ORCID Profile
0000-0002-0850-230X
Current Organisation
Fuzhou University
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420374.V1
Abstract: File contains genes that have focal somatic copy number deletions.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2022
DOI: 10.1038/S42003-022-04279-8
Abstract: Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus ( Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420380.V1
Abstract: File contains list of GISTIC Defined Recurrent SCNA genes that overlap between Humans and Dogs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6510633
Abstract: Abstract Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. i TP53 /i was the most frequently altered gene (83% of dogs have either mutations or SCNA in i TP53 /i ), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase i SETD2 /i , has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. b Significance: /b Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. i Cancer Res 78(13) 3421–31. ©2018 AACR /i . /
Publisher: Springer Science and Business Media LLC
Date: 23-09-2011
Publisher: Springer Science and Business Media LLC
Date: 06-05-2022
DOI: 10.1038/S41598-022-10853-1
Abstract: Transcriptomic analyses are commonly used to identify differentially expressed genes between patients and controls, or within in iduals across disease courses. These methods, whilst effective, cannot encompass the combinatorial effects of genes driving disease. We applied rule-based machine learning (RBML) models and rule networks (RN) to an existing paediatric Systemic Lupus Erythematosus (SLE) blood expression dataset, with the goal of developing gene networks to separate low and high disease activity (DA1 and DA3). The resultant model had an 81% accuracy to distinguish between DA1 and DA3, with unsupervised hierarchical clustering revealing additional subgroups indicative of the immune axis involved or state of disease flare. These subgroups correlated with clinical variables, suggesting that the gene sets identified may further the understanding of gene networks that act in concert to drive disease progression. This included roles for genes (i) induced by interferons ( IFI35 and OTOF ), (ii) key to SLE cell types ( KLRB1 encoding CD161), or (iii) with roles in autophagy and NF-κB pathway responses ( CKAP4 ). As demonstrated here, RBML approaches have the potential to reveal novel gene patterns from within a heterogeneous disease, facilitating patient clinical and therapeutic stratification.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2006
Publisher: Wiley
Date: 10-2004
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420371.V1
Abstract: File contains supplementary tables and figures for the main article. Supplementary Table 1 - Source for tools and databases used in the methods for analysis. Supplementary Table 2 - Summary of Somatic Point and Indel Mutation across the three breeds. Supplementary Table 3 - Summary of GISTIC-defined recurrent large-scale SCNAs and gene frequency. Supplementary Table 4 - List of GISTIC classified lification genes. See attached excel spreadsheet. Supplementary Table 5 - List of GISTIC classified deletion genes. See attached excel spreadsheet. Supplementary Table 6 - List of GISTIC genes and their predicted roles in cancer. Supplementary Table 7 - Significantly over-represented pathways for GISTIC- and MuSiC-defined genes. Supplementary Table 8 - Significantly mutated genes as identified by MuSiC and the proportion of s les per breed that show mutation in them. Supplementary Table 9 - Putative driver genes as detected by MutSigCV algorithm Supplementary Table 10 - Putative driver genes assessed by VEP high-impact mutations and their variant allele frequency. Supplementary Table 11 - Mutations and their effects on p53 protein. Supplementary Table 12 - Mutations and their effects on SETD2 protein. Supplementary Table 13 - Count of non-silent mutations per breed er germline for OSA susceptibility genes Supplementary Table 14 - Overlap of GISTIC-defined recurrent SCNA genes between humans and dogs. See attached excel spreadsheet.
