GWAS using low-pass whole genome sequence reveals a novel locus in canine congenital idiopathic megaesophagus.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal disorder of dogs wherein the esophagus is dilated and swallowing activity is reduced, causing regurgitation of ingesta. Affected individuals experience weight loss and malnourishment and are at risk for aspiration pneumonia, intussusception, and euthanasia. Great Danes have among the highest incidences of CIM across dog breeds, suggesting a genetic predisposition. We generated low-pass sequencing data for 83 Great Danes and used variant calls to impute missing whole genome single-nucleotide variants (SNVs) for each individual based on haplotypes phased from 624 high-coverage dog genomes, including 21 Great Danes. We validated the utility of our imputed data set for genome-wide association studies (GWASs) by mapping loci known to underlie coat phenotypes with simple and complex inheritance patterns. We conducted a GWAS for CIM with 2,010,300 SNVs, identifying a novel locus on canine chromosome 1 (P-val = 2.76 × 10-10). Associated SNVs are intergenic or intronic and are found in two clusters across a 1.7-Mb region. Inspection of coding regions in high-coverage genomes from affected Great Danes did not reveal candidate causal variants, suggesting that regulatory variants underlie CIM. Further studies are necessary to assess the role of these non-coding variants.

Design and Evaluation Challenges of Conversational Agents in Health Care and Well-being: Selective Review Study.

BACKGROUND: Health care and well-being are 2 main interconnected application areas of conversational agents (CAs). There is a significant increase in research, development, and commercial implementations in this area. In parallel to the increasing interest, new challenges in designing and evaluating CAs have emerged. OBJECTIVE: This study aims to identify key design, development, and evaluation challenges of CAs in health care and well-being research. The focus is on the very recent projects with their emerging challenges. METHODS: A review study was conducted with 17 invited studies, most of which were presented at the ACM (Association for Computing Machinery) CHI 2020 conference workshop on CAs for health and well-being. Eligibility criteria required the studies to involve a CA applied to a health or well-being project (ongoing or recently finished). The participating studies were asked to report on their projects' design and evaluation challenges. We used thematic analysis to review the studies. RESULTS: The findings include a range of topics from primary care to caring for older adults to health coaching. We identified 4 major themes: (1) Domain Information and Integration, (2) User-System Interaction and Partnership, (3) Evaluation, and (4) Conversational Competence. CONCLUSIONS: CAs proved their worth during the pandemic as health screening tools, and are expected to stay to further support various health care domains, especially personal health care. Growth in investment in CAs also shows the value as a personal assistant. Our study shows that while some challenges are shared with other CA application areas, safety and privacy remain the major challenges in the health care and well-being domains. An increased level of collaboration across different institutions and entities may be a promising direction to address some of the major challenges that otherwise would be too complex to be addressed by the projects with their limited scope and budget.

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.

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.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

Novel Y Chromosome Retrocopies in Canids Revealed through a Genome-Wide Association Study for Sex.

The lack of an annotated reference sequence for the canine Y chromosome has limited evolutionary studies, as well as our understanding of the role of Y-linked sequences in phenotypes with a sex bias. In genome-wide association studies (GWASs), we observed spurious associations with autosomal SNPs when sex was unbalanced in case-control cohorts and hypothesized that a subset of SNPs mapped to autosomes are in fact sex-linked. Using the Illumina 230K CanineHD array in a GWAS for sex, we identified SNPs that amplify in both sexes but possess significant allele frequency differences between males and females. We found 48 SNPs mapping to 14 regions of eight autosomes and the X chromosome that are Y-linked, appearing heterozygous in males and monomorphic in females. Within these 14 regions are eight genes: three autosomal and five X-linked. We investigated the autosomal genes (MITF, PPP2CB, and WNK1) and determined that the SNPs are diverged nucleotides in retrocopies that have transposed to the Y chromosome. MITFY and WNK1Y are expressed and appeared recently in the Canidae lineage, whereas PPP2CBY represents a much older insertion with no evidence of expression in the dog. This work reveals novel canid Y chromosome sequences and provides evidence for gene transposition to the Y from autosomes and the X.

A glycine transporter SLC6A5 frameshift mutation causes startle disease in Spanish greyhounds.

