Comparative Mammalian Genomics

比较哺乳动物基因组学

• 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
• 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

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 我们的犬类研究专注于发现在疾病易感性和生长调节中重要的基因。这项工作是通过与狗主人，育种者和养犬俱乐部合作完成的，而不是在现场繁殖或饲养任何狗。迄今为止，这些努力已产生了几份引人注目的文件。 家犬表现出巨大的表型多样性。在最近的一篇论文中，我们通过对来自80个家犬品种、83个野生犬科动物和10个远交非洲犬的915只狗进行基因分型，跨越60，968个单核苷酸多态性（SNP），生成了犬遗传变异的高密度图谱（Boyko等人，PLoS Biology，2010）。耦合这个基因组资源与外部测量品种标准和个人以及骨骼测量博物馆标本，我们确定了51个区域的狗基因组与品种之间的表型变异在57个性状。基于这些数据和精细的映射，我们发现并发表了控制身体大小，腿长和腿宽等的基因。 我们目前正在扩大我们对身体大小的研究，以尝试和鉴定有助于骨骼大小连续体的所有主要基因（Hoopes等人，Mamm Genome，2012），在这样做的过程中，我们确定了人类骨骼疾病的候选基因。 与人类相反，我们发现，在狗的品种中，少数数量性状基因座（小于或= 3）解释了我们研究的大多数性状的大多数表型变异。此外，许多基因组区域显示出最近选择的特征，其中大多数高度分化的区域与品种定义性状相关，如身体大小，被毛特征和耳朵松软。我们的研究结果表明，使用基因型个体数据库在家犬中绘制多个性状的有效性，并强调了人为选择在改变这一重要物种关键性状的遗传结构中所发挥的重要作用。 一组新的研究集中在影响头骨形状的基因上（Schoenebeck等人，PLoS Genetics，2012）。 使用品种内关联映射与51测量使用浸入式MicroScribe数字化仪博物馆标本，我们表明，头骨形状是由至少5个数量性状基因座（QTL）。具体而言，我们表明，至少有五个遗传位点负责区分长头和brachycephalic狗品种的颅骨骼的差异。 我们使用全基因组测序的详细分析揭示了BMP 3基因中的错义突变。斑马鱼的验证研究表明，Bmp 3在颅发育中的功能是古老的。描述了包括BMP 3或侧接BMP 3的人类微缺失。虽然与这些微缺失相关的颅面异常归因于附近基因PRKG 2的丢失，但我们的研究结果表明，BMP 3单倍不足也可能导致4 q21综合征的临床特征。 此外，我们提出，孤立的BMP 3功能障碍可能是人类头部疾病的基础，其遗传病因仍然未知。 我们还在继续我们的GWAS系列，旨在寻找狗的癌症易感性位点。 正在进行的研究包括绘制苏格兰梗和西高地白色梗以及最近的谢尔蒂犬膀胱移行细胞癌（TCC）的基因座。 我们还继续了对手指鳞状细胞癌的研究，完成了两项全基因组关联研究（GWAS）。 我们最近也推进了对组织细胞癌的研究。 我们将GWAS与遗传精细作图相结合，以鉴定伯尔尼山狗（BMD）中跨越CDKN 2A多肿瘤抑制基因座的癌症相关的非编码序列变体（Shearin等人，Cancer Epidemiol Bio and Prev 2012），其患有15-25%的恶性组织细胞增多症。来自携带病例相关序列变异的狗的组织细胞前体细胞在体外更容易扩增，并且比来自对照狗的细胞表达更少的p16。BMD中几种癌症相关序列变体的新连锁显示了较低突变率的非编码序列变体如何联合收割机组合以解除肿瘤抑制基因座的调节，从而引起高突变率、独特的多发性癌症综合征。 总之，我们的工作旨在了解遗传变异在调节表型中的作用，这些表型有助于形态学和疾病易感性。因此，在过去一年里，各方面都取得了重大进展，并发表了多份文件。