Publisher: American Dairy Science Association
Date: 10-2009
Abstract: The bovine Muc1 protein is synthesized by mammary epithelial cells and shed into milk as an integral component of the milk fat globule membrane however, the structure and functions of this mucin, particularly in relation to lactation, are poorly defined. The objectives of this investigation were to investigate the Muc1 gene and protein structures in the context of lactation and to test the hypothesis that Muc1 has a role in innate immune defense. Polymerase chain reaction analysis of genomic DNA from 630 cattle revealed extensive polymorphism in the variable number of tandem repeats (VNTR) in the bovine Muc1 gene. Nine allelic variants spanning 7 to 23 VNTR units, each encoding 20 AA, were identified. Three alleles, containing 11, 14, and 16 VNTR units, respectively, were predominant. In addition, a polymorphism in one of the VNTR units has the potential to introduce a unique site for N-linked glycosylation. Statistical analysis indicated weak associations between the VNTR alleles and milk protein and fat percentages in a progeny-tested population of Holstein-Friesian dairy cattle. No association with somatic cell count could be demonstrated. Bovine Muc1 was purified from milk fat globule membranes and characterized. The protein was highly glycosylated, primarily with O-linked sialylated T-antigen [Neu5Ac(alpha2-3)-Gal(beta1-3)-GalNAcalpha1] and, to a lesser extent, with N-linked oligosaccharides, which together accounted for approximately 60% of the apparent mass of Muc1. Purified bovine Muc1 directly bound fluorescently labeled Escherichia coli BioParticles (Invitrogen, Mount Waverley, Australia) and inhibited their binding to bovine mammary epithelial cells grown in vitro. It was also demonstrated that the expression of Muc1 mRNA in bovine mammary epithelial cells was markedly upregulated by lipopolysaccharide. Muc1 may be a pattern recognition protein that has the capacity to sequester bacteria and prevent their attachment to epithelial surfaces by immobilizing and subsequently shedding Muc1-bound bacteria from the cell surface. It was concluded that bovine Muc1 is probably an inducible innate immune effector and an important component of the first line of defense against bacterial invasion of epithelial surfaces, particularly mammary epithelial surfaces and the neonatal gut.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420377.V1
Abstract: File contains genes that have focal somatic copy number lifications
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Publisher: Public Library of Science (PLoS)
Date: 12-08-2014
Publisher: Springer Science and Business Media LLC
Date: 03-2010
DOI: 10.1038/NATURE08832
Abstract: Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic ersity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2020
DOI: 10.1038/S41598-020-74580-1
Abstract: Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC ( n = 765). The selected genes were either from human BC studies ( n = 294) or from within canine mammary tumor associated regions ( n = 471). A set of predominantly estrogen receptor positive tumors (ER + 85%) and their normal tissue counterparts (n = 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes ( q ≤ 0.01) were PIK3CA ( 28 % of patients), TP53 ( 21% ) and CDH1 ( 11% ). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A , together 28%) . Mutations in KMT2C were mutually exclusive with PI3KCA mutations ( p ≤ 0. 001 ) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was lified. Mutational signature analyses pointed towards APOBEC deaminase activity ( COSMIC signature 2 ) and DNA mismatch repair ( COSMIC signature 6 ). We noticed two significantly distinct patterns related to patient age TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age- erse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.
Publisher: Wiley
Date: 02-2009
DOI: 10.1111/J.1365-2052.2008.01799.X
Abstract: The male-specific region of the ovine Y chromosome (MSY) remains poorly characterized, yet sequence variants from this region have the potential to reveal the wild progenitor of domestic sheep or ex les of domestic and wild paternal introgression. The 5' promoter region of the sex-determining gene SRY was re-sequenced using a subset of wild sheep including bighorn (Ovis canadensis), thinhorn (Ovis dalli spp.), urial (Ovis vignei), argali (Ovis ammon), mouflon (Ovis musimon) and domestic sheep (Ovis aries). Seven novel SNPs (oY2-oY8) were revealed these were polymorphic between but not within species. Re-sequencing and fragment analysis was applied to the MSY microsatellite SRYM18. It contains a complex compound repeat structure and sequencing of three novel size fragments revealed that a pentanucleotide element remained fixed, whilst a dinucleotide element displayed variability within species. Comparison of the sequence between species revealed that urial and argali sheep grouped more closely to the mouflon and domestic breeds than the pachyceriforms (bighorn and thinhorn). SNP and microsatellite data were combined to define six previously undetected haplotypes. Analysis revealed the mouflon as the only species to share a haplotype with domestic sheep, consistent with its status as a feral domesticate that has undergone male-mediated exchange with domestic animals. A comparison of the remaining wild species and domestic sheep revealed that O. aries is free from signatures of wild sheep introgression.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420383.V1
Abstract: Supplementary Figure 1 - Workflow for Somatic Point and Indel Mutation detection. Supplementary Figure 2 - Heatmap counts of s les with recurrent focal SCNAs per chromosome. Supplementary Figure 3 - oaCGH profiles penetrance plots and GISTIC analysis. Supplementary Figure 4 - Venn diagrams of shared and unique somatic point mutations and somatic indel mutations across the three breeds. Supplementary Figure 5 - Scatter plot shows age of diagnosis is positively correlated to the mutation counts across all breeds. Supplementary Figure 6 - Mutational signature distribution per breed shows enrichment for the novel signature in Golden Retriever. Supplementary Figure 7 - Overview and functional classes for the mutations in histone modifier genes across the three breeds. Supplementary Figure 8 - Overview of germ-line candidate mutation across three breeds and their functional impacts.