Startle disease, or hyperekplexia, is a glycinergic disorder characterized by hypertonia and apnea that is triggered by noise and/or touch. Mutations in five genes have been associated with startle disease in humans, dogs, cattle, and mice. We identified a novel recessive startle disease in a family of Spanish greyhounds. Whole genome resequencing of an affected dog revealed a homozygous two base pair deletion in the ninth exon of SLC6A5, encoding the presynaptic glycine transporter. The deletion is predicted to cause a frameshift, p.S460FfsX47, leading to a premature stop codon that truncates over a third of the protein. Family members were genotyped for the deletion, and findings were consistent with an autosomal recessive inheritance pattern. The pathogenic variant was absent from 34 unrelated greyhounds, 659 domestic dogs of pure and mixed breeds, and 54 wild canids, suggesting it occurred recently and may be private to the family. The findings of this study can be used to inform future breeding decisions and prevent dissemination of the deleterious allele in greyhounds.

Length variations within the Merle retrotransposon of canine PMEL: correlating genotype with phenotype.

BACKGROUND: The antisense insertion of a canine short interspersed element (SINEC_Cf) in the pigmentation gene PMEL (or SILV) causes a coat pattern phenotype in dogs termed merle. Merle is a semi-dominant trait characterized by patches of full pigmentation on a diluted background. The oligo(dT) tract of the Merle retrotransposon is long and uninterrupted and is prone to dramatic truncation. Phenotypically wild-type individuals carrying shorter oligo(dT) lengths of the Merle allele have been previously described and termed cryptic merles. Two additional coat patterns, dilute merle (uniform, steely-grey coat) and harlequin merle (white background with black patches), also appear in breeds segregating the Merle allele. RESULTS: Sequencing of all PMEL exons in a dilute and a harlequin merle reveals that variation exists solely within the oligo(dT) tract of the SINEC_Cf insertion. In fragment analyses from 259 dogs heterozygous for Merle, we observed a spectrum of oligo(dT) lengths spanning 25 to 105 base pairs (bp), with ranges that correspond to the four varieties of the merle phenotype: cryptic (25-55 bp), dilute (66-74 bp), standard (78-86 bp), and harlequin (81-105 bp). Somatic contractions of the oligo(dT) were observed in 43% of standard and 51% of harlequin merle dogs. A small proportion (4.6%) of the study cohort inherited de novo contractions or expansions of the Merle allele that resulted in dilute or harlequin coat patterns, respectively. CONCLUSIONS: The phenotypic consequence of the Merle SINE insertion directly depends upon oligo(dT) length. In transcription, we propose that the use of an alternative splice site increases with oligo(dT) length, resulting in insufficient PMEL and a pigment dilution spectrum, from dark grey to complete hypopigmentation. We further propose that during replication, contractions and expansions increase in frequency with oligo(dT) length, causing coat variegation (somatic events in melanocytes) and the spontaneous appearance of varieties of the merle phenotype (germline events).

Exome sequencing reveals independent SGCD deletions causing limb girdle muscular dystrophy in Boston terriers.

BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited autosomal myopathies that preferentially affect voluntary muscles of the shoulders and hips. LGMD has been clinically described in several breeds of dogs, but the responsible mutations are unknown. The clinical presentation in dogs is characterized by marked muscle weakness and atrophy in the shoulder and hips during puppyhood. METHODS: Following clinical evaluation, the identification of the dystrophic histological phenotype on muscle histology, and demonstration of the absence of sarcoglycan-sarcospan complex by immunostaining, whole exome sequencing was performed on five Boston terriers: one affected dog and its three family members and one unrelated affected dog. RESULTS: Within sarcoglycan-δ (SGCD), a two base pair deletion segregating with LGMD in the family was discovered, and a deletion encompassing exons 7 and 8 was found in the unrelated dog. Both mutations are predicted to cause an absence of SGCD protein, confirmed by immunohistochemistry. The mutations are private to each family. CONCLUSIONS: Here, we describe the first cases of canine LGMD characterized at the molecular level with the classification of LGMD2F.

Steering the conversation: A linguistic exploration of natural language interactions with a digital assistant during simulated driving.

