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，以创造具有独特特征的人群。结果，品种内有强大的表型同质性以及疾病易感性。这些特征在Ostrander Lab深入探讨。 犬整个基因组序列 我们一直在Dog10k上进行工作，我们的实验室在那里与DRS扮演共同领导角色。中国科学院的Gu-Dong Wang和Yaping Zhang。与世界各地的其他18个实验室合作，我们旨在在未来五年内生成10,000只犬的整个基因组序列（WGS）。到目前为止，约有3000个完成。 Ostrander Lab贡献的样本的序列已公开，其余的联盟数据当前可用。目的是将来自美国，非洲，欧洲和亚洲的300个注册品种中的每只中的每种狗排序（20-30倍），以及混合品种，乡村狗和野生犬（Ostrander等，2019; Wang等，2019）。 在另一项努力中，我们从772只狗（Plassais等，2019）对WGS序列进行了深度检查，记录了超过9100万个单核苷酸和小indels，从而为迄今为止伴随动物物种创造了最大的基因组变异目录。使用选择性扫描分析和基因组广泛的关联研究（GWAS），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，这些变异突出了在人类中突变的基因，这些基因有助于脂肪酸代谢，肥胖，肥胖和代谢综合征。其他变体，例如控制耳朵的大小和形状的变体，在人类突变时会产生听力障碍。其他人与衰老有关。还有一些与皮草类型有关（Parker等，2019； Whitaker等，2020）。因此，我们证明，使用WGS进行的GWAS扫描是不仅可以找到基因，而且是复杂性状的变体的强大方法，因此扩大了伴侣动物系统对哺乳动物生物学研究的实用性（Plassais等，2019; Whitaker等，2019）。 老化 我们已经开始研究狗的衰老和寿命。我们首先表征了104个拉布拉多猎犬（Labrador Referievers）的甲基瘤，其年龄范围为16岁，在哺乳动物同时块中达到了> 150个覆盖范围（Wang等，2020）。与人类甲基甲基的比较揭示了一种非线性关系，该关系转化了狗至人类的年份，并使两种物种之间主要生理里程碑的时机保持一致，并扩展到小鼠。保守的变化集中在发育基因网络上，足以翻译年龄和多种哺乳动物的抗衰老干预措施的影响。这些结果不仅将甲基化作为诊断年龄读数，而且还作为生理老化里程碑的跨物种翻译者。关于较大数据集的其他研究正在进行中。 犬类种群结构和孟德尔病基因图 我们继续对犬种结构的大规模研究（Parker等，2017），以便更好地为疾病映射研究提供信息。我们组装了存在的最多样化的狗品种数据集，反映了广泛的表型变化和遗产。我们继续揭示发展的地理模式和共同特征的独立起源。我们的分析表征了品种发展的复杂性（Ali等，2020），解决了有关品种起源的长期问题，迁移对地理上不同品种的影响，以及通过推断，狗品种中的性状和疾病等位基因的转移（Marchant等，2019）。我们已经表明，我们可以跟踪变异等位基因的历史，并提供有关其他特定疾病下一步可能出现的其他品种的预测。这项工作是所有在狗遗传疾病映射中的研究的基础，因为它通过确定每个分析的品种应如何分配，从而为研究设计提供了信息。 品种起源 最近，我们完成了两种类型的狗品种的整体基因组比较：那些运动能力很高，包括运动狩猎品种和梗犬，它们以其多动症而闻名（Kim等，2018）。这些是在连续体的末端的组和功能的末端。我们发现，心血管，肌肉和神经元功能的基因在运动狩猎品种中被强烈选择。我们还发现了与梗犬多动，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，因为我们试图确定负责梗犬子集中刻板印象行为的变体并确定其在人类中的作用。 这项工作的自然产物是我们继续合作，以更好地了解驯化过程。这些研究强调了特别可延展的基因座，提供了对理解人类变异最重要的基因的见解。现在，我们正在与格雷格·拉尔森（Greger Larson）共同领导一项研究，以检查来自美洲数百只古代狗的骨骼的基因组序列，以了解早期定居期间狗和人的迁移。 犬类癌 我们仍然坚定地致力于为组织细胞肉瘤，浸润性膀胱癌和胃癌制定犬类癌基因。我们检查了犬类侵入性尿路上皮癌的RNASEQ表达模式，并发现了两个不同的肿瘤簇和与人膀胱肿瘤的失调区域共享区域（Parker等，2019）。因为在病理学，对治疗和年龄在发病时的反应和年龄的侵入性尿路上皮癌（IUC）是高度相似的，所以狗是测试和开发目标药物的绝佳模型，使犬和人类都受益。我们在犬肿瘤和正常组织上进行了RNASEQ，鉴定了一组富集特征，以区分有或没有BRAFV595E（人类中的BRAFV600E）突变的IUC肿瘤以及具有过多数量失调基因的基因组区域。 BRAFV595E携带肿瘤的基因比BRAF野生型肿瘤具有明显更多的失调基因，反之亦然，有398个基因区分了两个簇。关键基因是细胞周期调节，免疫反应和膜转运的基因。在最近的评论中，我们总结了人类癌症研究的狗模型的优势（Ostrander等，2019）。 我们继续与合作者合作研究可传染性肿瘤的研究。在我们较早的合作（Magres等，2018）的基础上，我们表明，假定的肿瘤抑制剂RASL11A的5'未翻译区域中的单点突变显着促进肿瘤回归（Magres等，2019）。 RASL11a在回归肿瘤中表达，但在野生型，未注册的肿瘤中保持沉默，与其在人类癌症中的下调一致。从扩展过程中，这项工作表明RASL11激活可能提供肿瘤抑制的一般机制。 稀有和濒临灭绝的狗 Ostrander Lab仍致力于帮助较大的动物基因组学社区回答保护生物学领域的问题。我们获得了一个非凡的机会，可以对来自印度尼西亚巴布亚的三只高地野狗收集的样品进行核基因组研究。我们假设这些实际上是新几内亚唱歌的狗，这种物种被认为在野外灭绝，仅在保护中心存在。我们对高地野狗进行了第一个核基因组分析，我们表明它们确实是新几内亚唱歌的狗的代表，因此是营救这种不寻常的，接近灭绝的物种的候选人（Surbatki等人，2020年）。