Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer.

Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene.

An idiopathic epilepsy (IE) risk haplotype on canine chromosome (CFA) 14 has been reported to interact with the CFA37 common risk haplotype in the Belgian shepherd (BS). Additional IE cases and control dogs were genotyped for the risk haplotypes to validate these previous findings. In the new cohort, the interaction between the two regions significantly elevated IE risk. When the haplotypes were analyzed individually, particular haplotypes on both CFA14 (ACTG) and 37 (GG) were associated with elevated IE risk, though only the CFA37 AA was significantly associated (p < 0.003) with reduced risk in the new cohort. However, the CFA14 ACTG risk was statistically significant when the new and previous cohort data were combined. The frequency of the ACTG haplotype was four-fold higher in BS dogs than in other breeds. Whole genome sequence analysis revealed that a 3-base pair predicted disruptive insertion in the RAPGEF5 gene, which is adjacent to the CFA14 risk haplotype. RAPGEF5 is involved in the Wnt-ß-catenin signaling pathway that is crucial for normal brain function. Although this risk variant does not fully predict the likelihood of a BS developing IE, the association with a variant in a candidate gene may provide insight into the genetic control of canine IE.

Congenital idiopathic megaesophagus in the German shepherd dog is a sex-differentiated trait and is associated with an intronic variable number tandem repeat in Melanin-Concentrating Hormone Receptor 2.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy.

Unique Transcriptomic Changes Underlie Hormonal Interactions During Mammary Histomorphogenesis in Female Pigs.

Successful lactation and the risk for developing breast cancer depend on growth and differentiation of the mammary gland (MG) epithelium that is regulated by ovarian steroids (17ß-estradiol [E] and progesterone [P]) and pituitary-derived prolactin (PRL). Given that the MG of pigs share histomorphogenic features present in the normal human breast, we sought to define the transcriptional responses within the MG of pigs following exposure to all combinations of these hormones. Hormone-ablated female pigs were administered combinations of E, medroxyprogesterone 17-acetate (source of P), and either haloperidol (to induce PRL) or 2-bromo-α-ergocryptine. We subsequently monitored phenotypic changes in the MG including mitosis, receptors for E and P (ESR1 and PGR), level of phosphorylated STAT5 (pSTAT5), and the frequency of terminal ductal lobular unit (TDLU) subtypes; these changes were then associated with all transcriptomic changes. Estrogen altered the expression of approximately 20% of all genes that were mostly associated with mitosis, whereas PRL stimulated elements of fatty acid metabolism and an inflammatory response. Several outcomes, including increased pSTAT5, highlighted the ability of E to enhance PRL action. Regression of transcriptomic changes against several MG phenotypes revealed 1669 genes correlated with proliferation, among which 29 were E inducible. Additional gene expression signatures were associated with TDLU formation and the frequency of ESR1 or PGR. These data provide a link between the hormone-regulated genome and phenome of the MG in a species having a complex histoarchitecture like that in the human breast, and highlight an underexplored synergy between the actions of E and PRL during MG development.

Pleiotropic Loci Associated With Foot Disorders and Common Periparturient Diseases in Holstein Cattle.

Lameness is an animal welfare issue that incurs substantial financial and environmental costs. This condition is commonly caused by digital dermatitis (DD), sole ulcers (SU), and white line disease (WLD). Susceptibility to these three foot disorders is due in part to genetics, indicating that genomic selection against these foot lesions can be used to reduce lameness prevalence. It is unclear whether selection against foot lesions will lead to increased susceptibility to other common diseases such as mastitis and metritis. Thus, the aim of this study was to determine the genetic correlation between causes of lameness and other common health disorders to identify loci contributing to the correlation. Genetic correlation estimates between SU and DD and between SU and WLD were significantly different from zero (p < 0.05), whereas estimates between DD and mastitis, DD and milk fever, and SU and metritis were suggestive (p < 0.1). All five of these genetic correlation estimates were positive. Two-trait genome-wide association studies (GWAS) for each of these five pairs of traits revealed common regions of association on BTA1 and BTA8 for pairs that included DD or SU as one of the traits, respectively. Other regions of association were unique to the pair of traits and not observed in GWAS for other pairs of traits. The positive genetic correlation estimates between foot disorders and other health disorders imply that selection against foot disorders may also decrease susceptibility to other health disorders. Linkage disequilibrium blocks defined around significant and suggestive SNPs from the two-trait GWAS included genes and QTL that were functionally relevant, supporting that these regions included pleiotropic loci.