Given the proliferation of 'intelligent' and 'socially-aware' digital assistants embodying everyday mobile technology - and the undeniable logic that utilising voice-activated controls and interfaces in cars reduces the visual and manual distraction of interacting with in-vehicle devices - it appears inevitable that next generation vehicles will be embodied by digital assistants and utilise spoken language as a method of interaction. From a design perspective, defining the language and interaction style that a digital driving assistant should adopt is contingent on the role that they play within the social fabric and context in which they are situated. We therefore conducted a qualitative, Wizard-of-Oz study to explore how drivers might interact linguistically with a natural language digital driving assistant. Twenty-five participants drove for 10 min in a medium-fidelity driving simulator while interacting with a state-of-the-art, high-functioning, conversational digital driving assistant. All exchanges were transcribed and analysed using recognised linguistic techniques, such as discourse and conversation analysis, normally reserved for interpersonal investigation. Language usage patterns demonstrate that interactions with the digital assistant were fundamentally social in nature, with participants affording the assistant equal social status and high-level cognitive processing capability. For example, participants were polite, actively controlled turn-taking during the conversation, and used back-channelling, fillers and hesitation, as they might in human communication. Furthermore, participants expected the digital assistant to understand and process complex requests mitigated with hedging words and expressions, and peppered with vague language and deictic references requiring shared contextual information and mutual understanding. Findings are presented in six themes which emerged during the analysis - formulating responses; turn-taking; back-channelling, fillers and hesitation; vague language; mitigating requests and politeness and praise. The results can be used to inform the design of future in-vehicle natural language systems, in particular to help manage the tension between designing for an engaging dialogue (important for technology acceptance) and designing for an effective dialogue (important to minimise distraction in a driving context).

Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci.

Juvenile dermatomyositis (JDM) is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, spontaneous disease of dogs also termed dermatomyositis (DMS). As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC) (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01), particularly in homozygosity (P-val = 0.0001). However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12) and 31 (P-val = 3.95X10-8). Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys) and MAP3K7CL (c.383_392ACTCCACAAA>GACT) on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction.

Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy.

Nemaline myopathy (NM) is a congenital muscle disorder associated with muscle weakness, hypotonia, and rod bodies in the skeletal muscle fibers. Mutations in 10 genes have been implicated in human NM, but spontaneous cases in dogs have not been genetically characterized. We identified a novel recessive myopathy in a family of line-bred American bulldogs (ABDs); rod bodies in muscle biopsies established this as NM. Using SNP profiles from the nuclear family, we evaluated inheritance patterns at candidate loci and prioritized TNNT1 and NEB for further investigation. Whole exome sequencing of the dam, two affected littermates, and an unaffected littermate revealed a nonsense mutation in NEB (g.52734272 C>A, S8042X). Whole tissue gel electrophoresis and western blots confirmed a lack of full-length NEB in affected tissues, suggesting nonsense-mediated decay. The pathogenic variant was absent from 120 dogs of 24 other breeds and 100 unrelated ABDs, suggesting that it occurred recently and may be private to the family. This study presents the first molecularly characterized large animal model of NM, which could provide new opportunities for therapeutic approaches.

A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers.

Congenital myasthenic syndromes (CMSs) are a group of rare genetic disorders of the neuromuscular junction resulting in structural or functional causes of fatigable weakness that usually begins early in life. Mutations in pre-synaptic, synaptic and post-synaptic proteins have been demonstrated in human cases, with more than half involving aberrations in nicotinic acetylcholine receptor (AChR) subunits. CMS was first recognized in dogs in 1974 as an autosomal recessive trait in Jack Russell Terriers (JRTs). A deficiency of junctional AChRs was demonstrated. Here we characterize a CMS in 2 contemporary cases of JRT littermates with classic clinical and electromyographic findings, and immunochemical confirmation of an approximately 90% reduction in AChR protein content. Loci encoding the 5 AChR subunits were evaluated using microsatellite markers, and CHRNB1 and CHRNE were identified as candidate genes. Sequences of the splice sites and exons of both genes revealed a single base insertion in exon 7 of CHRNE that predicts a frameshift mutation and a premature stop codon. We further demonstrated this pathogenic mutation in CHRNE in archival tissues from unrelated JRTs studied 34 years ago.

A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome.

Congenital myasthenic syndromes (CMSs) are heterogeneous neuromuscular disorders characterized by skeletal muscle weakness caused by disruption of signal transmission across the neuromuscular junction (NMJ). CMSs are rarely encountered in veterinary medicine, and causative mutations have only been identified in Old Danish Pointing Dogs and Brahman cattle to date. Herein, we characterize a novel CMS in 2 Labrador Retriever littermates with an early onset of marked generalized muscle weakness. Because the sire and dam share 2 recent common ancestors, CMS is likely the result of recessive alleles inherited identical by descent (IBD). Genome-wide SNP profiles generated from the Illumina HD array for 9 nuclear family members were used to determine genomic inheritance patterns in chromosomal regions encompassing 18 functional candidate genes. SNP haplotypes spanning 3 genes were consistent with autosomal recessive transmission, and microsatellite data showed that only the segment encompassing COLQ was inherited IBD. COLQ encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of signal transduction in the NMJ. Sequences from COLQ revealed a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type. A recent study in which 2 human CMS patients were found to be homozygous for an identical COLQ mutation (c.1010T>C; I337T) provides further evidence that this mutation is pathogenic. This report describes the first COLQ mutation in canine CMS and demonstrates the utility of SNP profiles from nuclear family members for the identification of private mutations.

