Direct-To-Consumer DNA testing of 6,000 dogs reveals 98.6-kb duplication causing blue eyes and heterochromia in Siberian Huskies

Summary 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 1 . These databases are having a transformative effect on human genomic research, yielding insights on increasingly complex traits, behaviors, and disease by including many thousands of individuals in genome-wide association studies (GWAS) 2, 3 . 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 4–6 , because selection and breeding have led to dramatic phenotypic diversity underlain by a simple genetic structure 7, 8 . 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 a validation panel of nearly 3,000 more, the largest canine GWAS to date. We discovered a novel association with blue eyes on chromosome 18 ( P = 1x10 -65 ) 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 hox gene ALX4 , which plays an important role in mammalian eye development 9, 10 . This duplication was largely restricted to Siberian Huskies and is highly, but not completely, penetrant. These results underscore the power of consumer-data-driven discovery in nonhuman 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.