| 1. |
- Ahsan, Muhammad, et al.
(author)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-ChiP data
- 2013
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Other publication (other academic/artistic)abstract
- Quantitative trait loci (QTL) mapping is a first step to identify chromosomal regions harboring genetic polymorphisms that regulate complex traits. Searching causative mutations for observed effects is sometimes a daunting task as even after fine mapping of the QTL, millions of base pairs including many genes will typically need to be explored. There is thus a great need for efficient bioinformatics strategies to trace the causative mutation(s). Here, we searched for gene transcripts along with mutations regulating body weight at 56 days traits in the Virginia chicken lines – an experimental population comprising two lines that have been divergently selected for 56 days body weight for more than 50 generations. Several QTL regions have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line (AIL). Candidate transcripts and mutations were here sought in the parts of the QTL regions where the highest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, 47 Mbp or 35% of the actual QTL regions, were identified by comparing the allele frequencies in the genomes of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions with 12X ABI SOLID genome resequencing of DNA pools. Gene transcripts in the target segments, obtained using the Ensembl genome browser 67, were analyzed with DAVID bioinformatic database to investigate their role in any growth-related functions. Single nucleotide polymorphisms (SNPs) in target segments obtained from resequencing data were analyzed with Variant Effect Predictor (VEP) tool to find their location and functional consequences in gene transcripts. Non-synonymous SNPs (nsSNPs) were scored for their effects on protein function with PASE software (Li et al., submitted). Finally, we present most important candidate gene transcripts from each QTL segment for further functional validation. For example, the cysteine rich transmembrane BMP regulator 1 (chordin-like) gene has growth factor binding and cell growth functions. It carries a nsSNP with high allele frequency difference (0.97) between lines, PASE (0.67) and conservation scores (0.63). Another candidate, glucagon is involved in anorexia and appetite regulation carrying a CpG mutation with high allele frequency difference (0.87) between lines.
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| 2. |
- Ahsan, Muhammad, et al.
(author)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-chip data.
- 2013
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 4
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Journal article (peer-reviewed)abstract
- Mapping of chromosomal regions harboring genetic polymorphisms that regulate complex traits is usually followed by a search for the causative mutations underlying the observed effects. This is often a challenging task even after fine mapping, as millions of base pairs including many genes will typically need to be investigated. Thus to trace the causative mutation(s) there is a great need for efficient bioinformatic strategies. Here, we searched for genes and mutations regulating growth in the Virginia chicken lines - an experimental population comprising two lines that have been divergently selected for body weight at 56 days for more than 50 generations. Several quantitative trait loci (QTL) have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line. We have further analyzed the QTL regions where the largest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, covering about 37% of the actual QTL regions, were identified by comparing the allele frequencies of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions from genome resequencing of DNA pools. Based on a combination of criteria including significance of the QTL, allele frequency difference of identified mutations between the selected lines, gene information on relevance for growth, and the predicted functional effects of identified mutations we propose here a subset of candidate mutations of highest priority for further evaluation in functional studies. The candidate mutations were identified within the GCG, IGFBP2, GRB14, CRIM1, FGF16, VEGFR-2, ALG11, EDN1, SNX6, and BIRC7 genes. We believe that the proposed method of combining different types of genomic information increases the probability that the genes underlying the observed QTL effects are represented among the candidate mutations identified.
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| 3. |
- Arendt, Maja Louise, et al.
(author)
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The ABCC4 gene is associated with pyometra in golden retriever dogs
- 2021
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
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Journal article (peer-reviewed)abstract
- Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3-66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 x 10(-6), passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.
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| 4. |
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| 5. |
- Bianchi, Matteo, et al.
(author)
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A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Journal article (peer-reviewed)abstract
- Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds-the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared similar to 167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
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| 6. |
- Christmas, Matthew, et al.
