OMIA (Online Mendelian Inheritance in Animals): an enhanced platform and integration into the Entrez search interface at NCBI

Online Mendelian Inheritance in Animals (OMIA) is a comprehensive, annotated catalogue of inherited disorders and other familial traits in animals other than humans and mice. Structured as a comparative biology resource, OMIA is a comprehensive resource of phenotypic information on heritable animal traits and genes in a strongly comparative context, relating traits to genes where possible. OMIA is modelled on and is complementary to Online Mendelian Inheritance in Man (OMIM). OMIA has been moved to a MySQL database at the Australian National Genomic Information Service (ANGIS) and can be accessed at . It has also been integrated into the Entrez search interface at the National Center for Biotechnology Information (NCBI; ). Curation of OMIA data by researchers working on particular species and disorders has also been enabled

DEVELOPMENT OF INTEGRATED CATTLE GENOMICS KNOWLEDGE BASE

Systems biology approaches being applied to animal breeding represent an opportunity to derive greater benefits from animal production systems. The increasingly detailed investigations in systems biology have led to a large amount of data dispersed over various sources; therefore, a centralized knowledge base is in demand. In this study, we have integrated cattle genomics data of heterogeneous sources and types and developed a bioinformatics tool to study genotype-phenotype associations in cattle: http://integromics-time.com/integromics-database/. The tool enables revealing genomic overlaps within trait-associated loci and identification of potential functional candidates. It might be also used as a tool for planning genotype– phenotype research in cattle

Gephebase, a database of genotype-phenotype relationships for natural and domesticated variation in Eukaryotes

International audienceGephebase is a manually-curated database compiling our accumulated knowledge of the genes and mutations that underlie natural, domesticated and experimental phenotypic variation in all Eukaryotes-mostly animals, plants and yeasts. Gephebase aims to compile studies where the genotype-phenotype association (based on linkage mapping, association mapping or a candidate gene approach) is relatively well supported. Human clinical traits and aberrant mutant phenotypes in laboratory organisms are not included and can be found in other databases (e.g. OMIM, OMIA, Monarch Initiative). Gephebase contains more than 1700 entries. Each entry corresponds to an allelic difference at a given gene and its associated phenotypic change(s) between two species or two individuals of the same species, and is enriched with molecular details , taxonomic information, and bibliographic information. Users can easily browse entries and perform searches at various levels using boolean operators (e.g. transposable elements, snakes, carotenoid content , Doebley). Data is exportable in spreadsheet format. This database allows to perform meta-analyses to extract global trends about the living world and the research fields. Gephebase should also help breeders , conservationists and others to identify promising target genes for crop improvement, parasite/pest control, bioconservation and genetic diagnostic. It is freely available at www.gephebase.org

Fido-SNP: the first webserver for scoring the impact of single nucleotide variants in the dog genome

As the amount of genomic variation data increases, tools that are able to score the functional impact of single nucleotide variants become more and more necessary. While there are several prediction servers available for interpreting the effects of variants in the human genome, only few have been developed for other species, and none were specifically designed for species of veterinary interest such as the dog. Here, we present Fido-SNP the first predictor able to discriminate between Pathogenic and Benign single-nucleotide variants in the dog genome. Fido-SNP is a binary classifier based on the Gradient Boosting algorithm. It is able to classify and score the impact of variants in both coding and non-coding regions based on sequence features within seconds. When validated on a previously unseen set of annotated variants from the OMIA database, Fido-SNP reaches 88% overall accuracy, 0.77 Matthews correlation coefficient and 0.91 Area Under the ROC Curve

Canine whole exome sequencing : hip, hip, hurray?: the quest for genetic solutions for phenotypical problems