Publisher: Informa UK Limited
Date: 25-06-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420386.V1
Abstract: File contains additional information regarding methods for identifying putative driver genes with MutSigCV and high-impact mutations based analysis. Also methods for predicting impacts of TP53 and SETD2 genes. And further information about the oaCGH analysis for somatic copy number aberrations across a subset of 22 dogs.
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2020
DOI: 10.1101/2020.07.02.185108
Abstract: Here we present a new high-quality canine reference genome with gap number reduced 41-fold, from 23,836 to 585. Analysis of existing and novel data, RNA-seq, miRNA-seq and ATAC-seq, revealed a large proportion of these harboured previously hidden elements, including genes, promoters and miRNAs. Short-read dark regions were detected, and genomic regions completed, including the DLA, TCR and 366 cancer genes. 10x sequencing of 27 dogs uncovered a total of 22.1 million SNPs, Indels and larger structural variants (SVs). 1.4% overlap with protein coding genes and could provide a source of normal or aberrant phenotypic modifications.
Publisher: Cold Spring Harbor Laboratory
Date: 04-06-2019
DOI: 10.1101/660241
Abstract: There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of lab typing. Here we aimed to combine results from available software, minimising the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1 000 Swedish genomes, and a framework for future HLA interrogation. HLA 2-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, -B, -C class II: HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1 ). A high confidence population set (SweHLA) was determined using an n-1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and in idual programs benchmarked to SweHLA. Per allele, 875 to 988 of the 1 000 s les were genotyped in SweHLA 920 s les had at least seven loci. While a small fraction of reference alleles were common to all software (class I=1.9% and class II=4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations ( .83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency 2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to in idual HLA software biases.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/0008-5472.CAN-17-3558
Abstract: Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. Cancer Res 78(13) 3421–31. ©2018 AACR.
Publisher: Cold Spring Harbor Laboratory
Date: 04-11-2022
DOI: 10.1101/2022.11.04.515141
Abstract: A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate region approximately 50 kb downstream of the Endothelin 3 ( EDN3 ) gene. EDN3 and other endothelin family members are associated with blood pressure regulation in humans and other species, but similar association studies in horses are lacking. We hypothesized that the sweep region includes a regulatory element acting on EDN3 transcription, ultimately affecting blood pressure regulation and athletic performance in horses. Selective sweep fine- mapping identified a 5.5 kb haplotype of 14 SNPs shared within Coldblooded trotters (CBT) and Standardbreds (SB). Most SNPs overlapped potential transcription factor binding sites, and haplotype analysis showed significant association with all tested performance traits in CBTs and earnings in SBs. From those, two haplotypes were defined: an elite performing haplotype (EPH) and a sub-elite performing haplotype (SPH). While the majority of SNPs in the haplotype were part of the standing variation already found in pre-domestication horses, there has been an increase in the frequencies of the alternative alleles during the whole history of horse domestication. Horses homozygous for EPH had significantly higher plasma levels of EDN3, lower levels of EDN1, and lower exercise-related blood pressure compared to SPH homozygous horses. Additionally, a global proteomic analysis of plasma from EPH or SPH homozygous horses revealed higher levels of proteins involved in pathways related to immune response and complement activation in the SPH horses. This is the first study to demonstrate an association between the EDN3 gene, blood pressure regulation, and athletic performance in horses. The results advance our understanding of the molecular genetics of athletic performance, exercise-related blood pressure regulation, and biological processes activated by intense exercise. The