(author)
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A genomic and morphometric analysis of alpine bumblebees : Ongoing reductions in tongue length but no clear genetic component
- 2022
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In: Molecular Ecology. - : John Wiley & Sons. - 0962-1083 .- 1365-294X. ; 31:4, s. 1111-1127
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Journal article (peer-reviewed)abstract
- Over the last six decades, populations of the bumblebees Bombus sylvicola and Bombus balteatus in Colorado have experienced decreases in tongue length, a trait important for plant-pollinator mutualisms. It has been hypothesized that this observation reflects selection resulting from shifts in floral composition under climate change. Here we used morphometrics and population genomics to determine whether morphological change is ongoing, investigate the genetic basis of morphological variation, and analyse population structure in these populations. We generated a genome assembly of B. balteatus. We then analysed whole-genome sequencing data and morphometric measurements of 580 samples of both species from seven high-altitude localities. Out of 281 samples originally identified as B. sylvicola, 67 formed a separate genetic cluster comprising a newly-discovered cryptic species ("incognitus"). However, an absence of genetic structure within species suggests that gene flow is common between mountains. We found a significant decrease in tongue length between bees collected between 2012-2014 and in 2017, indicating that morphological shifts are ongoing. We did not discover any genetic associations with tongue length, but a SNP related to production of a proteolytic digestive enzyme was implicated in body size variation. We identified evidence of covariance between kinship and both tongue length and body size, which is suggestive of a genetic component of these traits, although it is possible that shared environmental effects between colonies are responsible. Our results provide evidence for ongoing modification of a morphological trait important for pollination and indicate that this trait probably has a complex genetic and environmental basis.
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| 7. |
- Christmas, Matthew, et al.
(author)
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Genetic Barriers to Historical Gene Flow between Cryptic Species of Alpine Bumblebees Revealed by Comparative Population Genomics
- 2021
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In: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 38:8, s. 3126-3143
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Journal article (peer-reviewed)abstract
- Evidence is accumulating that gene flow commonly occurs between recently diverged species, despite the existence of barriers to gene flow in their genomes. However, we still know little about what regions of the genome become barriers to gene flow and how such barriers form. Here, we compare genetic differentiation across the genomes of bumblebee species living in sympatry and allopatry to reveal the potential impact of gene flow during species divergence and uncover genetic barrier loci. We first compared the genomes of the alpine bumblebee Bombus sylvicola and a previously unidentified sister species living in sympatry in the Rocky Mountains, revealing prominent islands of elevated genetic divergence in the genome that colocalize with centromeres and regions of low recombination. This same pattern is observed between the genomes of another pair of closely related species living in allopatry (B. bifarius and B. vancouverensis). Strikingly however, the genomic islands exhibit significantly elevated absolute divergence (d(XY)) in the sympatric, but not the allopatric, comparison indicating that they contain loci that have acted as barriers to historical gene flow in sympatry. Our results suggest that intrinsic barriers to gene flow between species may often accumulate in regions of low recombination and near centromeres through processes such as genetic hitchhiking, and that divergence in these regions is accentuated in the presence of gene flow.
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| 8. |
- Dramiński, Michał, 1980-, et al.
(author)
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Monte Carlo feature selection and interdependency discovery in supervised classification
- 2010
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In: Advances in Machine Learning. - Heidelberg : Springer. - 9783642051784
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Book chapter (other academic/artistic)abstract
- Applications of machine learning techniques in Life Sciences are the main applications forcing a paradigm shift in the way these techniques are used. Rather than obtaining the best possible supervised classifier, the Life Scientist needs to know which features contribute best to classifying distinct classes and what are the interdependencies between the features. To this end we significantly extend our earlier work [Dramiński et al. (2008)] that introduced an effective and reliable method for ranking features according to their importance for classification. We begin with adding a method for finding a cut-off between informative and non-informative fea- tures and then continue with a development of a methodology and an implementa- tion of a procedure for determining interdependencies between informative features. The reliability of our approach rests on multiple construction of tree classifiers. Essentially, each classifier is trained on a randomly chosen subset of the original data using only a fraction of all of the observed features. This approach is conceptually simple yet computer-intensive. The methodology is validated on a large and difficult task of modelling HIV-1 reverse transcriptase resistance to drugs which is a good example of the aforementioned paradigm shift. We construct a classifier but of the main interest is the identification of mutation points (i.e. features) and their combinations that model drug resistance.
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| 9. |
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| 10. |
- Forsberg, Simon, et al.
(author)
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The Shepherds' Tale : A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Journal article (peer-reviewed)abstract
- Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.
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