Publications by authors named "Elaine A Ostrander"

271 Publications

Human-modified canids in human-modified landscapes: The evolutionary consequences of hybridization for grey wolves and free-ranging domestic dogs.

Evol Appl 2021 Oct 21;14(10):2433-2456. Epub 2021 Jun 21.

Museum and Institute of Zoology Polish Academy of Sciences Warsaw Poland.

Introgressive hybridization between domestic animals and their wild relatives is an indirect form of human-induced evolution, altering gene pools and phenotypic traits of wild and domestic populations. Although this process is well documented in many taxa, its evolutionary consequences are poorly understood. In this study, we assess introgression patterns in admixed populations of Eurasian wolves and free-ranging domestic dogs (FRDs), identifying chromosomal regions with significantly overrepresented hybrid ancestry and assessing whether genes located within these regions show signatures of selection. Although the dog admixture proportion in West Eurasian wolves (2.7%) was greater than the wolf admixture proportion in FRDs (0.75%), the number and average length of chromosomal blocks showing significant overrepresentation of hybrid ancestry were smaller in wolves than FRDs. In wolves, 6% of genes located within these blocks showed signatures of positive selection compared to 23% in FRDs. We found that introgression from wolves may provide a considerable adaptive advantage to FRDs, counterbalancing some of the negative effects of domestication, which can include reduced genetic diversity and excessive tameness. In wolves, introgression from FRDs is mostly driven by drift, with a small number of positively selected genes associated with brain function and behaviour. The predominance of drift may be the consequence of small effective size of wolf populations, which reduces efficiency of selection for weakly advantageous or against weakly disadvantageous introgressed variants. Small wolf population sizes result largely from human-induced habitat loss and hunting, thus linking introgression rates to anthropogenic processes. Our results imply that maintenance of large population sizes should be an important element of wolf management strategies aimed at reducing introgression rates of dog-derived variants.
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http://dx.doi.org/10.1111/eva.13257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549620PMC
October 2021

Best practices for analyzing imputed genotypes from low-pass sequencing in dogs.

Mamm Genome 2021 Sep 8. Epub 2021 Sep 8.

Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50, Room 5351, Bethesda, MD, 20892 , USA.

Although DNA array-based approaches for genome-wide association studies (GWAS) permit the collection of thousands of low-cost genotypes, it is often at the expense of resolution and completeness, as SNP chip technologies are ultimately limited by SNPs chosen during array development. An alternative low-cost approach is low-pass whole genome sequencing (WGS) followed by imputation. Rather than relying on high levels of genotype confidence at a set of select loci, low-pass WGS and imputation rely on the combined information from millions of randomly sampled low-confidence genotypes. To investigate low-pass WGS and imputation in the dog, we assessed accuracy and performance by downsampling 97 high-coverage (> 15×) WGS datasets from 51 different breeds to approximately 1× coverage, simulating low-pass WGS. Using a reference panel of 676 dogs from 91 breeds, genotypes were imputed from the downsampled data and compared to a truth set of genotypes generated from high-coverage WGS. Using our truth set, we optimized a variant quality filtering strategy that retained approximately 80% of 14 M imputed sites and lowered the imputation error rate from 3.0% to 1.5%. Seven million sites remained with a MAF > 5% and an average imputation quality score of 0.95. Finally, we simulated the impact of imputation errors on outcomes for case-control GWAS, where small effect sizes were most impacted and medium-to-large effect sizes were minorly impacted. These analyses provide best practice guidelines for study design and data post-processing of low-pass WGS-imputed genotypes in dogs.
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http://dx.doi.org/10.1007/s00335-021-09914-zDOI Listing
September 2021

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

Eur J Epidemiol 2021 Sep 18;36(9):913-925. Epub 2021 Jul 18.

Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, University of Quebec, 531 boul. des Prairies, Laval, QC, H7V 1B7, Canada.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.
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http://dx.doi.org/10.1007/s10654-021-00781-1DOI Listing
September 2021

Pleistocene origins, western ghost lineages, and the emerging phylogeographic history of the red wolf and coyote.

Mol Ecol 2021 09 7;30(17):4292-4304. Epub 2021 Jul 7.

Palaeogenomics Group, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, Munich, Germany.

