Comparative Mammalian Genomics

比较哺乳动物基因组学

基本信息

批准号：
8565571
负责人：
elaine ostrander
金额：
$ 157.46万
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/8565571
关键词：
4q21 Affect African Architecture BMP3 gene Biology Body Size Breeding CDKN2A gene Candidate Disease Gene Canis familiaris Carcinoma Cells Cephalic Characteristics Clinical Collaborations Coupled Coupling Craniofacial Abnormalities Data Databases Development Digit structure Disease Disease susceptibility Ear Exhibits Functional RNA Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Growth Health Housing Human Immersion Investigative Technique In Vitro Incidence Individual Laboratories Leg Length Malignant Neoplasms Malignant histiocytosis Maps Measurement Missense Mutation Morphology Museums PRKG2 gene Paper Penetrance Phenotype Play Predisposition Publications Publishing Quantitative Trait Loci Regulation Resources Role Scientist Series Shapes Single Nucleotide Polymorphism Site Skeleton Specimen Squamous cell carcinoma Syndrome Techniques Tumor Suppressor Proteins Variant Width Work Zebrafish base bladder transitional cell carcinoma cancer risk comparative cranium density dog genome genome sequencing genome wide association study microdeletion novel precursor cell skeletal trait validation studies

项目摘要

Canines Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. Domestic dogs exhibit tremendous phenotypic diversity. In a recent paper we generated a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African dogs across 60,968 single-nucleotide polymorphisms (SNPs) (Boyko et al., PLoS Biology, 2010). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. Building on this data and fine mapping, we have found and published on genes controlling body size, leg length and width, among others. We are currently expanding our studies of body size to try and identify all major genes that contribute to the continuum of skeletal size (Hoopes et al., Mamm Genome, 2012), and in doing so, we identify genes that are candidates for human disorders of the skeleton. In contrast to humans we find that for across dog breeds a small number of quantitative trait loci (less or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species. A new set of studies focuses on genes that affect skull shape (Schoenebeck et al., PLoS Genetics, 2012). Using intrabreed association mapping with 51 measurements captured using an Immersion MicroScribe Digitizer on museum specimens, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Specifically, we show that at least five genetic loci are responsible for the cranioskeletal differences that differentiate dolichocephalic and brachycephalic dog breeds. Our detailed analysis using whole-genome sequencing uncovers a missense mutation in the BMP3 gene. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Microdeletions in humans that include or flank BMP3 are described. Although craniofacial abnormalities associated with these microdeletions were attributed to loss of PRKG2, a nearby gene, our results suggest that haploinsufficiency for BMP3 might also contribute to the clinical features of 4q21 syndrome. Furthermore, we propose that isolated BMP3 dysfunction could be the basis of human cephalic conditions whose genetic etiologies remain unknown. We are also continuing our series of GWAS aimed at finding loci for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma (TCC) of the bladder in the Scottish terrier and West Highland White terrier and very recently the Sheltie. We have also continued our work on squamous cell carcinoma of the digit, completing two genome wide association studies (GWAS). We have also recently advanced our studies of histiocytic carcinoma. We coupled a GWAS with genetic fine mapping to identify cancer- associated, non-coding sequence variants spanning the CDKN2A multiple tumor suppressor locus in Bernese Mountain Dogs (BMD) (Shearin et al., Cancer Epidemiol Bio and Prev 2012), who suffer from a 15-25% incidence of malignant histiocytosis. Histiocytic precursor cells from dogs carrying case-associated sequence variants expanded more readily in vitro and expressed less p16 than cells from control dogs. A novel linkage of several cancer- associating sequence variants in BMD show how lower penetrance non-coding sequence variants may combine to deregulate a tumor suppressor locus to cause a high penetrance, distinctive multiple cancer syndrome. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. As a result, the past year has been defined by significant progress on all fronts and resulted in the publication of multiple papers.

犬我们的犬类研究犬类研究集中于寻找对疾病易感性和生长调控重要的基因。这项工作是通过与狗的主人，育种者和狗窝俱乐部的合作来完成的，而不是通过现场繁殖或安置任何狗来完成的。迄今为止，这些努力造成了一些知名论文。家犬表现出巨大的表型多样性。在最近的一篇论文中，我们通过在60,968个单核苷酸多态性（SNP）中从80种家用狗品种，83种野生犬和10只杂种非洲狗（SNP）中产生了犬遗传变异的高密度图（Boyko等，Plos Biology，Plos Biology。，2010年）。将这种基因组资源与来自品种标准和个体的外部测量以及博物馆标本的骨骼测量结合在一起，我们确定了57种特征中品种之间与表型变异相关的51个狗基因组区域。在这些数据和精细映射的基础上，我们发现并发布了控制体型，腿长和宽度等基因。我们目前正在扩大对体型的研究，以尝试识别所有有助于骨骼大小连续体的主要基因（Hoopes等，Mamm Genome，2012），并且在这样做时，我们识别了候选人类疾病的基因骨骼。与人类相反，我们发现，对于整个狗，少数定量性状基因座（较少或= 3）解释了我们研究的大多数性状的大多数表型变化。此外，许多基因组区域都显示出最近选择的特征，其中大多数高度分化的区域都与定义品种特征（例如体型，外套特征和耳朵柔软度）相关。我们的结果表明，使用基因分型个体数据库在家犬中绘制多个特征的功效，并强调了人为指导选择在改变该重要物种中关键特征的遗传结构方面起着重要作用。一组新的研究重点是影响颅骨形状的基因（Schoenebeck等，PLOS Genetics，2012）。使用在博物馆标本上使用Immersion Microscribe数字化器捕获的51个测量值的内部结合映射，我们表明头骨形状至少受到五个定量性状位点（QTLS）的调节。具体而言，我们表明至少五个遗传基因座负责区分多左右和臂杆菌犬种的颅骨差异。我们使用全基因组测序的详细分析发现了BMP3基因中的错义突变。斑马鱼中的验证研究表明，颅骨发育中的BMP3功能是古老的。描述了人类中包括或侧面BMP3的微缺失。尽管与这些微缺失相关的颅面异常归因于PRKG2的丧失，但附近的基因，我们的结果表明，BMP3的单倍症也可能有助于4Q21综合征的临床特征。此外，我们建议孤立的BMP3功能障碍可能是人类遗传病因仍然未知的人类头皮条件的基础。我们还继续进行一系列GWA，旨在寻找狗的癌症易感性的基因座。正在进行的研究包括在苏格兰梗和西高地白梗和最近的Sheltie的膀胱中的过渡细胞癌（TCC）映射基因座。我们还继续研究了数字的鳞状细胞癌，完成了两项基因组广泛的关联研究（GWAS）。我们最近还提出了组织细胞癌的研究。我们将GWA与遗传细胞映射耦合，以鉴定跨越CDKN2A多重肿瘤抑制器基因座（BMD）（BMD）（Shearin等人，癌症Epidemiol Bio和Prev 2012）的癌症的非编码序列变体，这些变体均可识别癌症。恶性组织细胞增多症的发生率为15-25％。来自携带病例相关序列变体的狗的组织细胞前体细胞比对照狗的细胞更容易扩展，并且表达的p16较少。 BMD中几种癌症序列变体的一种新型连接表明，较低的渗透性非编码序列变体如何结合使用以消除肿瘤抑制基因座，从而导致高渗透率，具有较高的多重癌症综合征。总而言之，我们的工作旨在了解遗传变异在调节形态和疾病易感性促进表型中的作用。结果，过去一年的定义是由各个方面的重大进展定义，并导致了多篇论文的发表。