Mendelian Inheritance In Animals Research Articles

Equus in Online Mendelian Inheritance in Animals (OMIA).

Online Mendelian Inheritance in Animals (OMIA is a freely available information resource, which includes information for Equus inherited traits/diseases (collectively called phenes). The database focuses on Mendelian traits and their likely causal variants (mutations). Some of these Mendelian traits are favored by humans, e.g., coat color, while others are diseases. Additions to OMIA are based on publications of peer-reviewed research. Maintaining up-to-date information in OMIA is a challenge, owing to the multiplicity of species, the increase in the number of relevant publications, and as reference genomes and methods of citation continue to evolve. This challenge has been successfully aided by contributions from scientists from around the world. In some cases, those scientists are faculty members who charge their students with curation as an educational activity. Recently, OMIA has introduced computerized lists of standardized names and synonyms (called ontologies) for breeds of Equus and other animals and for phene categories. These ontologies facilitate increased connectivity between OMIA and other online resources. OMIA is and will continue to be a major reference resource for Mendelian phenes in the genus Equus.

An Overview of Canine Inherited Neurological Disorders with Known Causal Variants.

Hereditary neurological conditions documented in dogs encompass congenital, neonatal, and late-onset disorders, along with both progressive and non-progressive forms. In order to identify the causal variant of a disease, the main two approaches are genome-wide investigations and candidate gene investigation. Online Mendelian Inheritance in Animals currently lists 418 Mendelian disorders specific to dogs, of which 355 have their likely causal genetic variant identified. This review aims to summarize the current knowledge on the canine nervous system phenes and their genetic causal variant. It has been noted that the majority of these diseases have an autosomal recessive pattern of inheritance. Additionally, the dog breeds that are more prone to develop such diseases are the Golden Retriever, in which six inherited neurological disorders with a known causal variant have been documented, and the Belgian Shepherd, in which five such disorders have been documented. DNA tests can play a vital role in effectively managing and ultimately eradicating inherited diseases.

A de novo start‐lost variant in ANKRD28 in a Holstein calf with dwarfism

Osteochondrodysplasias comprise a broad spectrum of hereditary developmental disorders of bone and cartilage, but can also have significant effects on tendons, ligaments, and muscles (Warman et al., 2011). According to Online Mendelian Inheritance in Animals, there are six known dwarfism phenotypes in cattle, which are inherited both recessively and dominantly and are due to structural or signaling pathways disruptions (OMIA 000299-9913; Boegheim et al., 2017). A 3.5-month-old, female, purebred Holstein calf was reported because of its short stature, protruding scapulohumeral joints, increased concavity of the frontal bone, and bossing of the intercornual prominence (Figure S1). A whole-genome sequencing (WGS) approach was performed as described before (Jacinto et al., 2022) using genomic DNA extracted from blood of the affected calf, her dam, and from semen of her sire. Reads were mapped to the ARS-UCD1.2 assembly (Rosen et al., 2020) resulting in an average read depth of 20.7× in the calf, 21.8× in the dam, and 22.1× in the sire, and then processed as reported earlier (Jacinto et al., 2021). We hypothesized that the affected calf had a novel form of dwarfism and investigated the genetic origin. The trio-based WGS approach identified no homozygous protein-changing variants present exclusively in the genome of the affected calf. Consequently, a recessive inheritance seems unlikely. Given that the reported calf was the only case and dwarfism had never before been reported in the Canadian Holstein population, we hypothesized that a dominant mode of inheritance due to a de novo mutation event was more likely. We found three heterozygous private protein-changing variants present in the calf and absent in both parental genomes and in 5365 controls (Table S1). Review of the sequencing data for each of these heterozygous variants revealed that all were indeed de novo variants affecting different genes. Only one of these variants concerns an interesting putative candidate gene (ANKRD28) for the observed phenotype. This heterozygous variant at chr1:152807533C>CA represents a 1-bp insertion in exon 2 of the ANKRD28 gene that directly affect the translation initiation (start) codon (XM_024989836.1: c.2dupT; Figure S1). The predicted consequence of this start-lost variant is that amino acid Met1 is converted to Leu after activation of an upstream translation initiation site at cDNA position −20, resulting in N-terminal protein extension by insertion of six amino acids between Met1 and Gly2 (XP_024845604.1: p.Met1_Gly2insIleValGlyGlyLysAlaLeu). We propose the heterozygous c.2dupT variant as a candidate causative variant for the observed congenital disorder and ANKRD28 as a novel candidate gene for dwarfism phenotypes. The protein-altering nature of this de novo mutation strongly suggests the causality of the variant. The Genome Aggregation Database showed that ANKRD28 falls into the class of loss-of-function haploinsufficient genes (Karczewski et al., 2020). Therefore, two different situations could explain the perceived phenotype: either haploinsufficiency or co-expression of an N-terminally extended protein, leading to non- or abnormal expression of the mutant allele. Nonetheless, since this is a single case study and we have no functional confirmation, this result must be considered preliminary and should be interpreted with caution. It must also be noted that the analysis of short-read genomic data is not ideal for identifying larger structural variants. Further individual cases of dwarfism in cattle or other animal species could be investigated for ANKRD28 variants by DNA sequencing. We thank the Interfaculty Bioinformatics Unit of the University of Bern for providing high-performance computational infrastructure. Irene M. Häfliger was funded by the Swiss National Science Foundation, grant number 172911. Wayne Dickieson of Birkentree Holsteins is gratefully acknowledged. Open access funding provided by University of Bern. The authors declare no conflict of interest. The WGS data are available under the study accession no. PRJEB18113 at the European Nucleotide Archive (www.ebi.ac.uk/ena; calf SAMEA8565094, dam SAMEA8565093, sire SAMEA8565095). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects

BackgroundIchthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis.ResultsA 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds.ConclusionsThis study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).

A KRT71 Loss-of-Function Variant Results in Inner Root Sheath Dysplasia and Recessive Congenital Hypotrichosis of Hereford Cattle.

Genodermatoses, such as heritable skin disorders, mostly represent Mendelian conditions. Congenital hypotrichosis (HY) characterize a condition of being born with less hair than normal. The purpose of this study was to characterize the clinicopathological phenotype of a breed-specific non-syndromic form of HY in Hereford cattle and to identify the causative genetic variant for this recessive disorder. Affected calves showed a very short, fine, wooly, kinky and curly coat over all parts of the body, with a major expression in the ears, the inner part of the limbs, and in the thoracic-abdominal region. Histopathology showed a severely altered morphology of the inner root sheath (IRS) of the hair follicle with abnormal Huxley and Henle’s layers and severely dysplastic hair shafts. A genome-wide association study revealed an association signal on chromosome 5. Homozygosity mapping in a subset of cases refined the HY locus to a 690 kb critical interval encompassing a cluster of type II keratin encoding genes. Protein-coding exons of six positional candidate genes with known hair or hair follicle function were re-sequenced. This revealed a protein-changing variant in the KRT71 gene that encodes a type II keratin specifically expressed in the IRS of the hair follicle (c.281delTGTGCCCA; p.Met94AsnfsX14). Besides obvious phenocopies, a perfect concordance between the presence of this most likely pathogenic loss-of-function variant located in the head domain of KRT71 and the HY phenotype was found. This recessive KRT71-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002114-9913).

A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle.

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

The impact of identity by descent on fitness and disease in dogs

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves, and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in the Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs and that future work on understudied breeds may reveal new disease-causing variation.

Online Mendelian Inheritance in Animals (OMIA): a record of advances in animal genetics, freely available on the Internet for 25years.

For the last 25years, Online Mendelian Inheritance in Animals (OMIA) has been providing free global access to an ever-increasing record of discoveries made by animal geneticists around the world. To mark this 25-year milestone, this document provides a brief account (including some pre-history) of how OMIA came to be; some timelines of important discoveries and advances in the genetics of the animal species covered by OMIA, gleaned from the OMIA database; and an analysis of the current state of knowledge regarding likely causal variants of single-locus traits in OMIA species, also gleaned from the OMIA database.

Deleterious AGXT Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep.

Severe oxalate nephropathy has been previously reported in sheep and is mostly associated with excessive oxalate in the diet. However, a rare native Dutch breed (Zwartbles) seems to be predisposed to an inherited juvenile form of primary hyperoxaluria and no causative genetic variant has been described so far. This study aims to characterize the phenotype and genetic etiology of the inherited metabolic disease observed in several purebred Zwartbles sheep. Affected animals present with a wide range of clinical signs including condition loss, inappetence, malaise, and, occasionally, respiratory signs, as well as an apparent sudden unexpected death. Histopathology revealed widespread oxalate crystal deposition in kidneys of the cases. Whole-genome sequencing of two affected sheep identified a missense variant in the ovine AGXT gene (c.584G>A; p.Cys195Tyr). Variants in AGXT are known to cause type I primary hyperoxaluria in dogs and humans. Herein, we present evidence that the observed clinicopathological phenotype can be described as a form of ovine type I primary hyperoxaluria. This disorder is explained by a breed-specific recessively inherited pathogenic AGXT variant. Genetic testing enables selection against this fatal disorder in Zwartbles sheep as well as more precise diagnosis in animals with similar clinical phenotype. Our results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 001672-9940).