The red wolf (Canis rufus) of the eastern US was driven to near-extinction by colonial-era persecution and habitat conversion, which facilitated coyote (C. latrans) range expansion and widespread hybridization with red wolves. The observation of some grey wolf (C. lupus) ancestry within red wolves sparked controversy over whether it was historically a subspecies of grey wolf with its predominant "coyote-like" ancestry obtained from post-colonial coyote hybridization (2-species hypothesis) versus a distinct species closely related to the coyote that hybridized with grey wolf (3-species hypothesis). We analysed mitogenomes sourced from before the 20th century bottleneck and coyote invasion, along with hundreds of modern amplicons, which led us to reject the 2-species model and to investigate a broader phylogeographic 3-species model suggested by the fossil record. Our findings broadly support this model, in which red wolves ranged the width of the American continent prior to arrival of the grey wolf to the mid-continent 60-80 ka; red wolves subsequently disappeared from the mid-continent, relegated to California and the eastern forests, which ushered in emergence of the coyote in their place (50-30 ka); by the early Holocene (12-10 ka), coyotes had expanded into California, where they admixed with and phenotypically replaced western red wolves in a process analogous to the 20th century coyote invasion of the eastern forests. Findings indicate that the red wolf pre-dated not only European colonization but human, and possibly coyote, presence in North America. These findings highlight the urgency of expanding conservation efforts for the red wolf.
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http://dx.doi.org/10.1111/mec.16048DOI Listing
September 2021

Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome.

Genes (Basel) 2021 05 30;12(6). Epub 2021 May 30.

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named "Tasha" initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good-quality draft, as with all assemblies produced at the time, it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein-coding genes. Here, we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies that increases sequence contiguity >100-fold, closes >23,000 gaps of the CanFam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.
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http://dx.doi.org/10.3390/genes12060847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228171PMC
May 2021

The effects of ionizing radiation on domestic dogs: a review of the atomic bomb testing era.

Biol Rev Camb Philos Soc 2021 10 13;96(5):1799-1815. Epub 2021 May 13.

Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, U.S.A.

Dogs were frequently employed as laboratory subjects during the era of atomic bomb testing (1950-1980), particularly in studies used to generate predictive data regarding the expected effects of accidental human occupational exposure to radiation. The bulk of these studies were only partly reported in the primary literature, despite providing vital information regarding the effects of radiation exposure on a model mammalian species. Herein we review this literature and summarize the biological effects in relation to the isotopes used and the method of radionuclide exposure. Overall, these studies demonstrate the wide range of developmental and physiological effects of exposure to radiation and radionuclides in a mid-sized mammal.
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http://dx.doi.org/10.1111/brv.12723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429057PMC
October 2021

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds.

PLoS Genet 2021 05 13;17(5):e1009543. Epub 2021 May 13.

Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald = 4.83x10-9) and 19 (Pwald = 2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.
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http://dx.doi.org/10.1371/journal.pgen.1009543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118335PMC
May 2021

Copy number variation underlies complex phenotypes in domestic dog breeds and other canids.

Genome Res 2021 May 16;31(5):762-774. Epub 2021 Apr 16.

IBE, Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC), Ciencies Experimentals i de la Salut, Barcelona 08003, Spain.

Extreme phenotypic diversity, a history of artificial selection, and socioeconomic value make domestic dog breeds a compelling subject for genomic research. Copy number variation (CNV) is known to account for a significant part of inter-individual genomic diversity in other systems. However, a comprehensive genome-wide study of structural variation as it relates to breed-specific phenotypes is lacking. We have generated whole genome CNV maps for more than 300 canids. Our data set extends the canine structural variation landscape to more than 100 dog breeds, including novel variants that cannot be assessed using microarray technologies. We have taken advantage of this data set to perform the first CNV-based genome-wide association study (GWAS) in canids. We identify 96 loci that display copy number differences across breeds, which are statistically associated with a previously compiled set of breed-specific morphometrics and disease susceptibilities. Among these, we highlight the discovery of a long-range interaction involving a CNV near and , which could influence breed standard height. Integration of the CNVs with chromatin interactions, long noncoding RNA expression, and single nucleotide variation highlights a subset of specific loci and genes with potential functional relevance and the prospect to explain trait variation between dog breeds.
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http://dx.doi.org/10.1101/gr.266049.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092016PMC
May 2021

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Eur Urol Oncol 2021 Aug 9;4(4):570-579. Epub 2021 Jan 9.

Institute of Biomedicine, University of Turku, Turku, Finland.

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 (p = 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.
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http://dx.doi.org/10.1016/j.euo.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233PMC
August 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Strategic vision for improving human health at The Forefront of Genomics.

