Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Ancient globetrotters—connectivity and putative native ranges of two cosmopolitan biofouling amphipods
    Beermann, Jan ; Hall-mullen, Allison K. ; Havermans, Charlotte ; Coolen, Joop W.P. ; Crooijmans, Richard P.M.A. ; Dibbits, Bert ; Held, Christoph ; Desiderato, Andrea - \ 2020
    PeerJ 8 (2020). - ISSN 2167-8359 - p. e9613 - e9613.
    amphipoda - biofouling - biological invasion - cosmopolitan distribution - marine dispersal - marine shipping
    The geographic distributions of some coastal marine species have appeared as
    cosmopolitan ever since they were first scientifically documented. In particular, for many benthic species that are associated with anthropogenic substrata, there is much mechanisms of dispersal. Here, we focused on two congeneric coastal crustaceans nearly all kinds of artificial hard substrata in temperate to warm seas. We hypothesized that shipping activities that started centuries ago. Mitochondrial DNA sequences of the CO1 fragment of specimens from distinct marine regions around the world were on putative native ranges of the two Jassa species. Populations of both species exhibited considerable genetic diversity with differing levels of geographic structure. For both species, at least two dominant haplotypes were shared among several geographic populations. Rapid demographic expansion and high migration rates between geographically distant regions support a scenario of ongoing dispersal all J. marmorata is the Northwest Atlantic, whereas the likely former native range of J. slatteryi is the Northern Pacific region. As corroborated by the genetic connectivity between populations, shipping still appears to be the more successful vector of the two species’ dispersal when compared to natural mechanisms. Historical invasion events that likely started centuries ago, along with current ongoing dispersal, confirm
    these species’ identities as true “neocosmopolitans”.
    Parallel genetic origin of foot feathering in birds
    Bortoluzzi, Chiara ; Megens, Hendrik-Jan ; Bosse, Mirte ; Derks, Martijn ; Dibbits, Bert ; Laport, Kimberley ; Weigend, Steffen ; Groenen, Martien ; Crooijmans, Richard - \ 2020
    Wageningen University
    PRJEB36674 - ERP119891 - chicken - parallel evolution - foot feathering - Gallus gallus
    Understanding the genetic basis of similar phenotypes shared between lineages is a long-lasting research interest. Even though animal evolution offers many examples of parallelism, for many phenotypes little is known about the underlying genes and mutations. We here use a combination of whole-genome sequencing, expression analyses, and comparative genomics to study the parallel genetic origin of ptilopody (Pti) in chicken. Ptilopody (or foot feathering) is a polygenic trait that can be observed in domesticated and wild avian species and is characterized by the partial or complete development of feathers on the ankle and feet. In domesticated birds, ptilopody is easily selected to fixation, though extensive variation in the type and level of feather development is often observed. By mean of a genome-wide association analysis, we identified two genomic regions associated with ptilopody. At one of the loci, we identified a 17 kb deletion affecting PITX1 expression, a gene known to encode a transcription regulator of hindlimb identity and development. Similarly to pigeon, at the second loci we observed ectopic expression of TBX5, a gene involved in forelimb identity and a key determinant of foot feather development. We also observed that the trait evolved only once as foot feathered birds share the same haplotype upstream TBX5. Our findings indicate that in chicken and pigeon ptilopody is determined by the same set of genes that affect similar molecular pathways. Our study confirms that ptilopody has evolved through parallel evolution in chicken and pigeon.
    Parallel Genetic Origin of Foot Feathering in Birds
    Bortoluzzi, Chiara ; Megens, Hendrik-Jan ; Bosse, Mirte ; Derks, Martijn F.L. ; Dibbits, Bert ; Laport, Kimberly ; Weigend, Steffen ; Groenen, Martien A.M. ; Crooijmans, Richard P.M.A. - \ 2020
    Molecular Biology and Evolution 37 (2020)9. - ISSN 0737-4038 - p. 2465 - 2476.