Novel haplotypes responsible for prenatal death in Nordic Red and Danish Jersey cattle

Haplotypes that are common in a population but not observed as homotypes in living animals may harbor lethal alleles that compromise embryo survival. In this study, we searched for homozygous-deficient haplotypes in the genomes of 19,309 Nordic Red Dairy (RDC) and 4,291 Danish Jersey (JER) cattle genotyped using the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA). For statistically significant deficient haplotypes, we evaluated the effect on nonreturn rate in at-risk matings (mating between carrier bull and daughter of carrier sire) versus not-at-risk matings (mating between noncarrier bull and daughter of noncarrier sire). Next, we analyzed whole-genome sequence variants from the 1000 Bull Genomes Project to identify putative causal variants underlying these haplotypes. In RDC, we identified 3 homozygous-deficient regions (HDR) that overlapped with known recessive lethal mutations: a 662-kb deletion on chromosome 12 in RDC [Online Mendelian Inheritance in Animals (OMIA) 001901-9913), a missense mutation in TUBD1, g.11063520T>C, in Braunvieh cattle (OMIA 001939-9913), and a 525-kb deletion on chromosome 23 in RDC (OMIA 001991-9913)]. In addition, we identified 15 novel HDR and their tag haplotypes for the underlying causative variants. The tag haplotype located between 39.2 and 40.3 Mbp on chromosome 18 had a negative effect on nonreturn rate in at-risk mating, confirming embryonic lethality. In Danish Jersey, we identified 12 novel HDR and their tag haplotypes for underlying causative variants. For 3 of these 12 tag haplotypes, insemination records of at-risk mating showed a negative effect on nonreturn rate, confirming the association with early embryonic mortality. Cattle that had both genotype and whole-genome sequence data were analyzed to detect the causative variants underlying each tag haplotype. However, none of the functional variants or deletions showed concordance with carrier status of the novel tag haplotypes. Carrier status of these detected haplotypes can be used to select bulls to reduce the frequencies of lethal alleles in the population and to avoid at-risk matings.

Genotypes and allele frequencies of buried SNPs in a bovine single-nucleotide polymorphism array in Japanese Black cattle.

Single nucleotide polymorphism (SNP) arrays are widely used for genetic and genomic analyses in cattle breeding; thus, data derived from SNP arrays have accumulated on a large scale nationwide. Commercial SNP arrays contain a considerable number of unassigned SNPs on the chromosome/position on the genome; these SNPs are excluded in subsequent analyses. Notably, the position-unassigned SNPs, or "buried SNPs" include some of the markers associated with genetic disease. In this study, we identified the position of buried SNPs using the Basic Local Alignment Search Tool against the surrounding sequences and characterized the relationship between SNPs and genetic diseases in Online Mendelian Inheritance in Animals based on the genomic position. We determined the position of 285 buried SNPs on the genome and surveyed the genotype and allele frequencies of these SNPs in 5,955 individual Japanese Black cattle. Eleven SNPs associated with genetic disease, which contained five buried SNPs, were found in the population with the risk allele frequency ranging from 0.00008396 to 0.46. These results indicate that buried SNPs in the bovine SNP array can be utilized to identify associations with genetic disorders from large scale accumulated SNP genotype data in Japanese Black cattle.