Nature 2020 10 28;586(7831):683-692. Epub 2020 Oct 28.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

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'.
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http://dx.doi.org/10.1038/s41586-020-2817-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869889PMC
October 2020

Genetic analysis of the modern Australian labradoodle dog breed reveals an excess of the poodle genome.

PLoS Genet 2020 09 10;16(9):e1008956. Epub 2020 Sep 10.

Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda MD, United States of America.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482835PMC
September 2020

New Guinea highland wild dogs are the original New Guinea singing dogs.

Proc Natl Acad Sci U S A 2020 09 31;117(39):24369-24376. Epub 2020 Aug 31.

National Human Genome Research Institute, National Institutes of Health, Bethesda MD 20892;

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.
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http://dx.doi.org/10.1073/pnas.2007242117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533868PMC
September 2020

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

Eur Urol 2021 03 14;79(3):353-361. Epub 2020 Aug 14.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1016/j.eururo.2020.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881048PMC
March 2021

Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome.

Cell Syst 2020 08 2;11(2):176-185.e6. Epub 2020 Jul 2.

Division of Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cels.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484147PMC
August 2020

Spontaneous Tumor Regression in Tasmanian Devils Associated with Activation.

Genetics 2020 08 18;215(4):1143-1152. Epub 2020 Jun 18.

School of Biological Sciences, Washington State University, Pullman, Washington 99164.

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 significantly contributes to tumor regression. was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with downregulation in human cancers. Induced expression significantly reduced tumor cell proliferation The RAS pathway is frequently altered in human cancers, and activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.
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http://dx.doi.org/10.1534/genetics.120.303428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404226PMC
August 2020

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs.

PLoS Genet 2020 03 30;16(3):e1008667. Epub 2020 Mar 30.

Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145271PMC
March 2020

RNAseq expression patterns of canine invasive urothelial carcinoma reveal two distinct tumor clusters and shared regions of dysregulation with human bladder tumors.

BMC Cancer 2020 Mar 24;20(1):251. Epub 2020 Mar 24.

National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bldg 50, Room 5351, Bethesda, MD, 20892, USA.

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.
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http://dx.doi.org/10.1186/s12885-020-06737-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092566PMC
March 2020

Copy number alterations are associated with metastatic-lethal progression in prostate cancer.

Prostate Cancer Prostatic Dis 2020 09 18;23(3):494-506. Epub 2020 Feb 18.

Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1038/s41391-020-0212-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725282PMC
September 2020

Whole Genome Analysis of a Single Scottish Deerhound Dog Family Provides Independent Corroboration That a Coding Variant Leads to Hairlessness.

G3 (Bethesda) 2020 01 7;10(1):293-297. Epub 2020 Jan 7.

Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

The breeds of domestic dog, , 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 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.
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http://dx.doi.org/10.1534/g3.119.400885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945040PMC
January 2020

Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health.

Natl Sci Rev 2019 Jul 10;6(4):810-824. Epub 2019 Apr 10.

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.

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 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.
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http://dx.doi.org/10.1093/nsr/nwz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776107PMC
July 2019

Dog10K: the International Consortium of Canine Genome Sequencing.

Natl Sci Rev 2019 Jul 29;6(4):611-613. Epub 2019 May 29.

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, China.

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http://dx.doi.org/10.1093/nsr/nwz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776106PMC
July 2019

A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: Development and validation studies.

Prostate 2019 10 2;79(14):1589-1596. Epub 2019 Aug 2.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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 ). 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.
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http://dx.doi.org/10.1002/pros.23882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715522PMC
October 2019

Homozygosity for Mobile Element Insertions Associated with Could Predict Success in Assistance Dog Training Programs.

Genes (Basel) 2019 06 9;10(6). Epub 2019 Jun 9.

Department of Ecology & Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA.

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 (Cfa6.6 and Cfa6.7), (Cfa6.66) and (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 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 to identify dogs with sociable traits compatible with successful assistance dog performance.
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http://dx.doi.org/10.3390/genes10060439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627829PMC
June 2019

An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome.

PLoS Genet 2019 05 16;15(5):e1008102. Epub 2019 May 16.

The Roslin Institute and Royal (Dick) School for Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521993PMC
May 2019

Hair of the Dog: Identification of a -Regulatory Module Predicted to Influence Canine Coat Composition.

Genes (Basel) 2019 04 26;10(5). Epub 2019 Apr 26.

Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20894, United States of America.

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.
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http://dx.doi.org/10.3390/genes10050323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562840PMC
April 2019
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