Comparative Mammalian Genomics

犬类 我们的犬类研究犬类研究的重点是寻找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、饲养员和养狗场俱乐部合作完成的，而不是通过在现场饲养或安置任何狗来完成的。到目前为止，这些努力已经产生了几篇备受瞩目的论文。 家犬表现出巨大的表型多样性。在最近的一篇论文中，我们通过对来自80个家养犬种、83个野犬品种和10个近交系非洲犬的915只狗的60,968个单核苷酸多态(SNPs)进行基因分型，生成了犬类遗传变异的高密度图谱(Boyko等人，PLoS Biology，2010)。将这个基因组资源与来自品种标准和个体的外部测量以及来自博物馆标本的骨骼测量相结合，我们识别了狗基因组的51个区域，这些区域与57个性状的品种之间的表型变异有关。在这些数据和精细图谱的基础上，我们发现并发表了控制身体大小、腿长和宽度等基因。我们目前正在扩大我们对身体大小的研究，试图确定所有有助于骨骼大小连续体的主要基因(Hoope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。 与人类相比，我们发现，对于跨犬种，少数数量性状基因座(少于或=3)解释了我们研究的大多数性状的大部分表型变异。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定义品种的特征有关，如体型、皮毛特征和耳朵松弛。我们的结果证明了使用基因分型个体数据库在家犬中定位多个性状的有效性，并强调了人类指导的选择在改变这一重要物种关键性状的遗传结构方面发挥的重要作用。 一组新的研究聚焦于影响头骨形状的基因(Schoenebeck等人，PLoS Genetics，2012)。通过使用Immersion Microcribe数字化仪对博物馆标本捕获的51个测量数据进行种内关联作图，我们发现头骨形状至少受5个数量性状基因座(QTL)控制。具体地说，我们发现至少有五个基因座导致了区别多头型和短头型犬种的头骨差异。我们使用全基因组测序的详细分析揭示了BMP3基因的错义突变。斑马鱼的验证研究表明，BMP3在颅骨发育中的作用由来已久。描述了人类中包含或侧翼BMP3的微缺失。虽然与这些微缺失相关的头面部异常归因于邻近基因PRKG2的丢失，但我们的结果表明BMP3单倍体不足也可能与4q21综合征的临床特征有关。此外，我们认为孤立的BMP3功能障碍可能是人类头面部疾病的基础，其遗传原因尚不清楚。 我们还在继续我们的GWAS系列研究，旨在寻找狗患癌症的易感性基因。正在进行的研究包括定位苏格兰梗和西高地白梗的膀胱移行细胞癌(TCC)的基因座，以及最近的夏尔蒂犬。我们还继续我们在手指鳞状细胞癌方面的工作，完成了两项全基因组关联研究(GWAS)。我们最近还推进了对组织细胞癌的研究。我们将GWAS与基因精细定位相结合，以识别跨越伯恩山犬(BMD)CDKN2A多肿瘤抑制基因座的癌症相关非编码序列变体(Searin等人，癌症流行病学生物和Prev 2012)，这些狗患有15%-25%的恶性组织细胞增多症。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张，并且比对照狗的细胞表达更少的p16。BMD中几个癌症相关序列变体的新连锁显示了低外显性非编码序列变体如何结合在一起来解除对肿瘤抑制基因的调控，从而导致高外显性、独特的多发性癌症综合征。 综上所述，我们的工作旨在了解遗传变异在调节表型中的作用，这些表型对形态和疾病易感性都有贡献。因此，过去一年的特点是各方面都取得了重大进展，并发表了多篇论文。

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.