Comparative Mammalian Genomics

比较哺乳动物基因组学

• 批准号: 10267107
• 负责人: elaine ostrander
• 金额: $ 232.51万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/10267107
• 关键词: 5' Untranslated Regions; Academy; Africa; Age; Age-Years; Aging; Alleles; Americas; Animals; Asia; Athletic; Attention; BRAF gene; Behavior; Behavioral; Biology; Bladder Neoplasm; Body Size; Body Weight; Breeding; Canis familiaris; Cardiovascular system; Catalogs; Cell Cycle Regulation; Chernobyl Nuclear Accident; Chinese People; Chromosome Mapping; Collaborations; Communities; Complex; DNA; Data; Data Set; Databases; Development; Developmental Gene; Diagnostic; Differentiated Gene; Disease; Down-Regulation; Drug Targeting; Ear; Europe; Evolution; Foundations; Frequencies; Genes; Genetic; Genetic Diseases; Genome; Genomic Segment; Genomics; Geography; Goals; Health; Hearing problem; Histiocytic sarcoma; Human; Hyperactive behavior; Immune response; Indonesia; International; Intervention; Labrador; Leadership; Leg; Length; Location; Longevity; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammals; Maps; Measures; Mendelian disorder; Metabolic syndrome; Methods; Methylation; Modeling; Modernization; Morphology; Mus; Muscle; Mutate; Mutation; Neurons; New Guinea; Normal tissue morphology; Nuclear; Nucleotides; Obesity; Oncogenes; Pathology; Pattern; Phenotype; Physiological; Play; Point Mutation; Population; Predisposition; Process; Recording of previous events; Research; Research Design; Resources; Rest; Role; Sampling; Scanning; Science; Scientist; Shapes; Site; Sports; Structure; Study models; System; Testing; Transitional Cell Carcinoma; Translating; Transmembrane Transport; Tumor Suppressor Proteins; Tumor Tissue; Variant; Work; age effect; anti aging; autism spectrum disorder; bone; cancer risk; companion animal; comparative; cranium; experimental study; fatty acid metabolism; genetic variant; genome analysis; genome wide association study; genomic variation; human data; insertion/deletion mutation; insight; large datasets; malignant stomach neoplasm; methylome; migration; pressure; programs; skeletal; trait; transcriptome sequencing; treatment response; tumor; whole genome

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 with unique traits. As a result, there is strong phenotypic homogeneity within breeds as well as disease predispositions. These traits are explored in depth in the Ostrander lab. Canine Whole Genome Sequence We have continued our work on Dog10K, where our lab plays a Co-Leadership role with Drs. Guo-Dong Wang and Yaping Zhang from the Chinese Academy of Sciences. Working with 18 other labs across the world we aim to generate whole genome sequence (WGS) for 10,000 canines in the next five years. Thus far, about 3000 are completed. Sequence from samples contributed by the Ostrander lab have been made public with the rest of the consortium data currently becoming available. The goal is to sequence (20-30x) multiple dogs from each of the 300 registered breeds from the U.S., Africa, Europe, and Asia as well as mixed breeds, village dogs, and wild canids (Ostrander et al., 2019; Wang et al., 2019). In a separate effort, we performed an depth examination of WGS sequence from 772 dogs (Plassais et al., 2019) documenting over 91 million single nucleotide and small indels, thus creating the largest catalog of genomic variation for a companion animal species to date. Using both selective sweep analyses and genome wide association studies (GWAS) we identified strong impact variants associated with 16 phenotypes, including body weight variation, which highlights genes that, when mutated in humans, contribute to fatty acid metabolism, obesity and metabolic syndrome. Other variants, such as those controlling ear size and shape, produce hearing disorders when mutated in humans. Others are associated with aging. Still others are associated with fur type (Parker et al., 2019; Whitaker et al., 2020). We thus demonstrate that GWAS scans performed with WGS are powerful methods for finding not only genes but also variants underlying complex traits, thus expanding the utility of companion animal systems for the study of mammalian biology (Plassais et al., 2019; Whitaker et al., 2019). Aging We have initiated studies on aging and lifespan in dogs. We first characterized the methylomes of 104 Labrador retrievers spanning a 16-year age range, achieving >150 coverage within mammalian syntenic blocks (Wang et al., 2020). 