    Understanding the genetic basis of similar phenotypes shared between lineages is a long-lasting research interest. Even though animal evolution offers many examples of parallelism, for many phenotypes little is known about the underlying genes and mutations. We here use a combination of whole-genome sequencing, expression analyses, and comparative genomics to study the parallel genetic origin of ptilopody (Pti) in chicken. Ptilopody (or foot feathering) is a polygenic trait that can be observed in domesticated and wild avian species and is characterized by the partial or complete development of feathers on the ankle and feet. In domesticated birds, ptilopody is easily selected to fixation, though extensive variation in the type and level of feather development is often observed. By means of a genome-wide association analysis, we identified two genomic regions associated with ptilopody. At one of the loci, we identified a 17-kb deletion affecting PITX1 expression, a gene known to encode a transcription regulator of hindlimb identity and development. Similarly to pigeon, at the second loci, we observed ectopic expression of TBX5, a gene involved in forelimb identity and a key determinant of foot feather development. We also observed that the trait evolved only once as foot-feathered birds share the same haplotype upstream TBX5. Our findings indicate that in chicken and pigeon ptilopody is determined by the same set of genes that affect similar molecular pathways. Our study confirms that ptilopody has evolved through parallel evolution in chicken and pigeon.
    Detection of a frameshift deletion in the SPTBN4 gene leads to prevention of severe myopathy and postnatal mortality in pigs
    Derks, M.F.L. ; Harlizius, B. ; Lopez, Marcos Soares ; Greijdanus-van der Putten, Sylvia ; Dibbits, B.W. ; Laport, K. ; Megens, H.J.W.C. ; Groenen, M. - \ 2019
    Wageningen University
    Repository for the study: Martijn F.L. Derks, Barbara Harlizius, Marcos S. Lopes, Sylvia W.M. Greijdanus-van der Putten, Bert Dibbits, Kimberley Laport, Hendrik-Jan Megens, Martien A.M. Groenen. Detection of a frameshift deletion in the SPTBN4 gene leads to prevention of severe myopathy and postnatal mortality in pigs. 2019. Published in Frontiers in Genetics, doi: 10.3389/fgene.2019.01226
    Detection of a Frameshift Deletion in the SPTBN4 Gene Leads to Prevention of Severe Myopathy and Postnatal Mortality in Pigs
    Derks, M.F.L. ; Harlizius, B. ; Lopez, Marcos Soares ; Greijdanus-van der Putten, Sylvia ; Dibbits, B.W. ; Laport, K. ; Megens, H.J.W.C. ; Groenen, M. - \ 2019
    Frontiers in Genetics Livestock Genomics 10 (2019). - ISSN 1664-8021 - 9 p.
    Piglet mortality is a complex phenotype that depends on the environment, selection on piglet health, but also on the interaction between the piglet and sow. However, also monogenic recessive defects contribute to piglet mortality. Selective breeding has decreased overall piglet mortality by improving both mothering abilities and piglet viability. However, variants underlying recessive monogenic defects are usually not well captured within the breeding values, potentially drifting to higher frequency as a result of intense selection or genetic drift. This study describes the identification by whole-genome sequencing of a recessive 16-bp deletion in the SPTBN4 gene causing postnatal mortality in a pig breeding line. The deletion induces a frameshift and a premature stop codon, producing an impaired and truncated spectrin beta non-erythrocytic 4 protein (SPTBN4). Applying medium density single nucleotide polymorphism (SNP) data available for all breeding animals, a pregnant carrier sow sired by a carrier boar was identified. Of the resulting piglets, two confirmed homozygous piglets suffered from severe myopathy, hind-limb paralysis, and tremors. Histopathological examination showed dispersed degeneration and decrease of cross-striations in the dorsal and hind-limb muscle fibers of the affected piglets. Hence, the affected piglets are unable to walk or drink, usually resulting in death within a few hours after birth. This study demonstrates how growing genomic resources in pig breeding can be applied to identify rare syndromes in breeding populations, that are usually poorly documented and often are not even known to have a genetic basis. The study allows to prevent carrier-by-carrier matings, thereby gradually decreasing the frequency of the detrimental allele and avoiding the birth of affected piglets, improving animal welfare. Finally, these “natural knockouts” increase our understanding of gene function within the mammalian clade, and provide a potential model for human disease.
    The Genomic Complexity of a Large Inversion in Great Tits
    Silva, Vinicius H. da; Laine, Veronika N. ; Bosse, Mirte ; Spurgin, Lewis G. ; Derks, Martijn F.L. ; Oers, Kees van; Dibbits, Bert ; Slate, Jon ; Crooijmans, Richard P.M.A. ; Visser, Marcel E. ; Groenen, Martien A.M. - \ 2019
    Genome Biology and Evolution 11 (2019)7. - ISSN 1759-6653 - p. 1870 - 1881.
