Dachshunds hereby confirming the original GWAS and thus providing further evidence for the association of this region with disk calcification.
Disk herniation is also seen in long- and smooth-haired Dachshunds. However, interestingly, both cases and controls within these two hair variants appear to be fixed for the haplotype found in wire-haired cases. Thus, presumably other loci must be involved in the development of the disease in long- and smooth-haired variants.
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This hypothesis is supported by the fact that when 18 controls and 15 cases of long- and smooth-hair were included in our original GWAS Mogensen et al. However, more dogs are needed to confirm this hypothesis. In terms of SNPs validated in the wire-haired dogs any of the three variants may have a potential functional impact on the phenotype in wire-haired dogs.
Resequencing of the target region in a larger number of affected and unaffected dogs might be necessary to eliminate some of the identified variants before a thorough follow-up on other highly ranked variants can be carried out. To characterize the CFA12 locus and potentially narrow down the candidate region we looked at the LD block pattern.
dachshund comprehensive owners guide Manual
Haploview identify seven LD blocks across the region associating with disk calcification. That this genomic region falls into a segment of strong LD is further documented by 28 of the 33 cases in the GWAS sharing the same haplotype across all 36 genome-wide significant markers within this region Mogensen et al. In addition several of the markers show more or less equivalent evidence of association for the given signal indicating that the markers are highly correlated. Given the high extent of LD within this region it is difficult to resolve whether two or more independent loci contribute independent effects to disk calcification.
Analyzing haplotype window effects could potentially pinpoint a haplotype window with a higher effect on disk calcification and thus define or narrow down the region of interest. From these results it therefore seems most likely that the causal genetic variant s are to be found within the CFA 36,,—37,, genomic region, which harbors the ncRNAs cfa-mirc-2 and cfa-mira as well as a part of RIMS1. However, all haplotype windows explain a fair proportion of the variance in the dataset, which is not surprising due to the large amount of LD within this region.
Dachshund Dog Characteristics
Therefore one needs to be careful when narrowing down the region to these three haplotype windows. A genetic prediction model for intervertebral disk calcification based on these haplotype effects analyses may form a valuable tool for genetic counseling in the wire-haired Dachshund population.
Genome-wide association studies has to a large extent focused on the detection of effects attributable to common SNPs. Even when a true causal variant is identified challenges remain in reconstructing the molecular mechanisms whereby the variant have an impact on the phenotype of interest and even more work is necessary in translating these findings into advantages in clinical care. Based on a literature search no genes with a direct biological link is present within the disease-associated region one could speculate whether the region contains a regulatory element controlling the expression levels of a causal gene located either upstream or downstream of the candidate region identified here.
One hypothesis is a regulatory variant affecting the expression level of COL9A1. Collagen IX serves as a minor component in the annulus fibrosus and the nucleus pulposus and is thought to be involved in maintaining network integrity in the normal disk. In the present study we validate the previously identified association of the locus CFA 36,,—38,, with disk calcification in an independent sample of wire-haired Dachshund thus providing strong evidence that variation within this locus affect the development of disk calcification in wire-haired Dachshunds.
Moreover, our results suggest that the locus falls within a region of strong LD hence complicating the identification of the causal variant. Our predictions on the effect of the nine different haplotype windows on disk calcification imply that the causal variant s are to be found within the CFA 36,,—37,, genomic region, however care must be taken when drawing this conclusion as all haplotype windows explain a reasonable part of the variability in the disk calcification dataset.
This study was confined to Dachshund registered in the DDC.
Information regarding size standard, miniature, and rabbit , hair variant wire-haired, long-haired and smooth-haired sex, age, and pedigree records were obtained from the Danish Kennel Club registry. For further information on the distribution of disk calcifications among cases and controls see Mogensen et al. For targeted resequencing one affected and one unaffected dog was selected. The affected dog had 12 disk calcifications as evaluated from the radiographic examination and was homozygous across the 36 significantly associated markers in the disease-associated region.
The unaffected dog had no disk calcifications and was homozygous for the opposite alleles of the affected dog across the entire region. Both were female standard wire-haired dogs and unrelated at great grandparental level. The probe set design was approved with the fraction of bases in the target region covered by probes being Unbound fragments were washed away. The target-enriched pool was eluted and recovered from the array and amplified by ligation-mediated PCR.
Quantitative fluorescence PCR qPCR was performed on pre- and post-enriched libraries to calculate relative-fold enrichment of the targeted region. Bowtie Langmead et al.
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