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. Additional studies on larger datasets are underway. Canine Population Structure and Mendelian Disease Gene Mapping We have continued our large and continuous study of canine breed structure (Parker et al., 2017) in order to better inform disease mapping studies. We assembled the most diverse dataset of dog breeds in existence, reflecting extensive phenotypic variation and heritage. We continue to uncover geographic patterns of development and the independent origins of common traits. Our analyses characterizes the complexities of breed development (Ali et al., 2020), resolving longstanding questions regarding breed origin, the effect of migration on geographically distinct breeds and, by inference, transfer of trait and disease alleles among dog breeds (Marchant et al., 2019). We have shown we can track the history of variant alleles, offering predictions as to additional breeds where specific diseases may appear next. This work is foundational to all studies in dog genetic disease mapping as it informs study design by determining how breeds should be partitioned for each analyses. Breed Origins We recently completed a whole genome comparison of two types of dog breeds: those that are highly athletic and include the sport-hunting breeds, and terriers, which are known for their hyperactivity (Kim et al., 2018). These are groups at the ends of a continuum in both form and function. We found that genes underlying cardiovascular, muscular, and neuronal function are under strong selection in sport-hunting breeds. We also found associations with genes for hyperactivity, autism and attention disorders in terriers. The latter result is one that we are currently expanding as we seek to identify variants responsible for stereotypical behaviors in subsets of terriers and determine their role in humans. A natural outgrowth of this work has been our continued collaborations to better understand the process of domestication. Such studies highlight loci that are particularly malleable, providing insights into the genes that are likely most important in understanding human variation. We are now co-leading a study with Greger Larson to examine genome sequence from bones from hundreds of ancient dogs from the Americas with an aim of understanding both the migration of dogs and people during early settlement. Canine Cancer We remain firmly committed to mapping canine cancer genes for histiocytic sarcoma, invasive bladder cancer and gastric cancer. We examined RNAseq expression patterns of canine invasive urothelial carcinomas and found two distinct tumor clusters and shared regions of dysregulation with human bladder tumors (Parker et al., 2019). Because invasive urothelial carcinoma (iUC) is highly similar between dogs and humans in terms of pathology, response to treatment and age at onset, the dog is an excellent model for testing and development of targeted drugs benefiting both canines and humans. We performed RNAseq on canine tumor and normal tissues identifying a set of enrichment profiles that distinguishing iUC tumors with and without BRAFV595E (BRAFV600E in humans) mutations, as well as genomic regions harboring excessive numbers of dysregulated genes. BRAFV595E carrying tumors shared significantly more dysregulated genes than BRAF wild-type tumors, and vice versa, with 398 genes differentiating the two clusters. Key genes are those