horse is one of the most common species used for studying athletic performance. For centuries, horses have been used by humans for transportation, agriculture and entertainment and this has resulted in selection for various traits related to athletic performance. A previous study discovered that a genetic region close to the Endothelin3 gene was associated with harness racing performance. Endothelin3 is known to be involved in blood pressure regulation and therefore we hypothesized that this region influences blood pressure and racing performance in horses. In this study we have used additional horses and fine-mapped the candidate region and we also measured blood pressure in Coldblooded trotters during exercise. Horses with two copies of the elite-performing haplotype had higher levels of Endothelin3 in plasma, lower blood pressure and better racing performance results, compared to horses with two copies of the sub-elite performing haplotype. We also discovered that horses with the sub-elite performing haplotype had higher levels of proteins related to the immune system in plasma. This study is the first to link Endothelin3 to blood pressure regulation and performance in horses. It broadens the understanding of the biological mechanisms behind blood pressure regulation as well as inflammation and coagulation system in relation to racing performance.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2014
Publisher: Elsevier BV
Date: 04-2006
Publisher: Wiley
Date: 05-2018
DOI: 10.14814/PHY2.13700
Publisher: Elsevier BV
Date: 12-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth’s vast and imperiled bio ersity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420386
Abstract: File contains additional information regarding methods for identifying putative driver genes with MutSigCV and high-impact mutations based analysis. Also methods for predicting impacts of TP53 and SETD2 genes. And further information about the oaCGH analysis for somatic copy number aberrations across a subset of 22 dogs.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2021
DOI: 10.1101/2021.06.03.446884
Abstract: Transcriptomic analyses are commonly used to identify differentially expressed genes between patients and controls, or within in iduals across disease courses. These methods, whilst effective, cannot encompass the combinatorial effects of genes driving disease. We applied rule-based machine learning (RBML) models and rule networks (RN) to an existing paediatric Systemic Lupus Erythematosus (SLE) blood expression dataset, with the goal of developing gene networks to separate low and high disease activity (DA1 and DA3). The resultant model had an 81% accuracy to distinguish between DA1 and DA3, with unsupervised hierarchical clustering revealing additional subgroups indicative of the immune axis involved or state of disease flare. These subgroups correlated with clinical variables, suggesting that the gene sets identified may further the understanding of gene networks that act in concert to drive disease progression. This included roles for genes i) induced by interferons ( IFI35 and OTOF ), ii) key to SLE cell types ( KLRB1 encoding CD161), or iii) with roles in autophagy and NF-κB pathway responses ( CKAP4 ). As demonstrated here, RBML approaches have the potential to reveal novel gene patterns from within a heterogeneous disease, facilitating patient clinical and therapeutic stratification.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420383
Abstract: Supplementary Figure 1 - Workflow for Somatic Point and Indel Mutation detection. Supplementary Figure 2 - Heatmap counts of s les with recurrent focal SCNAs per chromosome. Supplementary Figure 3 - oaCGH profiles penetrance plots and GISTIC analysis. Supplementary Figure 4 - Venn diagrams of shared and unique somatic point mutations and somatic indel mutations across the three breeds. Supplementary Figure 5 - Scatter plot shows age of diagnosis is positively correlated to the mutation counts across all breeds. Supplementary Figure 6 - Mutational signature distribution per breed shows enrichment for the novel signature in Golden Retriever. Supplementary Figure 7 - Overview and functional classes for the mutations in histone modifier genes across the three breeds. Supplementary Figure 8 - Overview of germ-line candidate mutation across three breeds and their functional impacts.