Enhancing student scientific literacy through participation in citizen science focused on companion animal behavior.

The Covid-19 pandemic served as the impetus to implement activities designed to engage students in the remote instructional environment while simultaneously developing scientific literacy skills. In a high enrollment general education animal science course, numerous activities were designed to improve scientific literacy. These included specifically developed videos covering strategies for reading published science literature, the utilization of topically relevant scientific articles that captured student interest, and engaging students in a citizen science exercise on whether dogs align themselves to the Earth's magnetic field during excretion behavior. Employing pre- and post-self-perception surveys coupled with tasking students to apply their scientific literacy skills in an assessment scenario demonstrated that students' self-perception of their scientific literacy improved 30% (P < 0.05) with approximately 80% of students accurately applying their literacy skills. The citizen science study on excretory behavior was modeled on previously published findings thereby providing an opportunity to validate the published work which had indicated that dogs align their bodies in a North-South axis during excretion. The present study did not demonstrate preferential alignment to any geomagnetic orientation which emphasized to the students the need for scientific replication. Inclusion of simple activities that were relevant to students' daily lives, and providing interpretive context for those activities, resulted in improved self-perceived scientific literacy.

Early-emerging and highly heritable sensitivity to human communication in dogs.

Human cognition is believed to be unique in part because of early-emerging social skills for cooperative communication.1 Comparative studies show that at 2.5 years old, children reason about the physical world similarly to other great apes, yet already possess cognitive skills for cooperative communication far exceeding those in our closest primate relatives.2,3 A growing body of research indicates that domestic dogs exhibit functional similarities to human children in their sensitivity to cooperative-communicative acts. From early in development, dogs flexibly respond to diverse forms of cooperative gestures.4,5 Like human children, dogs are sensitive to ostensive signals marking gestures as communicative, as well as contextual factors needed for inferences about these communicative acts.6-8 However, key questions about potential biological bases for these abilities remain untested. To investigate their developmental and genetic origins, we tested 375 8-week-old dog puppies on a battery of social-cognitive measures. We hypothesized that if dogs' skills for cooperating with humans are biologically prepared, then they should emerge robustly in early development, not require extensive socialization or learning, and exhibit heritable variation. Puppies were highly skillful at using diverse human gestures, and we found no evidence that their performance required learning. Critically, over 40% of the variation in dogs' point-following abilities and attention to human faces was attributable to genetic factors. Our results suggest that these social skills in dogs emerge early in development and are under strong genetic control.

Genome-Wide Association Studies Reveal Susceptibility Loci for Noninfectious Claw Lesions in Holstein Dairy Cattle.

Sole ulcers (SUs) and white line disease (WLD) are two common noninfectious claw lesions (NICL) that arise due to a compromised horn production and are frequent causes of lameness in dairy cattle, imposing welfare and profitability concerns. Low to moderate heritability estimates of SU and WLD susceptibility indicate that genetic selection could reduce their prevalence. To identify the susceptibility loci for SU, WLD, SU and/or WLD, and any type of noninfectious claw lesion, genome-wide association studies (GWAS) were performed using generalized linear mixed model (GLMM) regression, chunk-based association testing (CBAT), and a random forest (RF) approach. Cows from five commercial dairies in California were classified as controls having no lameness records and ≥6 years old (n = 102) or cases having SU (n = 152), WLD (n = 117), SU and/or WLD (SU + WLD, n = 198), or any type of noninfectious claw lesion (n = 217). The top single nucleotide polymorphisms (SNPs) were defined as those passing the Bonferroni-corrected suggestive and significance thresholds in the GLMM analysis or those that a validated RF model considered important. Effects of the top SNPs were quantified using Bayesian estimation. Linkage disequilibrium (LD) blocks defined by the top SNPs were explored for candidate genes and previously identified, functionally relevant quantitative trait loci. The GLMM and CBAT approaches revealed the same regions of association on BTA8 for SU and BTA13 common to WLD, SU + WLD, and NICL. These SNPs had effects significantly different from zero, and the LD blocks they defined explained a significant amount of phenotypic variance for each dataset (6.1-8.1%, p < 0.05), indicating the small but notable contribution of these regions to susceptibility. These regions contained candidate genes involved in wound healing, skin lesions, bone growth and mineralization, adipose tissue, and keratinization. The LD block defined by the most significant SNP on BTA8 for SU included a SNP previously associated with SU. The RF models were overfitted, indicating that the SNP effects were very small, thereby preventing meaningful interpretation of SNPs and any downstream analyses. These findings suggested that variants associated with various physiological systems may contribute to susceptibility for NICL, demonstrating the complexity of genetic predisposition.

