Cancer Genetics and Comparative Genomics

癌症遗传学和比较基因组学

基本信息

批准号：
10901691
负责人：
elaine ostrander
金额：
$ 209.75万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10901691
关键词：
6 year old Accidents Accounting Address Affect Age Aging Alaska Alleles American Americas Architecture Behavior Behavioral Biology Biopsy Body Size Body Weight Bone Growth Breeding Canidae Canis familiaris Cells Cessation of life Chernobyl Nuclear Accident Cities Clinical Collaborations Collection Communities Conserved Sequence Country DNA DNA Sequence Data Demography Development Diagnosis Disease Disease susceptibility Dose Early Diagnosis Early Intervention Enhancers Environment Epidermal Growth Factor Receptor Epigenetic Process European Evolution Exclusion Exposure to FRAP1 gene Family Galapagos Islands General Population Genes Genetic Genetic Structures Genetic study Genome Genomic Segment Genomics Geography Gray Wolf Greenland Growth Haplotypes Health Heredity Histiocytic sarcoma Hormones Human Human Genetics IGF1 gene Individual International Intervention Interview Ionizing radiation Leadership Longevity Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Measures Metabolic syndrome Methylation Mitochondrial DNA Modeling Modernization Morphology Mutate Mutation Nature Nuclear Accidents Nuclear Power Plants Nucleotides Obesity PIK3CG gene Pathway interactions Pattern Phenotype Phylogenetic Analysis Population Population Genetics Positioning Attribute Preventive Medicine Production Proteins Proto-Oncogene Proteins c-akt Publishing Radioactive Regional Disease Reporting Research Research Personnel Risk Role Sampling Science Shapes Site Sledding Sterilization Surveys Susceptibility Gene System Time Translations Travel Ultrasonography Untranslated RNA Urinalysis Urothelium Variant Veterinary Medicine Veterinary Schools Weight Work anti aging axon guidance cancer genetics cancer risk candidate identification citizen science companion animal comparative genomics dog genome druggable target experimental study fatty acid metabolism genetic variant genome sciences genome-wide genomic data human disease human migration insight methylome novel pet animal pressure programs public database repetitive behavior scaffold sex social media trait transcriptomics tumor urinary webinar whole genome wolves