Publisher: Public Library of Science (PLoS)
Date: 12-06-2009
Publisher: Public Library of Science (PLoS)
Date: 13-03-2014
Publisher: Wiley
Date: 02-11-2016
DOI: 10.1111/JOIM.12569
Abstract: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10 Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
Publisher: Oxford University Press (OUP)
Date: 03-2007
DOI: 10.1534/GENETICS.106.068353
Abstract: Archaeozoological evidence indicates that sheep were first domesticated in the Fertile Crescent. To search for DNA sequence ersity arising from previously undetected domestication events, this survey examined nine breeds of sheep from modern-day Turkey and Israel. A total of 2027 bp of mitochondrial DNA (mtDNA) sequence from 197 sheep revealed a total of 85 haplotypes and a high level of genetic ersity. Six in iduals carried three haplotypes, which clustered separately from the known ovine mtDNA lineages A, B, and C. Analysis of genetic distance, mismatch distribution, and comparisons with wild sheep confirmed that these represent two additional mtDNA lineages denoted D and E. The two haplogroup E sequences were found to link the previously identified groups A and C. The single haplogroup D sequence branched with the eastern mouflon (Ovis orientalis), urial (O. vignei), and argali (O. ammon) sheep. High sequence ersity (K = 1.86%, haplogroup D and O. orientalis) indicates that the wild progenitor of this domestic lineage remains unresolved. The identification in this study of evidence for additional domestication events adds to the emerging view that sheep were recruited from wild populations multiple times in the same way as for other livestock species such as goat, cattle, and pig.
Publisher: Wiley
Date: 25-06-2003
Publisher: Wiley
Date: 10-2006
DOI: 10.1111/J.1365-2052.2006.01496.X
Abstract: To date, investigations of genetic ersity and the origins of domestication in sheep have utilised autosomal microsatellites and variation in the mitochondrial genome. We present the first analysis of both domestic and wild sheep using genetic markers residing on the ovine Y chromosome. Analysis of a single nucleotide polymorphism (oY1) in the SRY promoter region revealed that allele A-oY1 was present in all wild bighorn sheep (Ovis canadensis), two subspecies of thinhorn sheep (Ovis dalli), European Mouflon (Ovis musimon) and the Barbary (Ammontragis lervia). A-oY1 also had the highest frequency (71.4%) within 458 domestic sheep drawn from 65 breeds s led from Africa, Asia, Australia, the Caribbean, Europe, the Middle East and Central Asia. Sequence analysis of a second locus, microsatellite SRYM18, revealed a compound repeat array displaying fixed differences, which identified bighorn and thinhorn sheep as distinct from the European Mouflon and domestic animals. Combined genotypic data identified 11 male-specific haplotypes that represented at least two separate lineages. Investigation of the geographical distribution of each haplotype revealed that one (H6) was both very common and widespread in the global s le of domestic breeds. The remaining haplotypes each displayed more restricted and informative distributions. For ex le, H5 was likely founded following the domestication of European breeds and was used to trace the recent transportation of animals to both the Caribbean and Australia. A high rate of Y chromosomal dispersal appears to have taken place during the development of domestic sheep as only 12.9% of the total observed variation was partitioned between major geographical regions.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2019
DOI: 10.1038/S41431-019-0559-2
Abstract: There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimizing the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1000 Swedish genomes, and a framework for future HLA interrogation. HLA 2nd-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A , HLA-B , HLA-C class II: HLA-DPA1 , HLA-DPB1 , HLA-DQA1 , HLA-DQB1 , HLA-DRB1 ). A high confidence population set (SweHLA) was determined using an n−1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and in idual programs benchmarked to SweHLA. Per gene, 875 to 988 of the 1000 s les were genotyped in SweHLA 920 s les had at least seven loci called. While a small fraction of reference alleles were common to all software (class I = 1.9% and class II = 4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations ( .83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency ) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to in idual HLA software biases.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2023
DOI: 10.1186/S13059-023-03023-7
Abstract: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 in iduals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. We report the analysis of 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 s led breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2017
DOI: 10.1038/NRG.2017.51
Abstract: With the generation of more than 100 sequenced vertebrate genomes in less than 25 years, the key question arises of how these resources can be used to inform new or ongoing projects. In the past, this erse collection of sequences from human as well as model and non-model organisms has been used to annotate the human genome and to increase the understanding of human disease. In the future, comparative vertebrate genomics in conjunction with additional genomic resources will yield insights into the processes of genome function, evolution, speciation, selection and adaptation, as well as the quantification of species ersity. In this Review, we discuss how the genomics of non-human organisms can provide insights into vertebrate biology and how this can contribute to the understanding of human physiology and health.
