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1.
BMC Genet ; 19(1): 49, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30060732

RESUMO

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.


Assuntos
Cavalos/genética , Hipersensibilidade/veterinária , Mordeduras e Picadas de Insetos/veterinária , Animais , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla/veterinária , Hipersensibilidade/genética , Mordeduras e Picadas de Insetos/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
2.
BMC Genomics ; 17(1): 839, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27793082

RESUMO

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.


Assuntos
Nanismo/veterinária , Galactosiltransferases/genética , Doenças dos Cavalos/genética , Instabilidade Articular/genética , Mutação , Sítios de Splice de RNA , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Feminino , Estudos de Associação Genética , Cavalos , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
3.
BMC Genomics ; 16: 761, 2015 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-26452345

RESUMO

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 <1.68 × 10(-6)). Next generation DNA sequence analysis of 4 cases and 6 controls of gene exons within the region revealed a mutation in ß-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2) as the likely cause of hydrocephalus in Friesian horses. The nonsense mutation XM_001491545 c.1423C>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.


Assuntos
Códon sem Sentido/genética , Doenças dos Cavalos/genética , Hidrocefalia/genética , N-Acetilgalactosaminiltransferases/genética , Alelos , Animais , Cruzamento , Éxons , Feminino , Estudo de Associação Genômica Ampla , Cavalos , Humanos , Hidrocefalia/patologia , Endogamia , Polimorfismo de Nucleotídeo Único , Gravidez
4.
Mol Ecol Resour ; 12(4): 753-70, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22487530

RESUMO

The vast amount of phenotypic information collected in some wild animal populations makes them extremely valuable for unravelling the genetics of ecologically important traits and understanding how populations adapt to changes in their environment. Next generation sequencing has revolutionized the development of large marker panels in species previously lacking genomic resources. In this study, a unique genomics toolkit was developed for the great tit (Parus major), a model species in ecology and behavioural biology. This toolkit consists of nearly 100,000 SNPs, over 250 million nucleotides of assembled genomic DNA and more than 80 million nucleotides of assembled expressed sequences. A SNP chip with 9193 SNP markers expected to be spaced evenly along the great tit genome was used to genotype 4702 birds from two of the most intensively studied natural vertebrate populations [Wytham Woods/Bagley Woods (United Kingdom) and de Hoge Veluwe/Westerheide (The Netherlands)]. We show that (i) SNPs identified in either of the two populations have a high genotyping success in the other population, (ii) the minor allele frequencies of the SNPs are highly correlated between the two populations and (iii) despite this high correlation, a large number of SNPs display significant differentiation (F(ST) ) between the populations, with an overrepresentation of genes involved in cardiovascular development close to these SNPs. The developed resources provide the basis for unravelling the genetics of important traits in many long-term studies of great tits. More generally, the protocols and pitfalls encountered will be of use for those developing similar resources.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Passeriformes/genética , Polimorfismo de Nucleotídeo Único , Animais , Frequência do Gene , Genética Populacional , Genômica , Genótipo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Análise de Sequência de DNA
5.
BMC Genomics ; 12: 94, 2011 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21291514

RESUMO

BACKGROUND: Variation within individual genomes ranges from single nucleotide polymorphisms (SNPs) to kilobase, and even megabase, sized structural variants (SVs), such as deletions, insertions, inversions, and more complex rearrangements. Although much is known about the extent of SVs in humans and mice, species in which they exert significant effects on phenotypes, very little is known about the extent of SVs in the 2.5-times smaller and less repetitive genome of the chicken. RESULTS: We identified hundreds of shared and divergent SVs in four commercial chicken lines relative to the reference chicken genome. The majority of SVs were found in intronic and intergenic regions, and we also found SVs in the coding regions. To identify the SVs, we combined high-throughput short read paired-end sequencing of genomic reduced representation libraries (RRLs) of pooled samples from 25 individuals and computational mapping of DNA sequences from a reference genome. CONCLUSION: We provide a first glimpse of the high abundance of small structural genomic variations in the chicken. Extrapolating our results, we estimate that there are thousands of rearrangements in the chicken genome, the majority of which are located in non-coding regions. We observed that structural variation contributes to genetic differentiation among current domesticated chicken breeds and the Red Jungle Fowl. We expect that, because of their high abundance, SVs might explain phenotypic differences and play a role in the evolution of the chicken genome. Finally, our study exemplifies an efficient and cost-effective approach for identifying structural variation in sequenced genomes.