项目摘要

Canine Genetics The tremendous phenotypic diversity of modern dog breeds represents the end point of a 20,000-year experiment. Each breed has undergone strong artificial selection for morphologic and behavioral traits to create populations that are unique in size, shape, behavior and disease susceptibility. Our multi-pronged approach to studying canine genetics demonstrates the utility of the canine system for developing a better genetic understanding of humans and their pets. Canine Whole Genome Sequence We have continued our leadership role with Dog10K (Ostrander et al., Natl Sci Rev, 2019), an International Consortium involving 18 labs that aims to generate whole genome sequence (WGS) across the Canidae. Thus far, about 4000 canines have been sequenced by the community, with nearly 2000 done by Dog10K (Meadows, Kidd et al., Submitted). The analysis includes in depth studies on the demography of breeds, single nucleotide and structural variants, analysis of mitochondrial DNA, and selection analysis. We generate the largest and most comprehensive analysis of the canine genome to date, providing the information for detailed studies of domestication, mapping morphologic and behavioral traits, and studies of disease susceptibility. Phylogenetic Studies Using genetic distance measures and genome-wide haplotype sharing we previously published evidence of phenotypic, behavioral, and geographic patterns of breed development (Parker et al., Cell Reports, 2017). We now expand our studies to focus on geographically isolated populations e.g., Alaska (Ali et al., J Heredity, 2023) and Patagonia (Barrios et al., PLOS Genetics, 2022). We know that where humans travel they bring their dogs, providing insight into early human migration patterns and, eventually, origins of disease. Ongoing studies focus on Greenland Sled Dogs, ancient dogs from the Americas, and modern dogs from the Galapagos Islands. Recent studies also address the genetic differences between European and American dogs of the same breed, e.g., the cancer-prone Bernese Mountain Dog, highlighting the importance of accurate ancestry information in genetic studies (Letko et al., Genes, 2023). Morphology We previously documented over 91 million canine genome variants for studies of breed morphology (Plassais et al., Nature Comm., 2019). We identify strong impact variants associated with 16 phenotypes, including body weight variation, highlighting genes that when mutated in humans contribute to fatty acid metabolism, obesity and metabolic syndrome. In our most recent study, we discovered the much sought after functional variants accounting for the association between the IGF1 gene and body size. IGF1 encodes a hormone related to normal and abnormal bone and tissue growth. Analyzing 1,431 genomes from ancient and modern canids we identified, for the first time, a single variant in an antisense long non-coding RNA (IGF1-AS) that interacts with IGF1, affecting protein production (Plassais et al., Current Biology, 2022). While the derived mutation predominates in both modern gray wolves and large domestic breeds, the ancestral allele, which predisposes to small size, was common in small-sized breeds and smaller wild canids. Our analyses demonstrate that this major regulator of canid body size nearly vanished in Pleistocene wolves, before its recent resurgence resulting from human-imposed selection for small-sized breed dogs. Invasive Urothelial Cancer (iUC) We have worked with clinical collaborators to determine the suitability of dogs with high breed-associated risk for naturally-occurring iUC to serve as models for early detection and intervention (Dhawan et al., Front Oncol, 2022). Scottish terriers (STs) 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for three years by physical exam, ultrasonography, and urinalysis, by colleagues at Purdue School of Veterinary Medicine. Biopsy-confirmed bladder cancer was detected in 27% of STs, including 29 with iUC. Transcriptomic signatures, including druggable targets, such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human iUC, and marked transcriptomic differences were noted between early and later canine tumors. The study suggests that breed dogs are important experimental systems for studies of iUC. Our current studies focus on susceptibility genes and variants in Shetland Sheepdogs. Dogs of Chernobyl Our Chernobyl study is the first of its kind, characterizing the genetic structure of three free-roaming dog populations (now over 350 dogs) living 15-45 km from the 1986 nuclear disaster site, including dogs living within the nuclear power plant (NPP) itself. We compared the genomes of Chernobyl dogs to several hundred breed dogs, as well as village dogs from adjacent countries (Spatola et al., Science Advances, 2023). We show that individuals from NPP and Chernobyl City (15 Km apart) are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression. Kinship analysis reveals 15 families, with the largest spanning all collection sites within the radioactive exclusion zone. This study is the first characterization of a domestic species in Chernobyl, establishing the importance of dogs for genetic studies into the effects of exposure to long-term, low-dose ionizing radiation. Aging Epigenetic estimators of age (known as clocks) may permit cross-species interventions that slow or reverse aging. Previous epigenetic clocks only applied to a single species at a time. In work with colleagues this year we describe reliable and highly accurate epigenetic clocks that apply to 93 breeds (Horvath et al., Proc Natl Acad Sci USA, 2022). The methylation profiles were generated using an established mammalian methylation array utilizing mammalian-species conserved sequences. Epigenetic clocks were constructed to estimate age and also average time to death. We also present two highly accurate human-dog dual species epigenetic clocks (R = 0.97), which we hypothesize may facilitate the ready translation from canine to human use (or vice versa) of anti-aging treatments being developed for longevity and preventive medicine. Finally, our studies reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. We then worked with additional collaborators (Rubbi et al., Epigenetics, 2022) using targeted bisulphite sequencing to identify novel associations between methylomes and sex, weight, and sterilization status. We also show that several factors moderate the relationship between epigenetic age and real age, such as body weight, which increases epigenetic aging. Behavior Our recent experiments (Dutrow et al., Cell, 2022) overcome longstanding difficulties in identifying genetic drivers of canine behavior by developing a framework for understanding relationships between breeds and the behaviors that define them. We utilized genetic data for over 4,000 domestic, semi-feral, and wild canids, and behavioral survey data for over 46,000 dogs. We identified ten major canine genetic lineages and their behavioral correlates, and we show that breed diversification is predominantly driven by non-coding regulatory variation. We determine that lineage-associated genes converge in neurodevelopmental co-expression networks, identifying a sheepdog-associated enrichment for interrelated axon guidance functions. This work presents a scaffold for canine diversification that positions the domestic dog as an unparalleled system for revealing the genetic origins of behavioral diversity. Building on this data we are now studying breed-specific and anomalous behaviors in herding-type