De hond is reeds duizenden jaren onze metgezel en heeft een opmerkelijke fenotypische diversiteit. De processen die tot deze diversiteit hebben geleid, hebben er echter onbedoeld ook voor gezorgd dat genetische aandoeningen frequent voorkomen. In deze thesis worden meerdere aspecten van deze genetische aandoeningen onderzocht. Het ontrafelen van genetische aandoeningen start met het bestuderen van het fenotype. Beslissen of iemand gezond of ziek is, is niet altijd gemakkelijk. Het ideale voorbeeld van een aandoening die moeilijk te fenotyperen is, is heupdysplasie. Verscheidene factoren beïnvloeden de prevalentie en diagnostiek van deze aandoening. In de zoektocht naar de genetische oorzaak van ziektes, kan men gebruik maken van “whole exome sequencing (WES)”. Bij WES wordt er specifiek gefocust op de exonen van de proteïne coderende genen. Door het uitbrengen van de WES designs ontdekten we dat er nood was aan software die kon omgaan met variabele overervingspatronen en gebruikt kon worden bij de hond. Met dat doel voor ogen werd het R-package “Mendelian” ontwikkeld. Aangezien WES bij de hond nieuw is, bestonden er nog geen richtlijnen over welke combinaties of aantallen het meest efficiënt zijn in genetische studies. Een analyse bracht aan het licht dat zelfs honden uit onverwante rassen tot 60% van hun varianten deelden. Omwille van deze hoge percentages verwachten we kleine aantallen honden nodig te hebben voor genetisch onderzoek en een beperkte genetische heterogeniteit. Eén van de uiteindelijke doelen van genetisch onderzoek is ziektebestrijding. Om de optimale strategie te bepalen, is het belangrijk om de prevalentie van de aandoening te kennen. Een populatiestudie bracht aan het licht dat de allelfrequenties van 9 verschillende ziektes sterk varieerden van ras tot ras. Uit de grote aantallen dragers blijkt dat puur fenotypische selectie een stuk minder efficiënt zal verlopen dan selectie met behulp van DNA testen

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms ( SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds ( a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines - in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases

Forward vs. reverse genetics: a bovine perspective based on visible and hidden phenotypes of inherited disorders

In modern cattle production, we have seen a negative trend for decades in reproduction while productivity and performance have improved. Although considered genetically complex, part of these fecundity, fertility, and rearing success issues are caused by Mendelian monogenic disorders. Traditionally, such disorders are investigated opportunistically based on their sporadic occurrence and through subsequent targeted analysis of affected individuals. This approach is called the forward genetic approach (FGA). Modern genomic technologies, such as single nucleotide polymorphism (SNP) array genotyping and whole-genome sequencing (WGS), allow for straightforward locus mapping and the identification of candidate causal variants in affected individuals or families. Nevertheless, a major drawback is the arbitrary sampling and availability of well-phenotyped individuals for research, especially for mostly invisible defects affecting fecundity, early embryonic death, and abortions. Therefore, the reverse genetic approach (RGA) is applied to screen for underlying recessive lethal or sub-lethal variants. This approach requires the availability of massive population-wide genomic data. By applying a haplotype screen for a significant deviation of the Hardy-Weinberg equilibrium, genomic regions potentially harboring candidate causal variants are identified. The subsequent generation of WGS data of haplotype carriers allows for the mining for pathogenic variants potentially causing a reduction in homozygosity. In the first part of my thesis, I present 18 successful, 1 inconclusive example, and 1 example addressing co-dominant effects of a known disorder. These FGA analyzes include heritable skin (n=7), bone (n=7), neuromuscular (n=1), eye (n=2), as well as syndromic disorders (n=3) in various European cattle breeds. Missense and frameshift variants in the IL17RA, DSP, and FA2H genes were described in three recessive genodermatoses: immunodeficiency with psoriasis-like skin alterations, syndromic ichthyosis, and ichthyosis congenita, respectively. Hypohidrotic ectodermal dysplasia was described as X-linked disorder that is associated with a gross deletion in the EDA gene. In dominant genodermatoses, a missense variant in COL5A2 was shown to lead to classical Ehlers-Danlos syndrome, an in-frame deletion in KRT5 was shown to cause epidermolysis bullosa simplex, and results of a study using an individual case of juvenile angiomatosis remained inconclusive. A recessive disorder described as hemifacial macrosomia was associated with a missense variant in LAMB1. Chondrodysplasia in a single family was shown to be caused by a de novo mutation in the bull leading to a stop-loss of the gene FGFR3. De novo mutations (missense and large deletions) in the COL2A1 and COL1A1 genes were associated with achondrogenesis type II (bulldog calf syndrome), and osteogenesis imperfecta type II, respectively. Another mutation that we found to affect bone morphology was a trisomy in chromosome 29 leading to proportional dwarfism with facial dysplasia. Congenital neuromuscular channelopathy was for the first time associated with a missense variant in KCNG1. Furthermore, a de novo missense variant in ADAMTSL4 and a recessive missense variant in CNGB3 were shown to cause congenital cataract and achromatopsia, respectively. Additionally, cases of pulmonary hypoplasia and anasarca syndrome were analyzed and shown to be caused by trisomy 20 in two unrelated calves and a recessively inherited missense variant in ADAMTS3. Moreover, the fatal syndromic disorder skeletal-cardo-enteric dysplasia was described to be caused by a de novo missense variant in MAP2K2. Finally, I investigated the effects on blood cholesterol and triglyceride levels of heterozygous carriers of the previously described APOB-related cholesterol deficiency. In the second part of my thesis, I present the outcome of the RGA in four main Swiss populations, that was validated with the SWISScow custom array. In the Brown Swiss dairy population, 72 haplotype regions showed significant depletions in homozygosity. Four of these haplotypes (BH6, BH14, BH24, and BH34) were associated with missense and nonsense variants in different genes (MARS2, MRPL55, CPT1C, and ACSL5, respectively). In the Original Braunvieh population, eight haplotype regions were identified. Candidate causal variants included a missense variant in TUBGCP5 gene associated with haplotype OH2, and a splice site frameshift variant in LIG3 gene associated with haplotype OH4. In the Holstein population, 24 haplotype regions were identified with a significant reduction of homozygosity. Subsequently, four novel candidate variants were proposed: a nonsense variant in KIR2DS1 for haplotype HH13, in-frame deletion in the genes NOTCH3 for HH21 haplotype, and RIOX1 for HH25 haplotype, and finally, a missense variant in PCDH15 for HH35 haplotype. In the Simmental population, eleven haplotype regions were detected. The haplotype SH5 was associated with a frameshift variant in DIS3 gene and the haplotypes SH8 and SH9 with missense variants in the CYP2B6 and NUBPL genes, respectively. For the breeds Brown Swiss, Original Braunvieh, and Holstein, association studies were carried out including traits describing fertility, birth, growth, and survival. Thereby most of the described mentioned haplotypes show additive effects. Regardless of the approach, all the described candidate causal variants can be used as a tool of precision diagnostics and represent a step forward towards personalized medicine in cattle. Furthermore, these variants can be easily genotyped and allow for targeted breeding to reduce the number of risk matings, which would lead to a reduction of affected animals and significant improvement in animal health and welfare

