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1.
Eur Urol Oncol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33436325

RESUMO

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

2.
Nature ; 586(7831): 683-692, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33116284

RESUMO

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.

3.
Proc Natl Acad Sci U S A ; 117(39): 24369-24376, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32868416

RESUMO

New Guinea singing dogs (NGSD) are identifiable by their namesake vocalizations, which are unlike any other canid population. Their novel behaviors and potential singular origin during dog domestication make them an attractive, but elusive, subject for evolutionary and conservation study. Although once plentiful on the island of New Guinea (NG), they were presumed to currently exist only in captivity. This conclusion was based on the lack of sightings in the lowlands of the island and the concurrent expansion of European- and Asian-derived dogs. We have analyzed the first nuclear genomes from a canid population discovered during a recent expedition to the highlands of NG. The extreme altitude (>4,000 m) of the highland wild dogs' (HWD) observed range and confirmed vocalizations indicate their potential to be a wild NGSD population. Comparison of single-nucleotide polymorphism genotypes shows strong similarity between HWD and the homogeneous captive NGSD, with the HWD showing significantly higher genetic diversity. Admixture analyses and estimation of shared haplotypes with phylogenetically diverse populations also indicates the HWD is a novel population within the distinct evolutionary lineage of Oceanic canids. Taken together, these data indicate the HWD possesses a distinct potential to aid in the conservation of NGSD both in the wild and under human care.

4.
PLoS Genet ; 16(9): e1008956, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32911491

RESUMO

The genomic diversity of the domestic dog is an invaluable resource for advancing understanding of mammalian biology, evolutionary biology, morphologic variation, and behavior. There are approximately 350 recognized breeds in the world today, many established through hybridization and selection followed by intense breeding programs aimed at retaining or enhancing specific traits. As a result, many breeds suffer from an excess of particular diseases, one of many factors leading to the recent trend of "designer breed" development, i.e. crossing purebred dogs from existing breeds in the hope that offspring will be enriched for desired traits and characteristics of the parental breeds. We used a dense panel of 150,106 SNPs to analyze the population structure of the Australian labradoodle (ALBD), to understand how such breeds are developed. Haplotype and admixture analyses show that breeds other than the poodle (POOD) and Labrador retriever (LAB) contributed to ALBD formation, but that the breed is, at the genetic level, predominantly POOD, with all small and large varieties contributing to its construction. Allele frequency analysis reveals that the breed is enhanced for variants associated with a poodle-like coat, which is perceived by breeders to have an association with hypoallergenicity. We observed little enhancement for LAB-specific alleles. This study provides a blueprint for understanding how dog breeds are formed, highlighting the limited scope of desired traits in defining new breeds.


Assuntos
Animais Domésticos/genética , Cães/genética , Seleção Genética/genética , Alelos , Animais , Austrália , Cruzamento/métodos , Frequência do Gene/genética , Testes Genéticos , Variação Genética , Genômica , Genótipo , Haplótipos , Fenótipo , Filogenia
5.
Eur Urol ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32800727

RESUMO

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

6.
Cell Syst ; 11(2): 176-185.e6, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32619550

RESUMO

All mammals progress through similar physiological stages throughout life, from early development to puberty, aging, and death. Yet, the extent to which this conserved physiology reflects underlying genomic events is unclear. Here, we map the common methylation changes experienced by mammalian genomes as they age, focusing on comparison of humans with dogs, an emerging model of aging. Using oligo-capture sequencing, we characterize methylomes of 104 Labrador retrievers spanning a 16-year age range, achieving >150× coverage within mammalian syntenic blocks. Comparison with human methylomes reveals a nonlinear relationship that translates dog-to-human years and aligns the timing of major physiological milestones between the two species, with extension to mice. Conserved changes center on developmental gene networks, which are sufficient to translate age and the effects of anti-aging interventions across multiple mammals. These results establish methylation not only as a diagnostic age readout but also as a cross-species translator of physiological aging milestones.

7.
Genetics ; 215(4): 1143-1152, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32554701

RESUMO

Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, <20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression. RASL11A was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with RASL11A downregulation in human cancers. Induced RASL11A expression significantly reduced tumor cell proliferation in vitro The RAS pathway is frequently altered in human cancers, and RASL11A activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.

8.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

9.
PLoS Genet ; 16(3): e1008667, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226005

RESUMO

Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.