犬类遗传学现代狗品种的巨大表型多样性代表了20，000年实验的终点。每个品种对形态和行为特征都有强烈的人工选择，以创造大小，形状，行为和疾病敏感性独特的种群。我们研究犬类遗传学的多管齐下方法证明了犬类系统对人类及其宠物有更好的遗传理解的实用性。犬整个基因组序列我们一直在Dog10k（Ostrander等人，Natl Sci Rev，2019年）继续领导角色，这是一个涉及18个实验室的国际财团，旨在在整个Canidae中产生整个基因组序列（WGS）。到目前为止，社区已经对大约4000只犬进行了测序，Dog10k完成了近2000杆（Meadows，Kidd等人，提交）。该分析包括对品种人口，单核苷酸和结构变异的深入研究，线粒体DNA的分析以及选择分析。我们迄今为止对犬类基因组进行了最大，最全面的分析，提供了有关驯化，绘制形态和行为特征以及疾病易感性研究的详细研究的信息。系统发育研究使用遗传距离措施和全基因组单倍型共享，我们先前发表了表型，行为和地理发展模式的证据（Parker等，Cell Reports，2017）。现在，我们将研究扩展到着重于地理孤立的人群，例如阿拉斯加（Ali等，J Heredity，2023）和Patagonia（Barrios等，Plos Genetics，2022）。我们知道，人类旅行的地方带来了狗，从而洞悉了早期人类移民模式，最终是疾病的起源。正在进行的研究集中于格陵兰雪橇犬，来自美洲的古老狗以及加拉帕戈斯群岛的现代狗。最近的研究还涉及同一品种的欧美狗之间的遗传差异，例如容易发生癌症的伯纳斯山犬，强调了遗传研究中准确祖先信息的重要性（Letko等人，Genes，2023）。形态学我们之前曾记录过超过9100万个犬类基因组变体，用于繁殖形态研究（Plassais等，Nature Comm。，2019）。我们确定了与16种表型相关的强大影响变异，包括体重变异，突出了人类突变时有助于脂肪酸代谢，肥胖和代谢综合征的基因。在我们的最新研究中，我们发现了众所周知的功能变体，这些功能变体考虑了IGF1基因与体型之间的关联。 IGF1编码与正常和异常骨和组织生长有关的激素。分析来自古代和现代罐头的1,431个基因组，我们首次在反义长的非编码RNA（IGF1-AS）中与IGF1相互作用，影响蛋白质的产生（Plassais等人，Current Biology，2022222222222222））。虽然衍生的突变主要在现代灰狼和大型家用品种中占主导地位，但易于体积的祖先等位基因在小型品种和较小的野生犬科中很常见。我们的分析表明，在更新世狼队中，这种主要的甘田体型的主要调节剂几乎消失在其最近的复兴，这是由于对小型品种狗的选择而造成的。侵入性尿路上皮癌（IUC）我们已经与临床合作者合作，以确定具有高品种相关风险的自然出现IUC风险的狗，以作为早期检测和干预的模型（Dhawan等人，Front Oncol，2022）。苏格兰梗（STS）6岁，没有体格检查，超声检查和尿液分析以6个月的间隔筛查三年的外部证据，并由普渡大学兽医学院的同事进行。在27％的ST中检测到活检确认的膀胱癌，其中包括29个IUC。犬和人IUC之间的转录组特征，包括EGFR和PI3K-AKT-MTOR途径，包括EGFR和PI3K-AKT-MTOR途径，在早期和犬类肿瘤之间非常相似。该研究表明，犬是用于研究IUC的重要实验系统。我们目前的研究集中于设得兰群岛羊皮的易感基因和变体。切尔诺贝利的狗我们的切尔诺贝利研究是第一个此类研究，表征了距1986年核灾难现场15-45公里的三个自由漫游狗种群（现在超过350只狗）的遗传结构，包括居住在核电站（NPP）中的狗（NPP）本身。我们将切尔诺贝尔狗的基因组与几百只繁殖犬以及来自相邻国家的乡村狗进行了比较（Spatola等，《科学进步》，2023年）。我们表明，来自NPP和切尔诺贝利市（相距15公里）的个体在遗传上是不同的，前者显示出增加的遗传相似性和分化。对共享祖先基因组段的分析突出了西方繁殖渗入程度和时机的差异。亲属分析揭示了15个家庭，其中最大的是放射性排除区域内的所有收集站点。这项研究是切尔诺贝利中家族物种的第一个特征，确立了狗在遗传研究中的重要性，以暴露于长期，低剂量电离辐射的影响。老化年龄的表观遗传估计量（称为时钟）可以允许跨物种干预措施缓慢或反向老化。以前的表观遗传钟一次仅应用于一个物种。在今年与同事的合作中，我们描述了适用于93个品种的可靠且高度准确的表观遗传时钟（Horvath等，Proc Natl Acad Sci USA，2022年）。使用已建立的哺乳动物甲基化阵列利用哺乳动物物种保守的序列生成甲基化谱。构建表观遗传时钟以估计年龄和平均死亡时间。我们还提出了两个高度准确的人狗双重物种表观遗传钟（r = 0.97），我们假设这可能会促进从犬类到人类使用（或VICE反之亦然）的抗衰老处理，以延长寿命和预防医学。最后，我们的研究揭示了个体甲基化位点，这些位点可能是繁殖重量与寿命之间的反比关系的基础。然后，我们与其他合作者（Rubbi等人，表观遗传学，2022）合作，使用靶向双石测序来鉴定甲基甲基与性别，体重和灭菌状态之间的新型关联。我们还表明，几个因素可以缓解表观遗传年龄与实际年龄（例如体重）之间的关系，从而增加表观遗传衰老。行为我们最近的实验（Dutrow等人，Cell，2022）克服了长期存在的困难，在识别犬类行为的遗传驱动因素方面，通过开发一个框架来理解品种之间的关系与定义它们的行为之间的关系。我们利用了4,000多个国内，半铁和野生犬和行为调查数据的遗传数据，可用于46,000多只狗。我们确定了十个主要的犬遗传谱系及其行为相关性，我们表明，品种多样化主要是由非编码调节变化驱动的。我们确定与谱系相关的基因在神经发育共表达网络中融合，从而确定了与绵羊相关的相关轴突指导函数的富集。这项工作为犬类多样化提供了脚手架，将家狗定位为无与伦比的系统，用于揭示行为多样性的遗传起源。在这些数据的基础上，我们现在正在研究放牧类型的特定品种和异常行为