Genetic characterization of Addison's disease in Bearded Collies.

BACKGROUND: Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. RESULTS: Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. CONCLUSION: Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.

Genome-Wide Association Studies Reveal Susceptibility Loci for Digital Dermatitis in Holstein Cattle.

Digital dermatitis (DD) causes lameness in dairy cattle. To detect the quantitative trait loci (QTL) associated with DD, genome-wide association studies (GWAS) were performed using high-density single nucleotide polymorphism (SNP) genotypes and binary case/control, quantitative (average number of FW per hoof trimming record) and recurrent (cases with ≥2 DD episodes vs. controls) phenotypes from cows across four dairies (controls n = 129 vs. FW n = 85). Linear mixed model (LMM) and random forest (RF) approaches identified the top SNPs, which were used as predictors in Bayesian regression models to assess the SNP predictive value. The LMM and RF analyses identified QTL regions containing candidate genes on Bos taurus autosome (BTA) 2 for the binary and recurrent phenotypes and BTA7 and 20 for the quantitative phenotype that related to epidermal integrity, immune function, and wound healing. Although larger sample sizes are necessary to reaffirm these small effect loci amidst a strong environmental effect, the sample cohort used in this study was sufficient for estimating SNP effects with a high predictive value.

Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs.

The Australian Terrier breed is the breed at highest risk for naturally-occurring diabetes mellitus in the United States, where it is 32 times more likely to develop diabetes compared to mixed breed dogs. However, the heritability and mode of inheritance of spontaneous diabetes in Australian Terriers has not been reported. The aim of this study was therefore to investigate the heritability and mode of inheritance of diabetes in Australian Terriers. A cohort of related Australian Terriers including 383 Australian Terriers without diabetes, 86 Australian Terriers with spontaneous diabetes, and 14 Australian Terriers with an unknown phenotype, was analyzed. A logistic regression model including the effects of sex was formulated to evaluate the heritability of diabetes. The inheritance pattern of spontaneous diabetes in Australian Terriers was investigated by use of complex segregation analysis. Six possible inheritance models were studied, and the Akaike Information Criterion was used to determine the best model for diabetes inheritance in Australian Terriers, among the models deemed biologically feasible. Heritability of diabetes in Australian Terriers was estimated at 0.18 (95% confidence interval 0.0-0.67). There was no significant difference in the effect of males and females on disease outcome. Complex segregation analysis suggested that the mode of diabetes inheritance in Australian Terriers is polygenic, with no evidence for a large effect single gene influencing diabetes. It is concluded that in the population of Australian Terriers bred in the United States, a relatively small degree of genetic variation contributes to spontaneous diabetes. A genetic uniformity for diabetes-susceptible genes within the population of Australian Terriers bred in the Unites States could increase the risk of diabetes in this cohort. These findings hold promise for future genetic studies of canine diabetes focused on this particular breed.

Variants in FtsJ RNA 2'-O-Methyltransferase 3 and Growth Hormone 1 are associated with small body size and a dental anomaly in dogs.