Publisher: Public Library of Science (PLoS)
Date: 09-10-2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6510633.V1
Abstract: Abstract Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. i TP53 /i was the most frequently altered gene (83% of dogs have either mutations or SCNA in i TP53 /i ), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase i SETD2 /i , has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. b Significance: /b Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. i Cancer Res 78(13) 3421–31. ©2018 AACR /i . /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420380
Abstract: File contains list of GISTIC Defined Recurrent SCNA genes that overlap between Humans and Dogs.
Publisher: Oxford University Press (OUP)
Date: 31-08-2005
Abstract: Sequence variation present within the mitochondrial genome was used to investigate genetic ersity within sheep breeds from Asia and Europe. Comparison of 2027 bp of sequence from 121 animals revealed 44 phylogenetically informative nucleotide positions and a single insertion/deletion. A total of 57 haplotypes were observed which formed two distinct clades. Type A haplotypes were found in breeds from Asia (India, Indonesia, Mongolia, and Tibet), while type B haplotypes were observed at the highest frequency in breeds sourced from Europe (nine breeds from Austria, Aland, Finland, Spain, and northwestern Russia). The distribution of haplotypes indicates sheep appear to have the weakest population structure and the highest rate of intercontinental dispersal of any domestic animal reported to date. Only 2.7% of the sequence variation observed was partitioned between continents, which is lower than both goat (approximately 10%) and cattle (approximately 50%). Diagnostic restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) tests which distinguish type A and B haplotypes were used to test an additional 223 animals from 17 breeds of European and Asian origin. A mixture of the two lineages was found in every breed except Suffolk and the Indian Garole, indicating introgression has played a major part during breed development and subsequent selection.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2020
DOI: 10.1038/S41586-020-2876-6
Abstract: The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic ersity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic ersity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from in idual reference genomes. By prioritizing phylogenetic ersity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of bio ersity.
Publisher: Oxford University Press (OUP)
Date: 2020
Publisher: American Dairy Science Association
Date: 06-2006
Publisher: Public Library of Science (PLoS)
Date: 17-03-2011
Publisher: Oxford University Press (OUP)
Date: 06-08-2015
DOI: 10.1093/BIOINFORMATICS/BTV426
Abstract: Summary: High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them. Results: We present cgmisc, an R package that enables enhanced data analysis and visualization of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualization of genomic data and utilizes the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data. Availability and implementation: The package is operating system-independent and is available from: gmisc-team/cgmisc Contact: marcin.kierczak@imbim.uu.se Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Wiley
Date: 24-08-2007
DOI: 10.1111/J.1365-2052.2007.01636.X
Abstract: This survey represents the first characterization of mitochondrial DNA ersity within three breeds of Indian sheep (two strains of the Deccani breed, as well as the Bannur and Garole breeds) from different geographic regions and with ergent phenotypic characteristics. A 1061-bp fragment of the mitochondrial genome spanning the control region, a portion of the 12S rRNA gene and the complete phenyl tRNA gene, was sequenced from 73 animals and compared with the corresponding published sequence from European and Asian breeds and the European Mouflon (Ovis musimon). Analysis of all 156 sequences revealed 73 haplotypes, 52 of which belonged to the Indian breeds. The three Indian breeds had no haplotypes in common, but one Indian haplotype was shared with European and other Asian breeds. The highest nucleotide and haplotype ersity was observed in the Bannur breed (0.00355 and 0.981 respectively), while the minimum was in the Sangamneri strain of the Deccani breed (0.00167 and 0.882 respectively). All 52 Indian haplotypes belonged to mitochondrial lineage A. Therefore, these Indian sheep are distinct from other Asian and European breeds studied so far. The relationships among the haplotypes showed strong breed structure and almost no introgression among these Indian breeds, consistent with Indian sheep husbandry, which discourages genetic exchange between breeds. These results have implications for the conservation of India's ovine bio ersity and suggest a common origin for the breeds investigated.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420374
Abstract: File contains genes that have focal somatic copy number deletions.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.JNEUMETH.2010.05.003