项目成果

期刊论文数量（57）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Homozygosity for Mobile Element Insertions Associated with WBSCR17 Could Predict Success in Assistance Dog Training Programs.

与 WBSCR17 相关的移动元件插入的纯合性可以预测辅助犬训练计划的成功。

DOI：
10.3390/genes10060439
发表时间：
2019
期刊：
Genes
影响因子：
3.5
作者：
Tandon,Dhriti;Ressler,Kyra;Petticord,Daniel;Papa,Andrea;Jiranek,Juliana;Wilkinson,Riley;Kartzinel,RebeccaY;Ostrander,ElaineA;Burney,Nathaniel;Borden,Carol;Udell,MoniqueAR;VonHoldt,BridgettM
通讯作者：
VonHoldt,BridgettM

Transmissible Tumors: Breaking the Cancer Paradigm.

DOI：
10.1016/j.tig.2015.10.001
发表时间：
2016-01
期刊：
Trends in genetics : TIG
影响因子：
0
作者：
Ostrander EA;Davis BW;Ostrander GK
通讯作者：
Ostrander GK

Variation of BMP3 contributes to dog breed skull diversity.

DOI：
10.1371/journal.pgen.1002849
发表时间：
2012
期刊：
PLoS genetics
影响因子：
4.5
作者：
Schoenebeck JJ;Hutchinson SA;Byers A;Beale HC;Carrington B;Faden DL;Rimbault M;Decker B;Kidd JM;Sood R;Boyko AR;Fondon JW 3rd;Wayne RK;Bustamante CD;Ciruna B;Ostrander EA
通讯作者：
Ostrander EA

Studies of modern Italian dog populations reveal multiple patterns for domestic breed evolution.

DOI：
10.1002/ece3.3842
发表时间：
2018-03
期刊：
Ecology and evolution
影响因子：
2.6
作者：
Talenti A;Dreger DL;Frattini S;Polli M;Marelli S;Harris AC;Liotta L;Cocco R;Hogan AN;Bigi D;Caniglia R;Parker HG;Pagnacco G;Ostrander EA;Crepaldi P
通讯作者：
Crepaldi P

Widespread, long-term admixture between grey wolves and domestic dogs across Eurasia and its implications for the conservation status of hybrids.

DOI：
10.1111/eva.12595
发表时间：
2018-06
期刊：
Evolutionary applications
影响因子：
4.1
作者：
Pilot M;Greco C;vonHoldt BM;Randi E;Jędrzejewski W;Sidorovich VE;Konopiński MK;Ostrander EA;Wayne RK
通讯作者：
Wayne RK