Domesticated dogs show unparalleled diversity in body size across breeds, but within breeds variation is limited by selective breeding. Many heritable diseases of dogs are found among breeds of similar sizes, suggesting that as in humans, alleles governing growth have pleiotropic effects. Here, we conducted independent genome-wide association studies in the small Shetland Sheepdog breed and discovered a locus on chromosome 9 that is associated with a dental abnormality called maxillary canine-tooth mesioversion (MCM) (P = 1.53 × 10-7) as well as two body size traits: height (P = 1.67 × 10-5) and weight (P = 1.16 × 10-7). Using whole-genome resequencing data, we identified variants in two proximal genes: FTSJ3, encoding an RNA methyltransferase, and GH1, encoding growth hormone. A substitution in FTSJ3 and a splice donor insertion in GH1 are strongly associated with MCM and reduced body size in Shetland Sheepdogs. We demonstrated in vitro that the GH1 variant leads to exon 3 skipping, predicting a mutant protein known to cause human pituitary dwarfism. Statistical modeling, however, indicates that the FTSJ3 variant is the stronger predictor of MCM and that each derived allele reduces body size by about 1 inch and 5 pounds. In a survey of 224 breeds, both FTSJ3 and GH1 variants are frequent among very small "toy" breeds and absent from larger breeds. Our findings indicate that a chromosome 9 locus harboring tightly linked variants in FTSJ3 and GH1 reduces growth in the Shetland Sheepdog and toy breed dogs and confers risk for MCM through vertical pleiotropy.

A Review of the Impact of Neuter Status on Expression of Inherited Conditions in Dogs.

Gonadectomy is an important reproductive management tool employed in many countries, and is highly prevalent in the US with an estimated 85% of dogs being neutered. Despite the societal benefits in pet population control, negative associations between neuter status, and health conditions have been reported in recent years. Most particularly observed are the consequences of early age neutering. Knowing that different physiological systems rely upon gonadal steroids during development and physiological maintenance, studies have been undertaken to assess the impact of neuter status on multiple body and organ systems. For some inherited conditions, neutering is associated with an increased risk of expression. Neutering has also been associated with altered metabolism and a predisposition for weight gain in dogs, which may confound the detected risk association between neutering and disease expression. This review summarizes the effects of neutering on cancer, orthopedic, and immune disorders in the dog and also explores the potentially exacerbating factor of body weight.

Heritability of Unilateral Elbow Dysplasia in the Dog: A Retrospective Study of Sire and Dam Influence.

Canine elbow dysplasia is a significant health issue affecting many breeds. Unfortunately, treatments remain relatively limited, so control of this disease often falls to selectively breeding for dogs with normal elbows. The objectives of this study were to evaluate the heritability of left-sided vs. right-sided elbow dysplasia, and to assess potential differential sire and the dam influence on offspring elbow status. In a retrospective study, elbow data from 130,117 dogs over 2 years old representing 17 breeds were obtained from the database of the Orthopedic Foundation for Animals and included in the study. Heritability estimates for unilateral elbow dysplasia varied between breeds (ranging from 0.01 to 0.36) and were similar between the left and right elbows. The estimated genetic correlation between disease in the left and right elbow ~1 in the majority of breeds, with the exception of the hybrids, Australian Shepherds, and the Australian Cattle Dogs, likely due to low numbers of affected individuals. The sire and dam had equal impact on the offspring's elbow status. Furthermore, there was no increased risk for the sire or dam to pass on the same unilaterality of their elbow dysplasia to their offspring. However, the overall risk of elbow dysplasia in the offspring did increase when one or both parents were affected, though this also varied based on breed. Understanding of the impact that the sire and dam have on the offspring and of the overall heritability of both bilateral and unilateral elbow dysplasia is important in guiding breeding decisions to reduce the incidence in future generations of dogs.

Frameshift Variant in MFSD12 Explains the Mushroom Coat Color Dilution in Shetland Ponies.

Mushroom is a unique coat color phenotype in Shetland Ponies characterized by the dilution of the chestnut coat color to a sepia tone and is hypothesized to be a recessive trait. A genome wide association study (GWAS), utilizing the Affymetrix 670K array (MNEc670k) and a single locus mixed linear model analysis (EMMAX), identified a locus on ECA7 for further investigation (Pcorrected = 2.08 × 10-10). This locus contained a 3 Mb run of homozygosity in the 12 mushroom ponies tested. Analysis of high throughput Illumina sequencing data from one mushroom Shetland pony compared to 87 genomes from horses of various breeds, uncovered a frameshift variant, p.Asp201fs, in the MFSD12 gene encoding the major facilitator superfamily domain containing 12 protein. This variant was perfectly concordant with phenotype in 96 Shetland Ponies (P = 1.15 × 10-22), was identified in the closely related Miniature Horse for which the mushroom phenotype is suspected to occur (fmu = 0.02), and was absent in 252 individuals from seven additional breeds not reported to have the mushroom phenotype. MFSD12 is highly expressed in melanocytes and variants in this gene in humans, mice, and dogs impact pigmentation. Given the role of MFSD12 in melanogenesis, we propose that p.Asp201fs is causal for the dilution observed in mushroom ponies.