for cell cycle regulation, immune response, and membrane transport. We have summarized and the strengths of the dog model for studies of human cancer in a recent review (Ostrander et al., 2019). We continue to partner with collaborators on studies of transmissible tumors. Building on our earlier collaboration (Magres et al., 2018), we show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression (Magres et al.,2019). RASL11A was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with its downregulation in human cancers. By extension, the work shows that RASL11 activation may provide a general mechanism for tumor inhibition. Rare and Endangered Dogs The Ostrander lab remains committed to helping the larger animal genomics community answer questions in the field of conservation biology. We received a remarkable opportunity to perform nuclear genome studies on samples collected from a rare siting of three highland wild dogs from Papua, Indonesia. We hypothesized that these were actually New Guinea Singing dogs, a species thought to have gone extinct in the wild and existing only in conservation centers. Performing the first nuclear genome analysis of highland wild dogs we show that they are, indeed, representatives of the New Guinea Singing dog, and are thus candidates to rescue this unusual, near extinct species (Surbatki et al., 2020).

犬遗传学 现代犬种的巨大表型多样性代表了 20,000 年实验的终点。每个品种都经过严格的形态和行为特征人工选择，以创造具有独特特征的种群。因此，品种内存在很强的表型同质性以及疾病易感性。奥斯特兰德实验室对这些特征进行了深入探索。 犬全基因组序列 我们继续开展 Dog10K 的工作，我们的实验室与 Drs. 共同领导角色。来自中国科学院的王国栋和张亚平。我们与世界各地的其他 18 个实验室合作，目标是在未来五年内为 10,000 只犬类生成全基因组序列 (WGS)。截至目前，已完成约3000个。 Ostrander 实验室提供的样本序列已公开，联盟的其余数据目前也已可用。目标是对来自美国、非洲、欧洲和亚洲的 300 个注册品种以及混合品种、乡村狗和野生犬科动物的多只狗进行测序 (20-30x)（Ostrander 等人，2019 年；Wang等人，2019）。 在另一项工作中，我们对 772 只狗的 WGS 序列进行了深度检查（Plassais 等，2019），记录了超过 9100 万个单核苷酸和小插入缺失，从而创建了迄今为止最大的伴侣动物物种基因组变异目录。通过选择性扫描分析和全基因组关联研究 (GWAS)，我们发现了与 16 种表型相关的强烈影响变异，包括体重变异，它突出显示了当人类发生突变时会导致脂肪酸代谢、肥胖和代谢综合征的基因。其他变异，例如那些控制耳朵大小和形状的变异，在人类中发生突变时会产生听力障碍。其他则与衰老有关。还有一些与毛皮类型有关（Parker 等人，2019；Whitaker 等人，2020）。因此，我们证明，使用 WGS 进行的 GWAS 扫描是不仅可以发现基因，还可以发现复杂性状背后的变异的强大方法，从而扩大了伴侣动物系统在哺乳动物生物学研究中的效用（Plassais 等，2019；Whitaker 等，2019）。 ，2019）。 老化 我们已经启动了关于狗的衰老和寿命的研究。我们首先对跨越 16 岁年龄范围的 104 只拉布拉多猎犬的甲基化组进行了表征，在哺乳动物同线性块内实现了 > 150 的覆盖率（Wang 等人，2020）。与人类甲基化组的比较揭示了一种非线性关系，这种关系可以翻译狗与人类的年龄，并调整两个物种之间主要生理里程碑的时间，并延伸到小鼠。保守的变化集中在发育基因网络上，这些网络足以转化多种哺乳动物的年龄和抗衰老干预措施的效果。这些结果表明甲基化不仅可以作为诊断年龄读数，而且可以作为生理衰老里程碑的跨物种翻译。对更大数据集的更多研究正在进行中。 犬类群体结构和孟德尔疾病基因图谱 我们继续对犬类品种结构进行大规模、连续的研究（Parker et al., 2017），以便更好地为疾病图谱研究提供信息。我们收集了现有最多样化的狗品种数据集，反映了广泛的表型变异和遗产。我们继续揭示发展的地理模式和共同特征的独立起源。我们的分析描述了品种发展的复杂性（Ali 等人，2020），解决了有关品种起源、迁徙对地理上不同品种的影响等长期存在的问题，并由此推断狗品种之间性状和疾病等位基因的转移（Marchant 等人） .，2019）。我们已经证明，我们可以追踪变异等位基因的历史，从而预测接下来可能出现特定疾病的其他品种。这项工作是所有犬类遗传疾病图谱研究的基础，因为它通过确定每次分析应如何划分品种来为研究设计提供信息。 品种起源 我们最近完成了两种狗品种的全基因组比较：运动能力很强的狗品种，包括运动狩猎品种，以及以多动而闻名的梗犬（Kim et al., 2018）。这些群体在形式和功能上都处于连续体的末端。我们发现，在运动狩猎品种中，心血管、肌肉和神经元功能的基因受到强烈的选择。我们还发现了与梗犬多动症、自闭症和注意力障碍基因的关联。后一个结果是我们目前正在扩展的结果，因为我们试图识别导致梗类亚群刻板行为的变异，并确定它们在人类中的作用。 这项工作的自然结果是我们不断合作，以更好地了解驯化过程。此类研究强调了特别具有可塑性的基因座，为理解人类变异可能最重要的基因提供了见解。我们现在正在与格雷格·拉尔森（Greger Larson）共同领导一项研究，检查来自美洲的数百只古代狗的骨骼基因组序列，目的是了解早期定居期间狗和人类的迁徙。 犬癌 我们仍然坚定地致力于绘制犬组织细胞肉瘤、浸润性膀胱癌和胃癌的癌症基因图谱。我们检查了犬浸润性尿路上皮癌的 RNAseq 表达模式，发现了两个不同的肿瘤簇和与人类膀胱肿瘤共享的失调区域 (Parker et al., 2019)。由于狗和人类的浸润性尿路上皮癌 (iUC) 在病理学、治疗反应和发病年龄方面高度相似，因此狗是测试和开发对犬类和人类都有益的靶向药物的绝佳模型。我们对犬肿瘤和正常组织进行了 RNAseq，确定了一组富集谱，可区分有或没有 BRAFV595E（人类为 BRAFV600E）突变的 iUC 肿瘤，以及含有过多失调基因的基因组区域。携带 BRAFV595E 的肿瘤比 BRAF 野生型肿瘤共享更多失调基因，反之亦然，有 398 个基因区分这两个簇。关键基因是细胞周期调节、免疫反应和膜运输的基因。我们在最近的一篇综述中总结了狗模型在人类癌症研究中的优势（Ostrander 等人，2019）。 我们继续与合作者合作研究传染性肿瘤。基于我们早期的合作 (Magres et al., 2018)，我们发现假定的肿瘤抑制因子 RASL11A 5' 非翻译区的单点突变显着促进肿瘤消退 (Magres et al., 2019)。 RASL11A 在消退的肿瘤中表达，但在野生型、非消退的肿瘤中沉默，这与其在人类癌症中的下调一致。推而广之，该工作表明 RASL11 激活可能提供肿瘤抑制的一般机制。 珍稀濒危犬类 奥斯特兰德实验室仍然致力于帮助更大的动物基因组学界回答保护生物学领域的问题。我们获得了一个绝佳的机会，可以对从印度尼西亚巴布亚的三只高地野狗的罕见地点采集的样本进行核基因组研究。我们假设这些实际上是新几内亚歌唱犬，这种物种被认为在野外已经灭绝，只存在于保护中心。对高地野狗进行首次核基因组分析，我们表明它们确实是新几内亚歌唱犬的代表，因此是拯救这种不寻常的、濒临灭绝的物种的候选者（Surbatki 等人，2020）。