    Parus major - CNVs - songbird - structural variation

    Chromosome inversions have clear effects on genome evolution and have been associated with speciation, adaptation, and the evolution of the sex chromosomes. In birds, these inversions may play an important role in hybridization of species and disassortative mating. We identified a large (≈64 Mb) inversion polymorphism in the great tit (Parus major) that encompasses almost 1,000 genes and more than 90% of Chromosome 1A. The inversion occurs at a low frequency in a set of over 2,300 genotyped great tits in the Netherlands with only 5% of the birds being heterozygous for the inversion. In an additional analysis of 29 resequenced birds from across Europe, we found two heterozygotes. The likely inversion breakpoints show considerable genomic complexity, including multiple copy number variable segments. We identified different haplotypes for the inversion, which differ in the degree of recombination in the center of the chromosome. Overall, this remarkable genetic variant is widespread among distinct great tit populations and future studies of the inversion haplotype, including how it affects the fitness of carriers, may help to understand the mechanisms that maintain it.

    Copy number variations in Friesian horses and genetic risk factors for insect bite hypersensitivity
    Schurink, A. ; Silva, Vinicius da; Velie, Brandon D. ; Dibbits, B.W. ; Crooijmans, R.P.M.A. ; François, Liesbeth ; Janssens, Steven ; Stinckens, Anneleen ; Blott, Sarah ; Buys, Nadine ; Lindgren, Gabriella ; Ducro, B.J. - \ 2018
    Wageningen University & Research
    copy number variations - Friesian horse - genome-wide association study - insect bite hypersensitivity
    Background Many common and relevant diseases affecting equine welfare have yet to be tested regarding structural variants such as copy number variations (CNVs). CNVs make up a substantial proportion of total genetic variability in populations of many species, resulting in more sequence differences between individuals than SNPs. Associations between CNVs and disease phenotypes have been established in several species, but equine CNV studies have been limited. Aim of this study was to identify CNVs and to perform a genome-wide association (GWA) study in Friesian horses to identify genomic loci associated with insect bite hypersensitivity (IBH), a common seasonal allergic dermatitis observed in many horse breeds worldwide. Results Genotypes were obtained using the AxiomÂŽ Equine Genotyping Array containing 670,796 SNPs. After quality control of genotypes, 15,041 CNVs and 5350 CNV regions (CNVRs) were identified in 222 Friesian horses. Coverage of the total genome by CNVRs was 11.2% with 49.2% of CNVRs containing genes. 58.0% of CNVRs were novel (i.e. so far only identified in Friesian horses). A SNP- and CNV-based GWA analysis was performed, where about half of the horses were affected by IBH. The SNP-based analysis showed a highly significant association between the MHC region on ECA20 and IBH in Friesian horses. Associations between the MHC region on ECA20 and IBH were also detected based on the CNV-based analysis. However, CNVs associated with IBH in Friesian horses were not often in close proximity to SNPs identified to be associated with IBH. Conclusions CNVs were identified in a large sample of the Friesian horse population, thereby contributing to our knowledge on CNVs in horses and facilitating our understanding of the equine genome and its phenotypic expression. A clear association was identified between the MHC region on ECA20 and IBH in Friesian horses based on both SNP- and CNV-based GWA studies. These results imply that MHC contributes to IBH sensitivity in Friesian horses. Although subsequent analyses are needed for verification, nucleotide differences, as well as more complex structural variations like CNVs, seem to contribute to IBH sensitivity. IBH should be considered as a common disease with a complex genomic architecture.
    Autosomal dwarfism study in chicken
    Wu, Zhou ; Derks, M.F.L. ; Dibbits, B.W. ; Megens, H.J.W.C. ; Groenen, M. ; Crooijmans, R.P.M.A. - \ 2018
    PRJEB25937 - ERP107903 - ERS2374285 - Gallu gallus
    Our work use the WGS data present the molecular genetic evidence for a novel mutation potentially underlying autosomal dwarfism in chicken. The identification of the adw mutation provides the basis for future studies towards dwarf status in different species, as well as the functional role of TMEM263 in growth and developmental pathways. Autosomal dwarfism (adw) in chicken is known as a growth deficiency caused by a recessive mutation. The features of autosomal dwarfism are known as a proportionally 30% growth reduction with short shank length. The adw variant was first recognized in the Cornell K-strain of White Leghorns but the genetic causal variant remained unknown. To detect the underlying causal variant underlying the trait of adw, fine mapping was conducted based on previous linkage research on chromosome 1. We found a nonsense mutation in the transmembrane protein 263 gene (TMEM263) that is completely associated with the autosomal dwarf phenotype. Variants were detected by comparing whole-genome sequencing data from white leghorns vs adw chicken. Many potential variants were identified but after filtering for the known variant with variant databases, only one potential variant remained associated with autosomal dwarfism. A stop gain variant in TMEM263 is found unique in dwarf chicken and absent in normal-sized controls. In human, TMEM263 is associated with bone mineral density and the protein interacts with growth hormone 1. Therefore the nonsense mutation in TMEM263 likely leads to a protein truncation and therefore affects its function.
    Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome
    Derks, Martijn F.L. ; Lopes, Marcos S. ; Bosse, Mirte ; Madsen, Ole ; Dibbits, Bert ; Harlizius, Barbara ; Groenen, Martien A.M. ; Megens, Hendrik Jan - \ 2018
    Plos Genetics 14 (2018)9. - ISSN 1553-7404 - 20 p.

    Livestock populations can be used to study recessive defects caused by deleterious alleles. The frequency of deleterious alleles including recessive lethal alleles can stay at high or moderate frequency within a population, especially if recessive lethal alleles exhibit an advantage for favourable traits in heterozygotes. In this study, we report such a recessive lethal deletion of 212kb (del) within the BBS9 gene in a breeding population of pigs. The deletion produces a truncated BBS9 protein expected to cause a complete loss-of-function, and we find a reduction of approximately 20% on the total number of piglets born from carrier by carrier matings. Homozygous del/del animals die mid- to late-gestation, as observed from high increase in numbers of mummified piglets resulting from carrier-by-carrier crosses. The moderate 10.8% carrier frequency (5.4% allele frequency) in this pig population suggests an advantage on a favourable trait in heterozygotes. Indeed, heterozygous carriers exhibit increased growth rate, an important selection trait in pig breeding. Increased growth and appetite together with a lower birth weight for carriers of the BBS9 null allele in pigs is analogous to the phenotype described in human and mouse for (naturally occurring) BBS9 null-mutants. We show that fetal death, however, is induced by reduced expression of the downstream BMPER gene, an essential gene for normal foetal development. In conclusion, this study describes a lethal 212kb deletion with pleiotropic effects on two different genes, one resulting in fetal death in homozygous state (BMPER), and the other increasing growth (BBS9) in heterozygous state. We provide strong evidence for balancing selection resulting in an unexpected high frequency of a lethal allele in the population. This study shows that the large amounts of genomic and phenotypic data routinely generated in modern commercial breeding programs deliver a powerful tool to monitor and control lethal alleles much more efficiently.

    Copy number variations in Friesian horses and genetic risk factors for insect bite hypersensitivity
    Schurink, Anouk ; Silva, Vinicius H. da; Velie, Brandon D. ; Dibbits, Bert W. ; Crooijmans, Richard P.M.A. ; François, Liesbeth ; Janssens, Steven ; Stinckens, Anneleen ; Blott, Sarah ; Buys, Nadine ; Lindgren, Gabriella ; Ducro, Bart J. - \ 2018
    BMC Genetics 19 (2018)1. - ISSN 1471-2156
    Copy number variations - Friesian horse - Genome-wide association study - Insect bite hypersensitivity

    Background: Many common and relevant diseases affecting equine welfare have yet to be tested regarding structural variants such as copy number variations (CNVs). CNVs make up a substantial proportion of total genetic variability in populations of many species, resulting in more sequence differences between individuals than SNPs. Associations between CNVs and disease phenotypes have been established in several species, but equine CNV studies have been limited. Aim of this study was to identify CNVs and to perform a genome-wide association (GWA) study in Friesian horses to identify genomic loci associated with insect bite hypersensitivity (IBH), a common seasonal allergic dermatitis observed in many horse breeds worldwide. Results: Genotypes were obtained using the Axiom® Equine Genotyping Array containing 670,796 SNPs. After quality control of genotypes, 15,041 CNVs and 5350 CNV regions (CNVRs) were identified in 222 Friesian horses. Coverage of the total genome by CNVRs was 11.2% with 49.2% of CNVRs containing genes. 58.0% of CNVRs were novel (i.e. so far only identified in Friesian horses). A SNP- and CNV-based GWA analysis was performed, where about half of the horses were affected by IBH. The SNP-based analysis showed a highly significant association between the MHC region on ECA20 and IBH in Friesian horses. Associations between the MHC region on ECA20 and IBH were also detected based on the CNV-based analysis. However, CNVs associated with IBH in Friesian horses were not often in close proximity to SNPs identified to be associated with IBH. Conclusions: CNVs were identified in a large sample of the Friesian horse population, thereby contributing to our knowledge on CNVs in horses and facilitating our understanding of the equine genome and its phenotypic expression. A clear association was identified between the MHC region on ECA20 and IBH in Friesian horses based on both SNP- and CNV-based GWA studies. These results imply that MHC contributes to IBH sensitivity in Friesian horses. Although subsequent analyses are needed for verification, nucleotide differences, as well as more complex structural variations like CNVs, seem to contribute to IBH sensitivity. IBH should be considered as a common disease with a complex genomic architecture.

