Abstract

Copy number variants (CNVs) are an important type of genetic variation and play a causal role in many diseases. However, they are also notoriously difficult to identify accurately from next-generation sequencing (NGS) data. For larger CNVs, genotyping arrays provide reasonable benchmark data, but NGS allows us to assay a far larger number of small (< 10kbp) CNVs that are poorly captured by array-based methods. The lack of high quality benchmark callsets of small-scale CNVs has limited our ability to assess and improve CNV calling algorithms for NGS data. To address this issue we developed a crowdsourcing framework, called CrowdVariant, that leverages Googles high-throughput crowdsourcing platform to create a high confidence set of copy number variants for NA24385 (NIST HG002/RM 8391), an Ashkenazim reference sample developed in partnership with the Genome In A Bottle Consortium. In a pilot study we show that crowdsourced classifications, even from non-experts, can be used to accurately assign copy number status to putative CNV calls and thereby identify a high-quality subset of these calls. We then scale our framework genome-wide to identify 1,781 high confidence CNVs, which multiple lines of evidence suggest are a substantial improvement over existing CNV callsets, and are likely to prove useful in benchmarking and improving CNV calling algorithms. Our crowdsourcing methodology may be a useful guide for other genomics applications.