Heritability and complex segregation analysis of diabetes mellitus in American Eskimo Dogs.

BACKGROUND: Heritability and mode of inheritance of spontaneous diabetes mellitus (DM) in American Eskimo Dogs (AED) are unknown. OBJECTIVE: Investigate the heritability and mode of inheritance of DM in AED. ANIMALS: An extended family of AED including 71 AED without DM, 47 AED with an unknown phenotype, and 38 AED with spontaneous DM. METHODS: Retrospective evaluation of inheritance. A logistic regression model was formulated to evaluate the heritability of DM, including effects of sex and neuter status. Subsequently, complex segregation analysis was employed to investigate the inheritance pattern of DM in AED. Six plausible models were considered, and the Akaike Information Criterion was used to determine the best of the biologically feasible models of inheritance of DM in AED. RESULTS: Heritability of DM in AED is estimated at 0.62 (95% posterior interval 0.01-0.99). Predicted DM probabilities for neutered females (NF), intact females (IF), neutered males (NM), and intact males (IM) were 0.76, 0.11, 0.63, and 0.12, respectively. There was no overlap between the 95% posterior intervals of disease probabilities in NF and IF or in NF and IM. Complex segregation analysis suggested that the mode of inheritance of DM in AED is polygenic, with no evidence for a single gene of large effect. CONCLUSIONS AND CLINICAL IMPORTANCE: The estimated heritability of DM in AED is high but has low precision. Diabetes mellitus transmission in AED appears to follow a polygenic inheritance. Breeders could successfully implement a breeding program to decrease the incidence of DM in AED.

DLA class II risk haplotypes for autoimmune diseases in the bearded collie offer insight to autoimmunity signatures across dog breeds.

BACKGROUND: Primary hypoadrenocorticism (Addison's disease, AD) and symmetrical lupoid onychodystrophy (SLO) are two clinical conditions with an autoimmune etiology that occur in multiple dog breeds. In man, autoimmunity is associated with polymorphisms in immune-related genes that result in a reduced threshold for, or defective regulation of, T cell activation. The major histocompatibility complex (MHC) class II genes encode molecules that participate in these functions, and polymorphisms within these genes have been associated with autoimmune conditions in dogs and humans. Bearded collies have a relatively high prevalence of autoimmune diseases, particularly AD and SLO. Our study assessed the relationship between particular MHC (dog leukocyte antigen, DLA) class II haplotypes and the two autoimmune diseases most common in this breed. Moreover, five unrelated breeds at increased risk for AD were studied for comparative purposes and analyzed in the context of extant literature. RESULTS: A single DLA class II three-locus haplotype, determined by sequence-based typing, was associated with increased risk for AD (DLA-DRB1*009:01/DQA1*001:01/DQB1*008:02) in bearded collies. Comparative analysis with the five additional breeds showed limited allele sharing, with DQA1*001:01 and DQB1*002:01 being the only alleles observed in all breeds. A distinct three-locus risk haplotype (DLA-DRB1*001:01/DQA1*001:01/DQB1*002:01) was associated with AD in the West Highland white terrier and Leonberger. Two different risk haplotypes were associated with increased risk for SLO in the bearded collie (DLA-DRB1*018:01/DQA1*001:01/DQB1*002:01 and DLA-DRB1*018:01/DQA1*001:01/ DQB1*008:02). CONCLUSION: Two-locus DQ haplotypes composed of DLA-DQA1*001:01 in association with DLA-DQB1*002:01 or DLA-DQB1*008:02 make up the four risk haplotypes identified in the present study and are also found in other risk haplotypes previously associated with diabetes mellitus and hypothyroidism across different dog breeds. Our findings build upon previously published data to suggest that this two-locus (DQ) model serves as a good indicator for susceptibility to multiple organ-specific autoimmune diseases in the canine population. However, it is also clear that additional loci are necessary for actual disease expression. Investigation of affected and unaffected dogs carrying these predisposing DQ haplotype signatures may allow for the identification of those additional genetic components that determine autoimmune disease expression and organ specificity.

