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Family Tree DNA's NGS-Based 'BigY' Service to Inform Future Generations of Ancestry Testing Chips


A new Y chromosome sequencing service could lead to a new generation of more informative microarrays for genetic genealogy and ancestry testing.

Called BigY, the offering is as much a project as a product, according to David Mittelman, CSO at Houston-based Gene by Gene, which operates Family Tree DNA. Founded in 1999, Family Tree DNA offers analysis of autosomal DNA, Y-DNA, and mitochondrial DNA to individuals for genealogical purposes. The company relies on microsatellite genotyping for its lower-complexity tests, as well as microarrays to support its $99, autosomal DNA test, Family Finder.

In the past few weeks, though, the consumer genomics firm added BigY, a next-generation sequencing-based service, to the mix. As the Y chromosome is inherited patrilineally, there is interest among some genetic genealogists for an in-depth test that will help them more clearly understand and distinguish their customers' paternal ancestry from one another. BigY is such a service. For $695 per sample, Family Tree DNA's BigY allows users to explore up to13 million base pairs of the Y chromosome, including 30,000 known SNPs, at an average coverage of between 55 and 80X.

Mittelman noted that the service, which has an eight-week turnaround time for new orders, is being marketed initially to existing Family Tree DNA customers who have already taken its 37-marker, microsatellite genotyping-based Y chromosome test.
"We will eventually make it more broadly available but for now it is more of an experimental research product," Mittelman said of selling it to experienced clients. In addition to advanced users, Family Tree DNA is filling orders for researchers as well. "Right now the most exciting thing about the BigY product is that you can find novel, previously uncharacterized variants on the Y chromosome and so this appeals to researchers and advanced users," he said.

While the new service broadens the consumer genomics market to include next-generation sequencing technology, it will also help Family Tree DNA to improve upon its existing generation of microarrays, currently a 700,000-marker chip modeled on Illumina's 24-sample HumanOmniExpress, Mittelman noted.

"I think the most obvious way to use BigY to improve arrays is to discover new genetic markers that would be useful to serve to customers," said Mittelman. "We could discover new markers using BigY but then make them widely available using arrays which are cheap, fast, and high-throughput."

BigY might also help Family Tree DNA to validate future array designs, according to Mittelman.

"Running BigY on a bunch of reference samples gives us a set of calls we can use to test new chip features," he said. "When you make a new probe on an array you want to have positive and negative control samples to make sure the probe correctly distinguishes between the samples," Mittelman added. "So that way the next-gen data works as validation data."

The service could arguably help the company compete against AncestryDNA, BritainsDNA, National Geographic's Genographic Project, and 23andMe, other companies and organizations that offer array-based autosomal DNA analysis services for ancestry testing or genealogical purposes.

"I think it is fair to say that we are the only company in this space that can offer in-house sequencing, Sanger and Illumina, as well as genotyping," said Mittelman. He noted that Family Tree DNA maintains its own informatics team and variant-calling tools, as well as a "massive database" with which it cross references its results.

"I think this gives us a great position in the market and puts us in the best position to deliver new and useful products to customers," said Mittelman. "With BigY I think we now have one of the largest databases of high-coverage Y chromosome sequence in the world," he claimed. "We have a massive database of STRs on the Y chromosome."

BigY and a new Y-tree

Family Tree DNA introduced BigY last year with an initial sale price of $495 per sample. In doing so, the company joined startup Full Genomes, a privately held Rockville, Md.-based firm, in offering a Y-chromosome sequencing service to consumer genomics customers.

Mittelman said that Family Tree DNA has had an "amazing response" to the service, with first orders that number in the thousands. To handle that demand, the company has reduced its initial turnaround time from between 10 and 12 weeks to eight weeks.

Customers submit buccal samples to Family Tree DNA by mail, and the company analyzes them in its Houston laboratories using the Illumina HiSeq platform and its own software. BigY targets 13.5 million positions, and, on average, between 11 and 13 million confident positions are reported back to customers, said Mittelman. The company also makes the data available for download so that users can reanalyze it using third-party tools, he noted.

While thousands have already opted for Family Tree DNA's BigY service, Mittelman predicted it will become "more mainstream" when the firm releases its new Y-tree later this year. Y-tree is a phylogenetic map, or tree, of known Y-DNA haplogroups based on identified SNP markers. Mittelman noted that while the current, 2010-era Y-tree is based on about 860 SNPs, the newer 2014 Y-tree will contain more than 6,000 SNPs.

"Chips are designed to capture known variation in a cost-effective way, and the key word here is 'known,'" said Mittelman. "Sequencing large numbers of Y chromosomes will reveal new SNPs and other variants that could be useful in building a better Y-tree and these new markers would then be something you would want to include on a chip so others can take advantage," he said.