Perinnöllisten riskitekijöiden tunnistaminen koirien autoimmuunisairauksissa

Autoimmune diseases are more common in dogs than in humans and are already threatening the future of some highly predisposed dog breeds. Susceptibility to autoimmune diseases is controlled by environmental and genetic factors, especially the major histocompatibility complex (MHC) gene region. Dogs show a similar physiology, disease presentation and clinical response as humans, making them an excellent disease model for autoimmune diseases common to both species. The genetic background of canine autoimmune disorders is largely unknown, but recent annotation of the dog genome and subsequent development of new genomic tools offer a unique opportunity to map novel autoimmune genes in various breeds. Many autoimmune disorders show breed-specific enrichment, supporting a strong genetic background. Furthermore, the presence of hundreds of breeds as genetic isolates facilitates gene mapping in complex autoimmune disorders. Identification of novel predisposing genes establishes breeds as models and may reveal novel candidate genes for the corresponding human disorders. Genetic studies will eventually shed light on common biological functions and interactions between genes and the environment. This study aimed to identify genetic risk factors in various autoimmune disorders, including systemic lupus erythematosus (SLE)-related diseases, comprising immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis arteritis (SMRA) as well as Addison s disease (AD) in Nova Scotia Duck Tolling Retrievers (NSDTRs) and chronic superficial keratitis (CSK) in German Shepherd dogs (GSDs). We used two different approaches to identify genetic risk factors. Firstly, a candidate gene approach was applied to test the potential association of MHC class II, also known as a dog leukocyte antigen (DLA) in canine species. Secondly, a genome-wide association study (GWAS) was performed to identify novel risk loci for SLE-related disease and AD in NSDTRs. We identified DLA risk haplotypes for an IMRD subphenotype of SLE-related disease, AD and CSK, but not in SMRA, and show that the MHC class II gene region is a major genetic risk factor in canine autoimmune diseases. An elevated risk was found for IMRD in dogs that carried the DLA-DRB1*00601/DQA1*005011/DQB1*02001 haplotype (OR = 2.0, 99% CI = 1.03-3.95, p = 0.01) and for ANA-positive IMRD dogs (OR = 2.3, 99% CI = 1.07-5.04, p-value 0.007). We also found that DLA-DRB1*01502/DQA*00601/DQB1*02301 haplotype was significantly associated with AD in NSDTRs (OR = 2.1, CI = 1.0-4.4, P = 0.044) and the DLA-DRB1*01501/DQA1*00601/DQB1*00301 haplotype with the CSK in GSDs (OR=2.67, CI=1.17-6.44, p= 0.02). In addition, we found that homozygosity for the risk haplotype increases the risk for each disease phenotype and that an overall homozygosity for the DLA region predisposes to CSK and AD. Our results have enabled the development of genetic tests to improve breeding practices by avoiding the production of puppies homozygous for risk haplotypes. We also performed the first successful GWAS for a complex disease in dogs. With less than 100 cases and 100 controls, we identified five risk loci for SLE-related disease and AD and found strong candidate genes involved in a novel T-cell activation pathway. We show that an inbred dog population has fewer risk factors, but each of them has a stronger genetic risk. Ongoing studies aim to identify the causative mutations and bring new knowledge to help diagnostics, treatment and understanding of the aetiology of SLE-related diseases.Autoimmuunisairaudet vaikuttavat oleellisesti koirien hyvinvointiin ja osa roduista on erityisen alttiita tietyille sairauksille, mikä viittaa perinnöllisten riskitekijöiden merkittävään vaikutukseen. Autoimmuunisairauksissa yksilön oma immuunipuolustusjärjestelmä hyökkää yksilön omaa kudosta vastaan ja taudin puhkeamiseen vaikuttavat usein sekä ympäristötekijät, että lukuisat perinnölliset riskitekijät, joista yleisin on major histocompatibility complex (MHC) geenialue (koirilla dog leukocyte antigen, DLA). Koirat kärsivät samoista perinnöllisistä sairauksista kuin ihmiset ja niiden puhkeamiseen vaikuttavat usein samat geenit ja signaalireitit. Koiraa voidaan siis käyttää mallintamaan myös ihmisten sairauksia. Koiran genomin emäsjärjestyksen selvittäminen, uudet tutkimuksen työkalut ja sadat geneettisesti erilaistuneet koirarodut mahdollistavat monitekijäisten sairauksien geenikartoituksen. Uusien alttiusgeenien löytäminen auttaa ymmärtämään myös yleisiä biologisia toimintoja ja geenien ja ympäristön vuorovaikutussuhteita. Tutkimuksen tarkoituksena oli tunnistaa perinnöllisiä riskitekijöitä seuraavien koirien autoimmuuniperäisten sairauksien taustalla: Novascotiannoutajien systemic lupus erythematosus (SLE)-tyyppinen sairaus, johon kuuluvat reumaattinen muoto (immune-mediated rheumatic disease, IMRD) ja steriili aivokalvontulehdus (steroid-responsive meningitis arteritis) sekä samalla rodulla esiintyvä Addisonin tauti ja saksanpaimenkoirilla yleisimmin esiintyvä silmäsairaus, pannus eli krooninen pinnallinen keratiitti (chronic superficial keratitis). Selvitimme DLA-alueen kolmen ehdokasgeenin DRB1, DQA1 ja DQB1 alleelit ja niiden muodostamat haplotyypit. Tunnistimme kolme riskihaplotyyppiä, jotka altistavat SLE-tyyppisen sairauden reumaattiseen muotoon, Addisonin tautiin tai pannukseen (OR=2.0 - 2.67) ja osoitimme MHC luokan II alueen olevan merkittävä riskitekijä myös koirien autoimmuunisairauksien taustalla. Lisäksi havaitsimme riskihaplotyypin homotsygotian lisäävän sairastumisriskiä huomattavasti (OR=4.9 8.9) ja yleisen, haplotyypistä riippumattoman DLA-alueen homotsygotian altistavan pannukselle (OR=4.37) ja Addisonin taudille (OR=6.7). Tutkimustuloksemme mahdollistavat geenitestit yhtenä osana jalostussuunnitelmia riskihaplotyypin suhteen homotsygoottisten pentueiden välttämiseksi. Teimme myös ensimmäisen menestyksekkään genominlaajuisen geenikartoituksen koirien monitekijäiseen sairauteen. Paikansimme viisi kromosomialuetta, jotka vaikuttavat SLE-tyyppiseen sairauteen ja Addisonin tautiin vertaamalla lähes 100:n sairaan ja 100 terveen kontrollikoiran perimää keskenään. Tunnistimme useita lupaavia ehdokasgeenejä, kuten DAPP1, PPP3CA, BANK1, SNRPE, VRK1, PTPN3 ja HOMER2, sekä uuden T-solujen aktivointireitin. Osoitimme myös, että sisäsiittoinen koirapopulaatio on erinomainen eläinmalli monitekijäisten sairauksien geenitaustan selvittämiseksi

Origin and Evolution of Deleterious Mutations in Horses

International audienc