A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle

BackgroundCattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarray-derived genotypes are available for thousands of artificial insemination bulls. Two young Nordic Red bulls delivered sperm with low progressive motility (i.e., asthenospermia) during a semen collection period of more than four months. The bulls were related through a common ancestor on both their paternal and maternal ancestry. Thus, a recessive mode of inheritance of asthenospermia was suspected.ResultsBoth bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50 Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98 Mb segment located on bovine chromosome 25. This haplotype was not found in the homozygous state in 8557 fertile bulls although five homozygous haplotype carriers were expected (P = 0.018). Whole genome-sequencing uncovered that both asthenospermic bulls were homozygous for a mutation that disrupts a canonical 5′ splice donor site of CCDC189 encoding the coiled-coil domain containing protein 189. Transcription analysis showed that the derived allele activates a cryptic splice site resulting in a frameshift and premature termination of translation. The mutated CCDC189 protein is truncated by more than 40%, thus lacking the flagellar C1a complex subunit C1a-32 that is supposed to modulate the physiological movement of the sperm flagella. The mutant allele occurs at a frequency of 2.5% in Nordic Red cattle.ConclusionsOur study in cattle uncovered that CCDC189 is required for physiological movement of sperm flagella thus enabling active progression of spermatozoa and fertilization. A direct gene test may be implemented to monitor the asthenospermia-associated allele and prevent the birth of homozygous bulls that are infertile. Our results have been integrated in the Online Mendelian Inheritance in Animals (OMIA) database (https://omia.org/OMIA002167/9913/).

The use of new technologies in horse selection

Received: 2018-09-12 | Accepted: 2018-11-27 | Available online: 2018-12-31 https://doi.org/10.15414/afz.2018.21.04.186-189 Most successful selection strategies are not in use in horse selection. This study describes the use of current strategies of selection in horse and tries to answers why well known, scientifically proven selection strategies are still not implemented. In the era of genomic selection (GS) in animal breeding, decision making in horse selection, even classical values (BV), are not fully taken advantage of. Breeding organizations (BO) which implement BVs as selection criteria in their programs show great success in genetic gain. However, a horse's achievements and the popularity of its relatives still plays an important role in selection level. Genomic based selection tools in horse have limitations in quantitative traits since it is difficult to establish reference population. Mendelian traits have been studied for several years, especially those related to horse health and functional longevity (long sport or race careers), yet there are still only a small number of validated mendelian traits offered for horses. The important benefit of GS is the prevention of related mating based on genomic data, in addition to pedigree data. The specialty in horse is the use of cloning. From the point of view of genetic variability, cloning is useful in enabling geldings or non-genetically infertile animals to carry genes to next generations. In sport and race BOs, stallions from foreign BOs are frequently used. In such cases a need for comparable BVs exists. These factors were the motivation behind the establishment of Interstallion 20 years ago. Due to difficulties in BO collaboration, Interstallion has not been as successful as planned. On the whole, it is expected that the sector of horse selection will need to change considerably in the future. Keywords: value, cloning selection, genomic selection, inbreeding, strategies References Arnason, T. (1984) Genetic studies on conformation and performance of Icelandic toelter horses: IV Best linear unbiased prediction of ten correlated traits by use of an animal model. Acta Agric. Scand. 34, 450–462. Broere Jazz (2018) Jazz – one in a million. [Online] Alblasserdam. Available at: http://www.broerejazz.com/en/sperma-bestellen/ [Accessed 12 August 2018]. FMITCHELL07 (2009) Inbreeding to broodmares: an in-depth statistical analysis of the Rasmussen Factor, Part 1 [Online] https://fmitchell07.wordpress.com/2009/07/29/inbreeding-to-broodmares-an-in-depth-statistical-analysis-of-the-rasmussen-factor-part-1/ [Accessed 12 August 2018]. Henderson, C. R. (1953) Estimation of variance and covariance components. Biometrics, 9, 226–252. Jorjani, H., Jakobsen, J., Hjerpe, E., Palucci, V., Durr, J. (2012) Status of genomic evaluation in the Brown Swiss populations. Interbull Bull., 46, pp. 46–54. 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(2009) Mace for horse evaluations. Interstallion: Workshop Le Pin au Haras, 26th March 2009. [Online. Available at: ] https://www.biw.kuleuven.be/Genlog/livgen/research/interstallion/workshop_LePin/I_MACE%20for%20horse%20evaluations.pdf [Accessed 12 August 2018]. Reed, T. (2018) Johan Knaap on genomic selection – an interview. [Online]. Available at: http://www.irish-warmblood.com/pdf/Johan_Knaap_on_Genomic_Selection.pdf [Accessed 6 September 2018]. Reis, A.P., Palmer, E., Nakhla, M. (2012) Biotechnologies of reproduction in the horse: what has changed? In: Book of Abstracts of the 63 rd Annual Meeting of the European Federation of Animal Science Wageningen. Wageningen: Wageningen Academic Publishers. Shelbourne Farm. (2018) Cruising Clones. [Online]. Available at: http://www.shelbournefarm.com/stallions/cruising-clones/ [Accessed 6 September 2018]. Stock, K., Quinn Brady, K., Christiansen, K., Viklund, A., Cervantes, I., Ricard, A., Ducro, B., Janssens, S. (2015). Breeding objectives and practices of sport horse studbooks : Results of a worldwide inventory. In: Book of Abstracts of the 66 th Annual Meeting of the European Federation of Animal Science Wageningen.Wageningen: Wageningen Academic Publishers. Stock, K., Viklund, A., Cervantes, I., Ricard, A., Christiansen, K., Vangen, O., Janssens, S. (2018). The role of Interstallion in supporting international sport horse by improved transparency. In: Book of Abstracts of the 69 th Annual Meeting of the European Federation of Animal Science Wageningen. Wageningen: Wageningen Academic Publishers. Thoren Hellsten, E. (2008) International Sport Horse Data for Genetic Evaluation. Doctoral Thesis. Uppsala: Swedish University of Agricultural Sciences. Waikato (2018) Waikato Stud offers a truly world-class stallion line up. [Online]. Available at: https://waikatostud.com/stallions/ [Accessed 6 September 2018]. WBFSH (2018) World federation for sport horses: Breeder and Studbook rankings. [Online]. 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Transcriptome analysis of comb and testis from Rose-comb Silky chicken (R1/R1) and Beijing Fatty wild type chicken (r/r)