Abstract: This study proposes a method for estimating force loss during fatiguing maximal isokinetic knee extension contractions using a set of features from surface EMG signals recorded from multiple locations over the quadriceps muscle. Nine healthy participants performed fatiguing tests which consisted of 50 and 75 isokinetic leg extensions at a speed of 30 degrees /s and 80 degrees /s in two experimental sessions on different days. The set of data recorded from one of the experimental sessions (at both velocities) was used to train a multi-layer perceptron neural network to associate force loss (direct measure of fatigue) to EMG features. The data from the other session (obtained from the tests at both velocities) were used for testing the neural network performance. The proposed method was compared with a previous approach for the assessment of fatigue (Mapping Index, MI) using a signal to noise metrics computed on the estimated trend of fatigue. The signal to noise ratio obtained with the proposed approach was greater (8.83+/-1.07) than that obtained with the MI (5.67+/-1.17) (P<0.05) when the subjects were analyzed in idually and when the network was trained over the entire subject group (8.07 vs. 4.42). In conclusion, the proposed approach allows estimation of force loss during maximal dynamic knee extensions from surface EMG signals with greater accuracy than previous methods.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420377
Abstract: File contains genes that have focal somatic copy number lifications
Publisher: Frontiers Media SA
Date: 15-07-2021
DOI: 10.3389/FGENE.2021.659042
Abstract: To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B ∗ 27 independent associations and assessing the impact of sex on this male biased disease. High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B ∗ 27 status. The amino acids driving association were also examined. Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B ∗ 27 positive population, HLA-A ∗ 24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in s le size. Stratifying by sex uncovered three novel risk variants restricted to the female population ( HLA-DQA1 ∗ 04.01, -DQB1 ∗ 04:02, -DRB1 ∗ 08:01 OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations. Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B ∗ 27 signals as well as replicating previous HLA-B ∗ 27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22420371
Abstract: File contains supplementary tables and figures for the main article. Supplementary Table 1 - Source for tools and databases used in the methods for analysis. Supplementary Table 2 - Summary of Somatic Point and Indel Mutation across the three breeds. Supplementary Table 3 - Summary of GISTIC-defined recurrent large-scale SCNAs and gene frequency. Supplementary Table 4 - List of GISTIC classified lification genes. See attached excel spreadsheet. Supplementary Table 5 - List of GISTIC classified deletion genes. See attached excel spreadsheet. Supplementary Table 6 - List of GISTIC genes and their predicted roles in cancer. Supplementary Table 7 - Significantly over-represented pathways for GISTIC- and MuSiC-defined genes. Supplementary Table 8 - Significantly mutated genes as identified by MuSiC and the proportion of s les per breed that show mutation in them. Supplementary Table 9 - Putative driver genes as detected by MutSigCV algorithm Supplementary Table 10 - Putative driver genes assessed by VEP high-impact mutations and their variant allele frequency. Supplementary Table 11 - Mutations and their effects on p53 protein. Supplementary Table 12 - Mutations and their effects on SETD2 protein. Supplementary Table 13 - Count of non-silent mutations per breed er germline for OSA susceptibility genes Supplementary Table 14 - Overlap of GISTIC-defined recurrent SCNA genes between humans and dogs. See attached excel spreadsheet.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2008
Abstract: The success of genome-wide scans depends on the strength and magnitude of linkage disequilibrium (LD) present within the populations under investigation. High density SNP arrays are currently in development for the sheep genome, however little is known about the behaviour of LD in this livestock species. This study examined the behaviour of LD within five sheep populations using two LD metrics, D' and x 2' . Four economically important Australian sheep flocks, three pure breeds (White Faced Suffolk, Poll Dorset, Merino) and a crossbred population (Merino × Border Leicester), along with an inbred Australian Merino museum flock were analysed. Short range LD (0 – 5 cM) was observed in all five populations, however the persistence with increasing distance and magnitude of LD varied considerably between populations. Average LD (x 2' ) for markers spaced up to 20 cM exceeded the non-syntenic average within the White Faced Suffolk, Poll Dorset and Macarthur Merino. LD decayed faster within the Merino and Merino × Border Leicester, with LD below or consistent with observed background levels. Using marker-marker LD as a guide to the behaviour of marker-QTL LD, estimates of minimum marker spacing were made. For a 95% probability of detecting QTL, a microsatellite marker would be required every 0.1 – 2.5 centimorgans, depending on the population used. Sheep populations were selected which were inbred (Macarthur Merino), highly heterogeneous (Merino) or intermediate between these two extremes. This facilitated analysis and comparison of LD (x 2' ) between populations. The strength and magnitude of LD was found to differ markedly between breeds and aligned closely with both observed levels of genetic ersity and expectations based on breed history. This confirmed that breed specific information is likely to be important for genome wide selection and during the design of successful genome scans where tens of thousands of markers will be required.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
