Comparative Mammalian Genomics

比较哺乳动物基因组学

• 批准号: 8948392
• 负责人: elaine ostrander
• 金额: $ 127.78万
• 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/8948392
• 关键词: Accounting; Adoption; Affect; Alleles; Behavior; Biology; Body Size; Brain; Breeding; Candidate Disease Gene; Canis familiaris; Cessation of life; Chromosome Mapping; Collaborations; Color; Data; Digit structure; Disease; Dog Diseases; Ensure; Evolution; Fishes; Gene Frequency; Genes; Genetic; Genetic Drift; Genetic Enhancer Element; Genome; Genomics; Genotype; HMGA2 gene; Head; Health; Hereditary Disease; Human; IGF1 gene; IGF1R gene; Laboratories; Length; Lesion; Link; Lytic; MADH2 gene; Malignant Neoplasms; Mammals; Maps; Metabolism; Missense Mutation; Modeling; Morphogenesis; Morphology; Mus; Museums; Natural Selections; Nature; Neoplasm Metastasis; Palate; Paper; Pattern; Pigmentation physiologic function; Pigments; Population; Population Sizes; Principal Component Analysis; Proprotein Convertase 1; Proteins; Publishing; Recurrence; Reporting; Role; STC2 gene; Scientist; Shapes; Squamous cell carcinoma; Stem Cell Factor; Techniques; Variant; Weight; Width; Wolves; Work; Zygomatic Arch; bone; cancer genetics; cancer risk; comparative; craniofacial; cranium; disorder risk; gene interaction; genetic variant; genome sequencing; genome wide association study; high risk; member; novel; preference; pressure; research study; response; skeletal; tool; trait

Canine Genetics Canine Origins Our canine studies are divided into genomics of domestication, morphologic variation, and disease gene mapping. With regard to the first we have published recent, high-profile papers that describe the domestication of dogs (vonHoldt et al., 2013). This builds on previous work, published in Nature, where we presented a refined description of how breeds are related to each other (vonHoldt et al., 2010). Very recently, in a collaboration led by Dr. John Novembre at UCLA, sequencing of wild canids revealed a severe 30-fold reduction in effective population size that likely occurred during the domestication bottleneck, which we now estimate occurred about 15,000 years ago (Freedman, 2014). These data also show that none of the extant wolf lineages from putative domestication centers are directly ancestral to dogs, implying that a now extinct population of wolves may be the missing link in dog evolution. Finally, the study demonstrates selection on genes affecting brain function, metabolism, and morphology, supporting a major role for regulatory evolution in domestication. We also show evidence for hybridization between dogs and wolves, and provide a tool kit with population-level statistical quantification that can detect recent dog-wolf hybridization using a panel of dog-wolf ancestry-informative SNPs with divergent allele frequency distributions (VonHoldt et al., 2013). Morphology A majority of our dog papers over the past four years reveal our growing understanding of canine genome organization and its relationship to morphologic variation between breeds. Our newest avenue of morphologic study is aimed at understanding the genetic underpinning of skull shape variation (Schoenebeck, 2014) which varies dramatically across breeds (Schoenebeck, 2013; Schoenebeck et al., 2012). To quantify the variation, we collected data from 533 museum skulls at 51 landmarks using a microscribe digitizer. The resulting principal components analysis (PCA) showed that the top four PCs account for about 77% of skull variance across breeds. PC1 describes profound changes in rostrum length and angle, palate and zygomatic arch width, and depth of the neurocranium; essentially the continuum of craniofacial features that extend between brachycephalic (short head like a bulldog) and dolichocephalic (long head like a greyhound) skulls. Our GWAS on PC1 revealed several loci. The CFA32 locus demonstrated a marked reduction in observed heterozygosity (Ho) and elevated genetic differentiation (FST), which are hallmarks of strong selection. We identified causative variants on CFA32 but whole genome sequence from 12 dog breeds of widely varying skull shapes allowed us to reduce it to one, an F452L missense mutation in the bone morphogenesis protein 3 (BMP3) gene (BMP3F452L). We also expanded our body size studies (Rimbault, 2013). In this paper we analyzed four loci discovered in a previous genome-wide association study to define small intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2. We then genotyped each marker, together with previously reported size-associated variants in the IGF1 and IGF1R genes, on a panel of 500 domestic dogs from 93 breeds, and identified the ancestral allele by genotyping the same markers on 30 wild canids. We observed that the derived alleles at all markers correlated with reduced body size. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. We show that 46%-52.5% of the variance in body size of dog breeds can be explained by seven markers in proximity to exceptional candidate genes. Among breeds with standard weights <41 kg (90 lb), the genotypes accounted for at least 64.3% of variance in weight. This work helps to advance our understanding of canine body size and body size genetics for mammals in general. Finally we did work on canine coat color, showing that a multi-gene interaction involving ASIP, RALY, MC1R, DEFB103, and a yet-unidentified modifier gene is required for expression of saddle tan color pattern (Dreger et al, 2013). Canine Cancer The tremendous phenotypic diversity of modern dog breeds represents the end point of a >15,000-year experiment in artificial and natural selection. Each breed has undergone strong artificial selection, in which dog fanciers selected for many traits including body size, fur type, color, skull shape, and even behavior, to create novel breeds. The adoption of the breed barrier rule that no dog may become a registered member of a breed unless both its dam and sire are registered members ensures a relatively closed genetic pool within each breed. As a result, there is strong phenotypic homogeneity within the breeds recognized including breed-associated genetic disease. Our recent genetic studies of dog disease have focused almost exclusively on cancer, which we argue is a strong model for human cancer genetics. Squamous cell carcinoma of the digit (SCCD) is a locally aggressive cancer typified by lytic bone lesions, recurrence, and occasional death from metastasis. Standard Poodles are among the breeds with the highest risk of SCCD, however only the dark pigmented standard poodles are susceptible. We conducted a GWAS using on black Standard Poodles, and demonstrated that the Kit Ligand (KITLG) locus is strongly associated with SCCD. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 10(-8)) (Karyadi 2013). Dogs without at least one allele with four copies in cis are not at any risk for disease (Karyadi, 2013). This locus is under strong selective pressure in dogs, likely in response to coat color preferences, as KITLG has been linked to pigmentation in humans, mice and fish.