Rose-comb was one of the chicken comb-variants first used by Bateson and Punnet in 1902 to demonstrate Mendelian inheritance in animals. Rose-comb is a monogenic trait that has been widely described in chickens. It is caused by a large structural rearrangement that leads to mis-expression of transcription factor MNR2 on chromosome 7. Rose-comb has pleiotropic effects in homozygous roosters, which is associated with poor sperm mobility. It was postulated that this is caused by the disruption of the CCDC108 gene located at the distal inversion breakpoint. In this study, we did the transcriptional profiling of combs and testes from Rose-comb Silky (RS) (R1/R1) and Beijing Fatty (BF) wild type chickens (r/r) using RNA-seq. We obtained 68,694,797 unique mapped reads and over 80% of the chicken genes were covered for each sample. In combs, we found that differentially expressed genes (DEGs) were significantly enriched in the retinol metabolism (RPE65, CYP26A1, and CYP26C1) and hedgehog-signaling pathway (PTCH1, GLI1, and HHIP), while genes related to cell differentiation and morphogenesis were down-regulated in R1/R1 chickens, suggesting that the transient expression of MNR2 might affect the expression of these genes and influence the development of comb tissue. For testes, DEGs were significantly enriched in the GO terms of binding activates and mitochondrial oxidation-reduction reactions. Our results suggested that the CCDC108 might be functionally related with mitochondrial oxidation-reduction reactions and caused subfertility of roosters. Compared with the genome average, the degree of expression variations within the inversion region did not show significant differences. However, DEGs near the breakpoints showed greater expression variance. Our results demonstrated that the large-scale rearrangements affected the gene expression only around the breakpoint in this case.

Predicted Molecular Effects of Sequence Variants Link to System Level of Disease.

Developments in experimental and computational biology are advancing our understanding of how protein sequence variation impacts molecular protein function. However, the leap from the micro level of molecular function to the macro level of the whole organism, e.g. disease, remains barred. Here, we present new results emphasizing earlier work that suggested some links from molecular function to disease. We focused on non-synonymous single nucleotide variants, also referred to as single amino acid variants (SAVs). Building upon OMIA (Online Mendelian Inheritance in Animals), we introduced a curated set of 117 disease-causing SAVs in animals. Methods optimized to capture effects upon molecular function often correctly predict human (OMIM) and animal (OMIA) Mendelian disease-causing variants. We also predicted effects of human disease-causing variants in the mouse model, i.e. we put OMIM SAVs into mouse orthologs. Overall, fewer variants were predicted with effect in the model organism than in the original organism. Our results, along with other recent studies, demonstrate that predictions of molecular effects capture some important aspects of disease. Thus, in silico methods focusing on the micro level of molecular function can help to understand the macro system level of disease.

Genetic testing in veterinary dermatology.