    A novel loss-of-function variant in transmembrane protein 263 (TMEM263) of autosomal dwarfism in chicken
    Wu, Zhou ; Derks, Martijn F.L. ; Dibbits, Bert ; Megens, Hendrik Jan ; Groenen, Martien A.M. ; Crooijmans, Richard P.M.A. - \ 2018
    Frontiers in Genetics Livestock Genomics 9 (2018). - ISSN 1664-8021
    Autosomal dwarfism - Body size - Chicken - Loss-of-function mutation - Recessive trait

    Autosomal dwarfism (adw) in chickens is a growth deficiency caused by a recessive mutation. Characteristic for adw is an approximately 30% growth reduction with short shank. The adw variant was first recognized in the Cornell K-strain of White Leghorns, but the genetic causal variant remained unknown. To identify the causal variant underlying the adw phenotype, fine mapping was conducted on chromosome 1, within 52-56 Mb. This region was known to harbor the causal variant from previous linkage studies. We compared whole-genome sequence data of this region from normal-sized and adw chickens in order to find the unique causal variant. We identified a novel nonsense mutation NP_001006244.1:p.(Trp59*), in the transmembrane protein 263 gene (TMEM263), completely associated with adw. The nonsense mutation truncates the transmembrane protein within the membrane-spanning domain, expected to cause a dysfunctional protein. TMEM263 is reported to be associated with bone mineral deposition in humans, and the protein shows interaction with growth hormone 1 (GH1). Our study presents molecular genetic evidence for a novel loss-of-function variant, which likely alters body growth and development in autosomal dwarf chicken.

    Affymetrix SNP array data for wild Dutch great tits (Parus major)
    Silva, Vinicius Da; Laine, Veronika N. ; Bosse, M. ; Oers, C.H.J. ; Dibbits, B.W. ; Visser, M.E. ; Crooijmans, R.P.M.A. ; Groenen, M. - \ 2018
    NIOO-KNAW
    GSE105131 - Parus major - PRJNA415009
    The great tit is a widely studied passerine bird species in ecology that, in the past decades, has provided important insights into speciation, phenology, behavior and microevolution. After completion of the great tit genome sequence, a customized high density 650k SNP array was developed enabling more detailed genomic studies in this species.