Assuntos
Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias da Próstata/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Fatores de Risco
10.
BMC Cancer ; 20(1): 251, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209086

RESUMO

BACKGROUND: Invasive urothelial carcinoma (iUC) is highly similar between dogs and humans in terms of pathologic presentation, molecular subtypes, response to treatment and age at onset. Thus, the dog is an established and relevant model for testing and development of targeted drugs benefiting both canine and human patients. We sought to identify gene expression patterns associated with two primary types of canine iUC tumors: those that express a common somatic mutation in the BRAF gene, and those that do not. METHODS: We performed RNAseq on tumor and normal tissues from pet dogs. Analysis of differential expression and clustering, and positional and individual expression was used to develop gene set enrichment profiles distinguishing iUC tumors with and without BRAFV595E mutations, as well as genomic regions harboring excessive numbers of dysregulated genes. RESULTS: We identified two expression clusters that are defined by the presence/absence of a BRAFV595E (BRAFV600E in humans) somatic mutation. BRAFV595E tumors shared significantly more dysregulated genes than BRAF wild-type tumors, and vice versa, with 398 genes differentiating the two clusters. Key genes fall into clades of limited function: tissue development, cell cycle regulation, immune response, and membrane transport. The genomic site with highest number of dysregulated genes overall lies in a locus corresponding to human chromosome 8q24, a region frequently amplified in human urothelial cancers. CONCLUSIONS: These data identify critical sets of genes that are differently regulated in association with an activating mutation in the MAPK/ERK pathway in canine iUC tumors. The experiments also highlight the value of the canine system in identifying expression patterns associated with a common, shared cancer.


Assuntos
Carcinoma de Células de Transição/veterinária , Doenças do Cão/genética , Perfilação da Expressão Gênica/veterinária , Redes Reguladoras de Genes , Neoplasias da Bexiga Urinária/veterinária , Animais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Doenças do Cão/patologia , Cães , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Sequência de RNA/veterinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
11.
Prostate Cancer Prostatic Dis ; 23(3): 494-506, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32071439

RESUMO

BACKGROUNDS: Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression. METHODS: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. RESULTS: We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score. CONCLUSIONS: This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.

12.
G3 (Bethesda) ; 10(1): 293-297, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31727632

RESUMO

The breeds of domestic dog, Canis lupus familiaris, display a range of coat types with variation in color, texture, length, curl, and growth pattern. One trait of interest is that of partial or full hairlessness, which is found in a small number of breeds. While the standard for some breeds, such as the Xoloitzcuintli, requires sparse hair on their extremities, others are entirely bald, including the American Hairless Terrier. We identified a small, rare family of Scottish Deerhounds in which coated parents produced a mixed litter of coated and hairless offspring. To identify the underlying variant, we performed whole genome sequencing of the dam and five offspring, comparing single nucleotide polymorphisms and small insertions/deletions against an established catalog of 91 million canine variants. Of 325 homozygous alternative alleles found in both hairless dogs, 56 displayed the expected pattern of segregation and only a single, high impact variant within a coding region was observed: a single base pair insertion in exon two of SGK3 leading to a potential frameshift, thus verifying recently published findings. In addition, we observed that gene expression levels between coated and hairless dogs are similar, suggesting a mechanism other than non-sense mediated decay is responsible for the phenotype.


Assuntos
Pelo Animal/crescimento & desenvolvimento , Cães/genética , Hipotricose/veterinária , Mutação , Proteínas Serina-Treonina Quinases/genética , Animais , Hipotricose/genética , Linhagem , Proteínas Serina-Treonina Quinases/metabolismo , Sequenciamento Completo do Genoma
14.
Natl Sci Rev ; 6(4): 810-824, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31598383

RESUMO

Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health.

15.
Prostate ; 79(14): 1589-1596, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376183

RESUMO

BACKGROUND: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. METHODS: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. RESULTS: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10-11 ). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). CONCLUSION: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/genética , Metástase Neoplásica/genética , Neoplasias da Próstata/genética , Receptores do Fator de Necrose Tumoral/genética , Cistatinas Salivares/genética , Fatores Genéricos de Transcrição/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica/patologia , Prognóstico , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , Curva ROC , Medição de Risco , Sensibilidade e Especificidade
16.
Genes (Basel) ; 10(6)2019 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31181852

RESUMO

Assistance dog training programs can see as many as 60% of their trainees dismissed. Many training programs utilize behavioral assays prior to admittance to identify likely successful candidates, yet such assays can be insconsistent. Recently, four canine retrotransposon mobile element insertions (MEIs) in or near genes WBSCR17 (Cfa6.6 and Cfa6.7), GTF2I (Cfa6.66) and POM121 (Cfa6.83) were identified in domestic dogs and gray wolves. Variations in these MEIs were significantly associated with a heightened propensity to initiate prolonged social contact or hypersociability. Using our dataset of 837 dogs, 228 of which had paired survey-based behavioral data, we discovered that one of the insertions in WBSCR17 is the most important predictor of dog sociable behaviors related to human proximity, measured by the Canine Behavioral Assessment Research Questionnaire (C-BARQ©). We found a positive correlation between insertions at Cfa6.6 and dog separation distress in the form of restlessness when about to be left alone by the owner. Lastly, assistance dogs showed significant heterozygosity deficiency at locus Cfa6.6 and higher frequency of insertions at Cfa6.6 and Cfa6.7. We suggest that training programs could utilize this genetic survey to screen for MEIs at WBSCR17 to identify dogs with sociable traits compatible with successful assistance dog performance.