Querying automated antibiotic susceptibility testing instruments: a novel population-based active surveillance method for multidrug-resistant gram-negative bacilli.

OBJECTIVE: To describe the implementation of a population-based surveillance system for multidrug-resistant gram-negative bacilli (MDR-GNB). DESIGN: Population-based active surveillance by the Georgia Emerging Infections Program. SETTING: Metropolitan Atlanta, starting November 2010. PATIENTS: Residents with MDR-GNB isolated from urine or a normally sterile site culture. METHODS: Surveillance was implemented in 3 phases: (1) surveying laboratory antibiotic susceptibility testing practices, (2) piloting surveillance to estimate the proportion of GNB that were MDR, and (3) maintaining ongoing active surveillance for carbapenem-nonsusceptible Enterobacteriaceae and Acinetobacter baumannii using the 2010 Clinical and Laboratory Standards Institute (CLSI) breakpoints. Pilot surveillance required developing and installing queries for GNB on the 3 types of automated testing instruments (ATIs), such as MicroScan, in Atlanta's clinical laboratories. Ongoing surveillance included establishing a process to extract data from ATIs consistently, review charts, manage data, and provide feedback to laboratories. RESULTS: Output from laboratory information systems typically used for surveillance would not reliably capture the CLSI breakpoints, but queries developed for the 3 ATIs did. In November 2010, 0.9% of Enterobacteriaceae isolates and 35.7% of A. baumannii isolates from 21 laboratories were carbapenem nonsusceptible. Over a 5-month period, 82 Enterobacteriaceae and 59 A. baumannii were identified as carbapenem nonsusceptible. CONCLUSIONS: Directly querying ATIs, a novel method of active surveillance for MDR-GNB, proved to be a reliable, sustainable, and accurate method that required moderate initial investment and modest maintenance. Ongoing surveillance is critical to assess the burden of and changes in MDR-GNB to inform prevention efforts.

Impact of changes in Clostridium difficile testing practices on stool rejection policies and C. difficile positivity rates across multiple laboratories in the United States.

We describe the adoption of nucleic acid amplification tests (NAAT) for Clostridium difficile diagnosis and their impact on stool rejection policies and C. difficile positivity rates. Of the laboratories with complete surveys, 51 (43%) reported using NAAT in 2011. Laboratories using NAAT had stricter rejection policies and increased positivity rates.

Effect of nucleic acid amplification testing on population-based incidence rates of Clostridium difficile infection.

Nucleic acid amplification testing (NAAT) is increasingly being adopted for diagnosis of Clostridium difficile infection (CDI). Data from 3 states conducting population-based CDI surveillance showed increases ranging from 43% to 67% in CDI incidence attributable to changing from toxin enzyme immunoassays to NAAT. CDI surveillance requires adjustment for testing methods.

Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs.

Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA-DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR > 17; P = 0.000125), while two haplotypes were found to confer protection from EPI (P = 0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.

Current status of genetic studies of exocrine pancreatic insufficiency in dogs.

Exocrine pancreatic insufficiency (EPI) is a disorder wherein the pancreas fails to secrete adequate amounts of digestive enzymes. In dogs, EPI is usually the consequence of an autoimmune disease known as pancreatic acinar atrophy. Originally believed to be a simple autosomal recessive disorder, a test-breeding recently revealed that EPI has a more complex mode of inheritance. The contributions of multiple genes, combined with environmental factors, may explain observed variability in clinical presentation and progression of this disease. Research efforts aim to identify genetic variations underlying EPI to assist breeders in their efforts to eliminate this disease from their breed and provide clinicians with new targets for therapeutic intervention and/or disease prevention. Genome-wide linkage, global gene expression, and candidate gene analyses have failed to identify a major locus or genetic variations in German Shepherd Dogs with EPI. Recently, genome-wide association studies revealed numerous genomic regions associated with EPI. Current studies are focused on alleles of the canine major histocompatibility complex. In this article we review findings from scientific investigations into the inheritance and genetic cause(s) of EPI in the purebred dog.