Abstract
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.
Highlights
Humans have been exerting multifarious selection on dogs since their domestication from wolves, including strong natural selection during adaptation to a domesticated lifestyle followed by intense artificial selection during modern breed formation [1,2,3]
By examining > 3,000 dogs from the Embark Veterinary, Inc. customer database, representing the first genome-wide association study (GWAS) driven by consumer genomics in dogs and the largest dog genome-wide association studies (GWAS) cohort to-date, we have shown that a region of canine chromosome 18 carrying a tandem duplication near the ALX4 gene is strongly associated with blue eye color variation, primarily in Siberian Huskies
We provide evidence that this duplication is associated with blue eye color in non-merle Australian Shepherds
Summary
Humans have been exerting multifarious selection on dogs since their domestication from wolves, including strong natural selection during adaptation to a domesticated lifestyle followed by intense artificial selection during modern breed formation [1,2,3]. Blue eyes first arose in Europeans [9] and may have been favored by sexual selection due to an aesthetic preference for rare phenotypic variants [10], as an informative recessive marker of paternity [11], and/or as a by-product of selection for skin de-pigmentation to increase UVB absorption [12]. Whatever the cause, this selection has acted on the regulatory machinery of OCA2 (Oculocutaneous Albinism II Melanosomal Transmembrane Protein), which controls transport of the melanin precursor tyrosine within the iris [13, 14]. Because blue eyes result from reduced melanin synthesis, other mutations affecting melanocyte and melanosome function in the retinal pigment epithelium (RPE) can recapitulate the phenotype [15]
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