Direct-to-consumer DNA testing of 6,000 dogs reveals 98.6-kb duplication associated with blue eyes and heterochromia in Siberian Huskies
Direct-to-consumer DNA testing of 6,000 dogs reveals 98.6-kb duplication associated with blue eyes and heterochromia in Siberian Huskies
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DOI：
10.1371/journal.pgen.1007648
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发表时间：
2018-10-01
期刊：
影响因子：
4.5
通讯作者：
Sams, Aaron J.
中科院分区：
文献类型：
--
作者：
Deane-Coe, Petra E.;Chu, Erin T.;Sams, Aaron J.
消费者基因组学通过将非常庞大的个人基因组数据数据库与通过网络调查自愿提交的表型信息联系起来，使基因发现达到前所未有的规模。这些数据库对人类基因组学研究产生了变革性的影响，通过将成千上万的个体纳入全基因组关联研究（GWAS），对日益复杂的特征、行为和疾病产生了深刻的见解。然而，消费者基因组数据的前景并不局限于人类研究。狗的基因组工具很容易获得，数百种因果孟德尔变异已经被描述，因为选择和育种导致了简单遗传结构下的戏剧性表型多样性。在这里，我们报告了首次在非人类模型中进行的消费者基因组学研究的结果：基于3000多只客户狗的蓝眼睛GWAS，其中包括近3000多只狗的验证小组，这是迄今为止最大的犬类GWAS。我们在18号染色体上发现了与蓝眼睛的新关联（P = 1.3x10(- 68)），并使用序列覆盖和微阵列探针强度数据来确定可能的因果变异：同源盒基因ALX4上游的98.6 kb重复，该基因在哺乳动物眼睛发育中起重要作用。这种重复主要局限于西伯利亚哈士奇犬，与蓝眼表型密切相关（卡方P = 5.2x10(-290)），并且高度（但不是完全）渗透。这些结果强调了消费者数据驱动的非人类物种发现的力量，特别是狗，在那里，主人对他们宠物的个人基因组信息有强烈的兴趣，对基于网络的调查有很高的参与度，并且潜在的基因结构是测绘研究的理想选择。
Consumer genomics enables genetic discovery on an unprecedented scale by linking very large databases of personal genomic data with phenotype information voluntarily submitted via web-based surveys. These databases are having a transformative effect on human genomics research, yielding insights on increasingly complex traits, behaviors, and disease by including many thousands of individuals in genome-wide association studies (GWAS). The promise of consumer genomic data is not limited to human research, however. Genomic tools for dogs are readily available, with hundreds of causal Mendelian variants already characterized, because selection and breeding have led to dramatic phenotypic diversity underlain by a simple genetic structure. Here, we report the results of the first consumer genomics study ever conducted in a non-human model: a GWAS of blue eyes based on more than 3,000 customer dogs with validation panels including nearly 3,000 more, the largest canine GWAS to date. We discovered a novel association with blue eyes on chromosome 18 (P = 1.3x10(- 68)) and used both sequence coverage and microarray probe intensity data to identify the putative causal variant: a 98.6-kb duplication directly upstream of the Homeobox gene ALX4, which plays an important role in mammalian eye development. This duplication is largely restricted to Siberian Huskies, is strongly associated with the blue-eyed phenotype (chi-square P = 5.2x10(-290)), and is highly, but not completely, penetrant. These results underscore the power of consumer-data-driven discovery in non-human species, especially dogs, where there is intense owner interest in the personal genomic information of their pets, a high level of engagement with web-based surveys, and an underlying genetic architecture ideal for mapping studies.