Assuntos
Genoma/genética , Variação Estrutural do Genoma/genética , Análise de Sequência de DNA/métodos , Animais , Galinhas
6.
Mol Ecol ; 19 Suppl 1: 89-99, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20331773

RESUMO

Identifying genes that underlie ecological traits will open exiting possibilities to study gene-environment interactions in shaping phenotypes and in measuring natural selection on genes. Evolutionary ecology has been pursuing these objectives for decades, but they come into reach now that next generation sequencing technologies have dramatically lowered the costs to obtain the genomic sequence information that is currently lacking for most ecologically important species. Here we describe how we generated over 2 billion basepairs of novel sequence information for an ecological model species, the great tit Parus major. We used over 16 million short sequence reads for the de novo assembly of a reference sequence consisting of 550 000 contigs, covering 2.5% of the genome of the great tit. This reference sequence was used as the scaffold for mapping of the sequence reads, which allowed for the detection of over 20 000 novel single nucleotide polymorphisms. Contigs harbouring 4272 of the single nucleotide polymorphisms could be mapped to a unique location on the recently sequenced zebra finch genome. Of all the great tit contigs, significantly more were mapped to the microchromosomes than to the intermediate and the macrochromosomes of the zebra finch, indicating a higher overall level of sequence conservation on the microchromosomes than on the other types of chromosomes. The large number of great tit contigs that can be aligned to the zebra finch genome shows that this genome provides a valuable framework for large scale genetics, e.g. QTL mapping or whole genome association studies, in passerines.


Assuntos
Passeriformes/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Animais , Hibridização Genômica Comparativa , Mapeamento de Sequências Contíguas , Tentilhões/genética , Biblioteca Gênica , Genômica/métodos , Alinhamento de Sequência
7.
BMC Genomics ; 10: 479, 2009 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-19835600

RESUMO

BACKGROUND: The development of second generation sequencing methods has enabled large scale DNA variation studies at moderate cost. For the high throughput discovery of single nucleotide polymorphisms (SNPs) in species lacking a sequenced reference genome, we set-up an analysis pipeline based on a short read de novo sequence assembler and a program designed to identify variation within short reads. To illustrate the potential of this technique, we present the results obtained with a randomly sheared, enzymatically generated, 2-3 kbp genome fraction of six pooled Meleagris gallopavo (turkey) individuals. RESULTS: A total of 100 million 36 bp reads were generated, representing approximately 5-6% (approximately 62 Mbp) of the turkey genome, with an estimated sequence depth of 58. Reads consisting of bases called with less than 1% error probability were selected and assembled into contigs. Subsequently, high throughput discovery of nucleotide variation was performed using sequences with more than 90% reliability by using the assembled contigs that were 50 bp or longer as the reference sequence. We identified more than 7,500 SNPs with a high probability of representing true nucleotide variation in turkeys. Increasing the reference genome by adding publicly available turkey BAC-end sequences increased the number of SNPs to over 11,000. A comparison with the sequenced chicken genome indicated that the assembled turkey contigs were distributed uniformly across the turkey genome. Genotyping of a representative sample of 340 SNPs resulted in a SNP conversion rate of 95%. The correlation of the minor allele count (MAC) and observed minor allele frequency (MAF) for the validated SNPs was 0.69. CONCLUSION: We provide an efficient and cost-effective approach for the identification of thousands of high quality SNPs in species currently lacking a sequenced genome and applied this to turkey. The methodology addresses a random fraction of the genome, resulting in an even distribution of SNPs across the targeted genome.


Assuntos
Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Perus/genética , Animais , Mapeamento de Sequências Contíguas , Frequência do Gene , Biblioteca Genômica , Genômica/métodos , Genótipo
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