Energetic efficiency and the first law: the California net energy system revisited.

Models of energy utilization used in livestock production predict input:output relationships well, for all the wrong reasons. Predictive accuracy in such models is not due to fidelity to biochemistry and laws of thermodynamics, but because they were developed to predict accurately, often with little regard to biochemical consistency. Relatively static linear statistical models limit thermodynamically relevant descriptions of energy utilization, especially maintenance, in growing beef cattle and are inadequate research tools, in either ordinary least squares (OLS) or Bayesian frameworks. Metabolizable energy intake (MEI) at recovered energy (RE) = 0 (MEm) and efficiencies of ME utilization for maintenance (km) and gain (kg) were estimated for 3 independent data sets using OLS or Bayesian frameworks. Estimates of MEm differed (P < 0.05) between OLS and Bayesian estimates and were not unique, indicating model misspecification. Bayesian estimates of MEm were monotonic, positive, and nonlinear f(MEI); the range was from 6.74 to 14.8 Mcal/d. Estimates of km, the ratio of heat energy (HE) at MEI = 0 to MEm, for the 3 data sets averaged 0.590 for OLS solutions, or 0.616 for the first derivative (km, dHE/dMEI for RE = 0) of a first-order function. The first derivative (dHE/dMEI) of the OLS function was > 1.0 for MEI > 22.1 Mcal/d, counter to the laws of thermodynamics and indicated model misspecification. The Bayesian estimate of km (0.420) differed (P < 0.05) from the OLS estimate and was consistent with the efficiency of ATP synthesis. Efficiency of ME use for gain for RE > 0 (kg, OLS solutions) averaged 0.397, solutions were nonunique and single-variable OLS models were misspecified (P < 0.050) for 2 of the 3 data sets. The OLS estimate of kg differed (P < 0.05) from the estimate of kg (0.676) determined in a Bayesian framework; the latter was calculated as dRE/dMEI for RE > 0. For OLS estimates km > kg; for estimates determined in a Bayesian framework km < kg, the former is inconsistent, while the latter is consistent with the thermodynamic favorability of reactions underlying maintenance and gain. Our results show that the use of relatively fixed coefficients of maintenance in current feeding standards, mathematical descriptions of metabolic processes and concepts regarding efficiencies of energy utilization in those systems need modification to be consistent with animal biology and the laws of thermodynamics.

Correlation of neuter status and expression of heritable disorders.

BACKGROUND: Gonadectomy, or neutering, is a very common surgery for dogs having many positive effects on behavior, health, and longevity. There are also certain risks associated with neutering including the development of orthopedic conditions, cognitive decline, and a predisposition to some neoplasias. This study was designed specifically to identify if a correlation exists between neuter status and inherited conditions in a large aggregate cohort of dogs representing many different breeds. RESULTS: Neutered dogs were at less risk for early and congenital conditions (aortic stenosis, early onset cataracts, mitral valve disease, patent ductus arteriosus, portosystemic shunt, and ventricular septal defect) than intact dogs. Neutering was also associated with reduced risk of dilated cardiomyopathy and gastric dilatation volvulus in males. Neutering was significantly associated with an increased risk for males and females for cancers (hemangiosarcoma, hyperadrenocorticism, lymphoma, mast cell tumor, and osteosarcoma), ruptured anterior cruciate ligament and epilepsy. Intervertebral disk disease was associated with increased risk in females only. For elbow dysplasia, hip dysplasia, lens luxation, and patellar luxation neutering had no significant effect on the risk for those conditions. Neutering was associated with a reduced risk of vehicular injury, a condition chosen as a control. CONCLUSIONS: In this retrospective study, several conditions showed an increased risk associated with neutering whereas other conditions were less likely to be expressed in neutered dogs. The complexity of the interactions between neutering and inherited conditions underscores the need for reflective consultation between the client and the clinician when considering neutering. The convenience and advantages of neutering dogs that will not be included in a breeding program must be weighed against possible risk associated with neutering.