Assuntos
Comportamento Animal , Sequências Repetitivas Dispersas/genética , N-Acetilgalactosaminiltransferases/genética , Animais , Cães , Educação , Feminino , Homozigoto , Humanos , Masculino , Fenótipo , Lobos/genética
17.
Genes (Basel) ; 10(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035530

RESUMO

Each domestic dog breed is characterized by a strict set of physical and behavioral characteristics by which breed members are judged and rewarded in conformation shows. One defining feature of particular interest is the coat, which is comprised of either a double- or single-layer of hair. The top coat contains coarse guard hairs and a softer undercoat, similar to that observed in wolves and assumed to be the ancestral state. The undercoat is absent in single-coated breeds which is assumed to be the derived state. We leveraged single nucleotide polymorphism (SNP) array and whole genome sequence (WGS) data to perform genome-wide association studies (GWAS), identifying a locus on chromosome (CFA) 28 which is strongly associated with coat number. Using WGS data, we identified a locus of 18.4 kilobases containing 62 significant variants within the intron of a long noncoding ribonucleic acid (lncRNA) upstream of ADRB1. Multiple lines of evidence highlight the locus as a potential cis-regulatory module. Specifically, two variants are found at high frequency in single-coated dogs and are rare in wolves, and both are predicted to affect transcription factor (TF) binding. This report is among the first to exploit WGS data for both GWAS and variant mapping to identify a breed-defining trait.


Assuntos
Cromossomos/genética , Estudo de Associação Genômica Ampla , Cabelo/crescimento & desenvolvimento , Animais , Cruzamento , Mapeamento Cromossômico , Cães , Regulação da Expressão Gênica/genética , Cabelo/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Genoma , Lobos/genética
18.
PLoS Genet ; 15(5): e1008102, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095560

RESUMO

In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79x10-16). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction.


Assuntos
Proteínas ADAMTS/genética , Doenças do Cão/genética , Mutação de Sentido Incorreto , Doença Pulmonar Obstrutiva Crônica/genética , Alelos , Animais , Cromossomos de Mamíferos/química , Suscetibilidade a Doenças , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/fisiopatologia , Cães , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Laringoscopia , Masculino , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Sistema Respiratório/anatomia & histologia , Sistema Respiratório/diagnóstico por imagem , Sistema Respiratório/fisiopatologia , Crânio/anatomia & histologia , Sequenciamento Completo do Genoma
19.
Nat Commun ; 10(1): 1489, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940804

RESUMO

Domestic dog breeds are characterized by an unrivaled diversity of morphologic traits and breed-associated behaviors resulting from human selective pressures. To identify the genetic underpinnings of such traits, we analyze 722 canine whole genome sequences (WGS), documenting over 91 million single nucleotide and small indels, creating a large catalog of genomic variation for a companion animal species. We undertake both selective sweep analyses and genome wide association studies (GWAS) inclusive of over 144 modern breeds, 54 wild canids and a hundred village dogs. Our results identify variants of strong impact associated with 16 phenotypes, including body weight variation which, when combined with existing data, explain greater than 90% of body size variation in dogs. We thus demonstrate that GWAS and selection scans performed with WGS are powerful complementary methods for expanding the utility of companion animal systems for the study of mammalian growth and biology.


Assuntos
Cães/genética , Animais , Animais Selvagens/genética , Animais Selvagens/fisiologia , Tamanho Corporal , Cruzamento , Cães/classificação , Cães/crescimento & desenvolvimento , Cães/fisiologia , Feminino , Variação Genética , Genoma , Estudo de Associação Genômica Ampla , Genômica , Masculino , Fenótipo , Seleção Genética , Sequenciamento Completo do Genoma
20.
Cancer Epidemiol Biomarkers Prev ; 28(4): 822-825, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30642840

RESUMO

BACKGROUND: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. METHODS: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. RESULTS: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. CONCLUSIONS: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. IMPACT: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.


Assuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos
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