Molecular genetics has made significant advances in the analysis of hereditary dermatoses during the last several years. To provide an update on currently available genetic tests for skin diseases of dogs, cats and horses, and to aid the veterinary clinician in the appropriate selection and applications of genetic tests. The scientific literature on the topic was critically reviewed. The list of known causative variants for genodermatoses and hair morphology traits was compiled by searching the Online Mendelian Inheritance in Animals (OMIA) database. Genetic testing has become an important diagnostic method in veterinary medicine. Genetic tests can help to establish the correct diagnosis in some diseases with relatively nonspecific signs. Genetic tests are also essential for sustainable breeding programmes and to help minimize the frequency of animals with hereditary diseases. Advances in genetic methodology and bioinformatics already allow genome-wide screening for potential disease causing mutations for research purposes. It is anticipated that this will become a routine process in clinical practice in the future. As specific DNA tests and broad genome-wide analyses come into more common use, it is critical that clinicians understand the proper application and interpretation of these test results.

Morphological mutations: lessons from the cockscomb.

Morphological mutations: lessons from the cockscomb.

Database resources of the National Center for Biotechnology Information

In addition to maintaining the GenBank® nucleic acid sequence database, the National Center for Biotechnology Information (NCBI, http://www.ncbi.nlm.nih.gov) provides analysis and retrieval resources for the data in GenBank and other biological data made available through the NCBI Web site. NCBI resources include Entrez, the Entrez Programming Utilities, MyNCBI, PubMed, PubMed Central, PubReader, Gene, the NCBI Taxonomy Browser, BLAST, BLAST Link, Primer-BLAST, COBALT, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, dbVar, Epigenomics, the Genetic Testing Registry, Genome and related tools, the Map Viewer, Trace Archive, Sequence Read Archive, BioProject, BioSample, ClinVar, MedGen, HIV-1/Human Protein Interaction Database, Gene Expression Omnibus, Probe, Online Mendelian Inheritance in Animals, the Molecular Modeling Database, the Conserved Domain Database, the Conserved Domain Architecture Retrieval Tool, Biosystems, Protein Clusters and the PubChem suite of small molecule databases. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All these resources can be accessed through the NCBI home page.

Snat: a SNP annotation tool for bovine by integrating various sources of genomic information

BackgroundMost recently, with maturing of bovine genome sequencing and high throughput SNP genotyping technologies, a large number of significant SNPs associated with economic important traits can be identified by genome-wide association studies (GWAS). To further determine true association findings in GWAS, the common strategy is to sift out most promising SNPs for follow-up replication studies. Hence it is crucial to explore the functional significance of the candidate SNPs in order to screen and select the potential functional ones. To systematically prioritize these statistically significant SNPs and facilitate follow-up replication studies, we developed a bovine SNP annotation tool (Snat) based on a web interface.ResultsWith Snat, various sources of genomic information are integrated and retrieved from several leading online databases, including SNP information from dbSNP, gene information from Entrez Gene, protein features from UniProt, linkage information from AnimalQTLdb, conserved elements from UCSC Genome Browser Database and gene functions from Gene Ontology (GO), KEGG PATHWAY and Online Mendelian Inheritance in Animals (OMIA). Snat provides two different applications, including a CGI-based web utility and a command-line version, to access the integrated database, target any single nucleotide loci of interest and perform multi-level functional annotations. For further validation of the practical significance of our study, SNPs involved in two commercial bovine SNP chips, i.e., the Affymetrix Bovine 10K chip array and the Illumina 50K chip array, have been annotated by Snat, and the corresponding outputs can be directly downloaded from Snat website. Furthermore, a real dataset involving 20 identified SNPs associated with milk yield in our recent GWAS was employed to demonstrate the practical significance of Snat.ConclusionsTo our best knowledge, Snat is one of first tools focusing on SNP annotation for livestock. Snat confers researchers with a convenient and powerful platform to aid functional analyses and accurate evaluation on genes/variants related to SNPs, and facilitates follow-up replication studies in the post-GWAS era.

Internet resources cataloguing inherited disorders in dogs

Up-to-date annotated catalogues of known inherited disorders in dogs are freely available on the Internet, providing vital information to existing and prospective dog owners, dog breeders, veterinarians, geneticists and others interested in the occurrence and control of inherited disorders. These resources are the Canine Inherited Disorders Database (CIDD), Inherited Diseases in Dogs (IDID) and Online Mendelian Inheritance in Animals (OMIA) the latter associated with Listing of Inherited Disorders in Animals (LIDA). The history and features of these resources are summarised.