犬遗传学 犬科动物的起源 我们的犬类研究分为驯化基因组学、形态变异和疾病基因图谱。关于第一个问题，我们最近发表了一些备受瞩目的论文，描述了狗的驯化（vonHoldt 等，2013）。这是建立在之前发表在《自然》杂志上的工作的基础上的，我们在《自然》杂志上对品种之间的关系进行了精确的描述（vonHoldt 等，2010）。最近，在加州大学洛杉矶分校 John Novembre 博士领导的一项合作中，对野生犬科动物的测序显示，有效种群规模严重减少了 30 倍，这可能发生在驯化瓶颈期间，我们现在估计发生在大约 15,000 年前（Freedman，2014）。这些数据还表明，来自假定的驯化中心的现存狼谱系都不是狗的直接祖先，这意味着现已灭绝的狼群可能是狗进化中缺失的一环。最后，该研究证明了影响大脑功能、新陈代谢和形态的基因选择，支持驯化中调控进化的重要作用。 我们还展示了狗和狼之间杂交的证据，并提供了一个具有群体水平统计量化的工具包，可以使用一组具有不同等位基因频率分布的狗狼祖先信息 SNP 来检测最近的狗狼杂交（VonHoldt 等，2013）。 形态学 过去四年来，我们的大多数狗论文揭示了我们对犬基因组组织及其与品种之间形态变异的关系的日益了解。我们最新的形态学研究旨在了解头骨形状变异的遗传基础（Schoenebeck，2014），不同品种的头骨形状变异差异很大（Schoenebeck，2013；Schoenebeck 等，2012）。为了量化差异，我们使用 microscribe 数字化仪收集了 51 个地标的 533 个博物馆头骨的数据。由此产生的主成分分析 (PCA) 显示，前 4 位 PC 约占不同品种头骨变异的 77%。 PC1 描述了喙部长度和角度、腭和颧弓宽度以及神经颅深度的深刻变化；本质上是在短头颅（像斗牛犬一样的短头）和长头颅（像灰狗一样的长头）头骨之间延伸的颅面特征的连续体。我们在 PC1 上的 GWAS 揭示了几个位点。 CFA32 基因座表现出观察到的杂合性 (Ho) 显着降低和遗传分化 (FST) 升高，这是强选择的标志。 我们确定了 CFA32 的致病变异，但来自 12 个头骨形状差异很大的犬种的全基因组序列使我们能够将其减少到一种，即骨形态发生蛋白 3 (BMP3) 基因 (BMP3F452L) 中的 F452L 错义突变。 我们还扩大了我们的体型研究（Rimbault，2013）。 在本文中，我们分析了先前全基因组关联研究中发现的四个基因座，以定义包括候选基因 GHR、HMGA2、SMAD2 和 STC2 的小区间。然后，我们对来自 93 个品种的 500 只家犬进行了每个标记的基因分型，以及之前报道的 IGF1 和 IGF1R 基因中与体型相关的变异，并通过对 30 只野生犬科动物进行相同标记的基因分型来鉴定祖先等位基因。我们观察到所有标记的衍生等位基因都与体型减小相关。然而，品种通常并不是在所有标记上都是固定的。大多数品种都存在多种基因型组合。我们发现，狗品种体型差异的 46%-52.5% 可以通过接近特殊候选基因的七个标记来解释。在标准体重<41公斤（90磅）的品种中，基因型至少占体重差异的64.3%。这项工作有助于增进我们对犬类体型和哺乳动物体型遗传学的了解。 最后，我们对犬科动物毛色进行了研究，结果表明，涉及 ASIP、RALY、MC1R、DEFB103 和尚未鉴定的修饰基因的多基因相互作用是马鞍棕褐色颜色图案表达所必需的（Dreger 等，2013）。 犬癌 现代犬种的巨大表型多样性代表了超过 15,000 年的人工和自然选择实验的终点。每个品种都经过了严格的人工选择，养狗者根据身体大小、毛皮类型、颜色、头骨形状甚至行为等许多特征进行选择，创造出新的品种。采用品种壁垒规则，除非其母亲和父亲都是注册成员，否则任何狗都不能成为该品种的注册成员，这确保了每个品种内相对封闭的遗传库。因此，在公认的品种中存在很强的表型同质性，包括与品种相关的遗传病。 我们最近对狗疾病的遗传学研究几乎完全集中在癌症上，我们认为这是人类癌症遗传学的强大模型。手指鳞状细胞癌 (SCCD) 是一种局部侵袭性癌症，其典型特征是溶骨性病变、复发和偶尔因转移而死亡。标准贵宾犬是 SCCD 风险最高的品种之一，但只有深色标准贵宾犬才易感。我们对黑色标准贵宾犬进行了 GWAS，并证明 Kit Ligand (KITLG) 基因座与 SCCD 密切相关。发现包含预测增强子元件的拷贝数变异 (CNV) 与 STPO 中的 SCCD 密切相关 (P = 1.72 10(-8)) (Karyadi 2013)。至少没有一个具有四个顺式拷贝的等位基因的狗没有任何患病风险（Karyadi，2013）。该基因座在狗身上受到强烈的选择压力，可能是对毛色偏好的反应，因为 KITLG 与人类、小鼠和鱼类的色素沉着有关。