DOI: 10.1038/S41598-018-26842-2
Abstract: Autoimmune Addison’s disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator ( AIRE ) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
Publisher: Elsevier BV
Date: 06-2007
Publisher: Springer Science and Business Media LLC
Date: 24-05-2013
Abstract: Phenomena such as incomplete lineage sorting, horizontal gene transfer, gene duplication and subsequent sub- and neo-functionalisation can result in distinct local phylogenetic relationships that are discordant with species phylogeny. In order to assess the possible biological roles for these sub isions, they must first be identified and characterised, preferably on a large scale and in an automated fashion. We developed Saguaro , a combination of a Hidden Markov Model (HMM) and a Self Organising Map (SOM), to characterise local phylogenetic relationships among aligned sequences using cacti , matrices of pair-wise distance measures. While the HMM determines the genomic boundaries from aligned sequences, the SOM hypothesises new cacti in an unsupervised and iterative fashion based on the regions that were modelled least well by existing cacti. After testing the software on simulated data, we demonstrate the utility of Saguaro by testing two different data sets: (i) 181 Dengue virus strains, and (ii) 5 primate genomes. Saguaro identifies regions under lineage-specific constraint for the first set, and genomic segments that we attribute to incomplete lineage sorting in the second dataset. Intriguingly for the primate data, Saguaro also classified an additional ~3% of the genome as most incompatible with the expected species phylogeny. A substantial fraction of these regions was found to overlap genes associated with both the innate and adaptive immune systems. Saguaro detects distinct cacti describing local phylogenetic relationships without requiring any a priori hypotheses. We have successfully demonstrated Saguaro ’s utility with two contrasting data sets, one containing many members with short sequences (Dengue viral strains: n = 181, genome size = 10,700 nt), and the other with few members but complex genomes (related primate species: n = 5, genome size = 3 Gb), suggesting that the software is applicable to a wide variety of experimental populations. Saguaro is written in C++, runs on the Linux operating system, and can be downloaded from saguarogw.sourceforge.net/ .
Publisher: Springer Science and Business Media LLC
Date: 31-01-2016
Publisher: BMJ
Date: 09-10-2020
DOI: 10.1136/ANNRHEUMDIS-2020-218636
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular ersity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy in iduals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in in idual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2021
DOI: 10.1038/S42003-021-01698-X
Abstract: We present GSD_1.0, a high-quality domestic dog reference genome with chromosome length scaffolds and contiguity increased 55-fold over CanFam3.1. Annotation with generated and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of lifted over CanFam3.1 gaps harboured previously hidden functional elements, including promoters, genes and miRNAs in GSD_1.0. A catalogue of canine “dark” regions was made to facilitate mapping rescue. Alignment in these regions is difficult, but we demonstrate that they harbour trait-associated variation. Key genomic regions were completed, including the Dog Leucocyte Antigen (DLA), T Cell Receptor (TCR) and 366 COSMIC cancer genes. 10x linked-read sequencing of 27 dogs (19 breeds) uncovered 22.1 million SNPs, indels and larger structural variants. Subsequent intersection with protein coding genes showed that 1.4% of these could directly influence gene products, and so provide a source of normal or aberrant phenotypic modifications.
Publisher: Wiley
Date: 23-12-2021
DOI: 10.1002/ART.41929
Abstract: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune‐related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene‐based aggregate testing, together with rare variant– and gene‐level enrichment analyses, was implemented to explore genotype–phenotype relations. Gene‐based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L , as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer New York
Date: 2014
Start Date: 2013
End Date: 2017
Funder: Svenska Forskningsrådet Formas
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