    CNVs are associated with genomic architecture in a songbird
    Silva, Vinicius H. da; Laine, Veronika N. ; Bosse, Mirte ; Oers, Kees van; Dibbits, Bert ; Visser, Marcel E. ; Crooijmans, Richard P.M.A. ; Groenen, Martien A.M. - \ 2018
    BMC Genomics 19 (2018)Supplement 2. - ISSN 1471-2164
    Duplication - Genetic variation - Inheritance - Parus major - Recombination

    Background: Understanding variation in genome structure is essential to understand phenotypic differences within populations and the evolutionary history of species. A promising form of this structural variation is copy number variation (CNV). CNVs can be generated by different recombination mechanisms, such as non-allelic homologous recombination, that rely on specific characteristics of the genome architecture. These structural variants can therefore be more abundant at particular genes ultimately leading to variation in phenotypes under selection. Detailed characterization of CNVs therefore can reveal evolutionary footprints of selection and provide insight in their contribution to phenotypic variation in wild populations. Results: Here we use genotypic data from a long-term population of great tits (Parus major), a widely studied passerine bird in ecology and evolution, to detect CNVs and identify genomic features prevailing within these regions. We used allele intensities and frequencies from high-density SNP array data from 2,175 birds. We detected 41,029 CNVs concatenated into 8,008 distinct CNV regions (CNVRs). We successfully validated 93.75% of the CNVs tested by qPCR, which were sampled at different frequencies and sizes. A mother-daughter family structure allowed for the evaluation of the inheritance of a number of these CNVs. Thereby, only CNVs with 40 probes or more display segregation in accordance with Mendelian inheritance, suggesting a high rate of false negative calls for smaller CNVs. As CNVRs are a coarse-grained map of CNV loci, we also inferred the frequency of coincident CNV start and end breakpoints. We observed frequency-dependent enrichment of these breakpoints at homologous regions, CpG sites and AT-rich intervals. A gene ontology enrichment analyses showed that CNVs are enriched in genes underpinning neural, cardiac and ion transport pathways. Conclusion: Great tit CNVs are present in almost half of the genes and prominent at repetitive-homologous and regulatory regions. Although overlapping genes under selection, the high number of false negatives make neutrality or association tests on CNVs detected here difficult. Therefore, CNVs should be further addressed in the light of their false negative rate and architecture to improve the comprehension of their association with phenotypes and evolutionary history.

    Wageningen University & Research Animal Breeding and Genomics FAANG data from three boars
    Derks, M.F.L. ; Lopes, Marcos S. ; Bosse, M. ; Madsen, O. ; Dibbits, B.W. ; Harlizius, Barbara ; Groenen, M. ; Megens, H.J.W.C. - \ 2017
    Wageningen University
    PRJEB19268 - PRJEB19268 - ERP021264 - ERX187799
    This study is part of the FAANG project.
    Hypermobility and short stature in Friesian horses is associated with an Ehlers-Danlos linkeropathy splice site mutation in B4GALT7
    Leegwater, Peter A.J. ; Vos-Loohuis, Manon ; Ducro, B.J. ; Boegheim, Iris J. ; Bastiaansen, J.W.M. ; Dibbits, B.W. ; Schurink, A. - \ 2016
    University Medical Center Utrecht (UMCU)
    PRJEB13863 - ERP015442
    Background Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short, ribs are dented, while the head looks adult-like at young age and the back appears as relatively normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses thus to improve our understanding of the disease process and mechanisms behind also at the human molecular level (‘one health’). Results We have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of four dwarfs and three control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C>T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.Arg17Lys of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene. With that we showed that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 3% compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation is a common manifestation in both of these syndromes. Conclusions We suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may reflect underlying conservation of nucleotide sequence that are required for efficient splicing.
    Copy number variations associated with insect bite hypersensitivity in Friesian horses
    Schurink, A. ; Silva, Vinicius da; Velie, B.D. ; Dibbits, B.W. ; Crooijmans, R.P.M.A. ; Francois, I. ; Stinckens, Anneleen ; Blott, Sarah ; Buys, N. ; Lindgren, G. ; Ducro, B.J. - \ 2016
    In: Book of Abstracts of the 67st Annual Meeting of the European Federation of Animal Science. - Wageningen : Wageningen Academic Publishers (Book of abstracts 22) - ISBN 9789086862849 - p. 286 - 286.
    Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7
    Leegwater, Peter A. ; Vos-Loohuis, Manon ; Ducro, Bart J. ; Boegheim, Iris J. ; Bastiaansen, John W.M. ; Dibbits, Bert W. ; Schurink, Anouk - \ 2016
    BMC Genomics 17 (2016)1. - ISSN 1471-2164
    Equus caballus - Extracellular matrix - Galactosyltransferase I - Genome - Growth retardation - Hypermobile joints - Linkeropathy - Proteoglycan

    Background: Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level. Results: We have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of two dwarfs and one control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C > T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.(Arg17Lys) of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene and we show that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 2 % compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation and ligamentous laxity are common manifestations of these syndromes. Conclusions: We suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may not be necessary at the protein level but instead may reflect underlying conservation of nucleotide sequence that are required for efficient splicing.

    A nonsense mutation causes hydrocephalus in Friesian horses
    Schurink, A. ; Ducro, B.J. ; Bastiaansen, J.W.M. ; Boegheim, I.J.M. ; Steenbeek, F.G. van; Vos-Loohuis, M. ; Nijman, I.J. ; Monroe, G.R. ; Hellinga, I. ; Dibbits, B.W. ; Back, W. ; Leegwater, P.A.J. - \ 2015
    hydrocephalus - friesian horses - mutation
    Hydrocephalus in Friesian horses is a developmental disorder that often results in stillbirth of affected foals and dystocia in dams. The occurrence is probably related to a founder effect and inbreeding in the population. The aim of our study was to identify the causal mutation for hydrocephalus in Friesian horses, as it will help in understanding its aetiology and allow selection against the disease allele using a DNA test. Genotypes were obtained using the Illumina® EquineSNP50 Genotyping BeadChip, where 29,270 SNPs remained after quality control. Significance level of genotype differences between cases (n = 13) and controls (n = 69) per SNP was determined with a χ2-test using the ccfast function in the GenABEL package in R. One strongly associated region was found and examined to identify overlapping regions of homozygosity between cases. Next generation DNA sequence analysis was performed of gene exons in the identified region on 4 cases and 6 controls. A genome-wide association study of hydrocephalus indicated the involvement of a region on ECA1 (P <1.68×10-6). All cases, and none of the controls, carried 2 copies of a 0.58 Mb haplotype. Next generation DNA sequence analysis revealed a nonsense mutation that was identical to a mutation identified in a human case of muscular dystrophy-dystroglycanopathy with hydrocephalus. All available cases and none of the controls were homozygous for the mutation. 32 controls were heterozygotes of which 17 were dams of cases and 36 controls were homozygous for the normal allele. Hydrocephalus in Friesian horses has an autosomal recessive mode of inheritance. A nonsense mutation is responsible for hydrocephalus in Friesian horses and classifies the phenotype as a muscular dystrophy-dystroglycanopathy. Currently, Friesian horses are tested for the presence of the disease allele, which allows selection against this allele and thereby reduction in losses and suffering caused by hydrocephalus in the Friesian horse population.
    Genomic analysis of hydrocephalus in Friesian horses
    Schurink, A. ; Ducro, B.J. ; Bastiaansen, J.W.M. ; Dibbits, B.W. ; Boegheim, I.J.M. ; Steenbeek, F.G. van; Vos-Loohuis, M. ; Nijman, I.J. ; Monroe, G.R. ; Hellinga, I. ; Back, W. ; Leegwater, P.A.J. - \ 2015
    A nonsense mutation in B3GALNT2 is concordant with hydrocephalus in Friesian horses
    Ducro, B.J. ; Schurink, A. ; Bastiaansen, J.W.M. ; Boegheim, I.J.M. ; Steenbeek, F.G. van; Vos-Loohuis, M. ; Nijman, I.J. ; Monroe, G.R. ; Hellinga, I. ; Dibbits, B.W. ; Back, W. ; Leegwater, P.A.J. - \ 2015
    BMC Genomics 16 (2015). - ISSN 1471-2164 - 9 p.
    Background Hydrocephalus in Friesian horses is a developmental disorder that often results in stillbirth of affected foals and dystocia in dams. The occurrence is probably related to a founder effect and inbreeding in the population. The aim of our study was to find genomic associations, to investigate the mode of inheritance, to allow a DNA test for hydrocephalus in Friesian horses to be developed. In case of a monogenic inheritance we aimed to identify the causal mutation. Results A genome-wide association study of hydrocephalus in 13 cases and 69 controls using 29,720 SNPs indicated the involvement of a region on ECA1 (P T corresponding to XP_001491595 p.Gln475* was identical to a B3GALNT2 mutation identified in a human case of muscular dystrophy-dystroglycanopathy with hydrocephalus. All 16 available cases and none of the controls were homozygous for the mutation, and all 17 obligate carriers (= dams of cases) were heterozygous. A random sample of the Friesian horse population (n¿=¿865) was tested for the mutation in a commercial laboratory. One-hundred and forty-seven horses were carrier and 718 horses were homozygous for the normal allele; the estimated allele frequency in the Friesian horse population is 0.085. Conclusions Hydrocephalus in Friesian horses has an autosomal recessive mode of inheritance. A nonsense mutation XM_001491545 c.1423C>T corresponding to XP_001491595 p.Gln475* in B3GALNT2 (1:75,859,296–75,909,376) is concordant with hydrocephalus in Friesian horses. Application of a DNA test in the breeding programme will reduce the losses caused by hydrocephalus in the Friesian horse population.
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