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Consumer Genomics Firms Hope Lower Costs, New Features Will Make Y Chromosome Sequencing Mainstream

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NEW YORK (GenomeWeb) – Consumer genomics companies that offer Y chromosome sequencing services are planning reductions in test prices as well as the introduction of new features — upgrades that could make the offerings more attractive to a broader customer base.

Should they make good on these pledges, industry observers believe that Y chromosome sequencing services – until now the domain of advanced genetic genealogists and academics – could become more popular.

"The current price of our Big Y test is under $600, and like everything else in technology the price will fall or the offering will become larger," said Bennett Greenspan, president of Family Tree DNA, one of the firms that offers Y chromosome sequencing services. "I think the test will become more mainstream as we begin to offer more features that surround the product later this year," he said. "That, along with a somewhat lower price, will likely make it a much more mainstream product next year."

Greenspan declined to elaborate publicly on Family Tree DNA's product development plans. Still, Full Genomes, its main competitor, has adopted a similar strategy of cost reduction and rolling out user-friendly analysis tools in order to reach more customers.

"I expect prices will come down further as sequencing costs drop and as Y chromosome enrichment strategies are refined," said Greg Magoon, a Y chromosome analysis consultant for Full Genomes. "Going forward, Full Genomes is upgrading to a longer read length, which will help to further expand the regions of the Y chromosome where we can extract useful and reliable results."

Those changes could translate into additional revenue growth for these consumer genomics players. While the market for the services does not approach the scale of the array-based autosomal DNA testing market, which has already attracted millions of customers via services like Family Tree DNA's Family Finder, Ancestry.com's AncestryDNA, 23andMe's Personal Genome Service, and National Geographic's Geno 2.0 Project, most of which run between $99 and $199, the potential size of the Y testing segment of the overall consumer genomics space is not by any means small, especially given the higher price tag associated with the services.

"My best guess would be somewhere in the hundreds of thousands of people for Y targeted sequencing," Magoon estimated, "based on the number of people who have already done Y-focused genetic testing for genetic genealogy."

Exceeded expectations

As the Y chromosome is inherited from father to son, the generation of such data allows academics and genetic genealogists to more accurately determine the relationships of men who share the same surname, or to follow the movement of populations through time.

"It allows users to map out different parts of their trees, and it's very useful for advanced surname projects," said David Mittelman, CSO at Tute Genomics and a consumer genomics advocate. "It's also a good tool for research use to trace the movement of male lines," added Mittelman, who was CSO at Family Tree DNA when the company launched the Big Y service. "There was a lot of demand for the test, so we built it."

Both Family Tree DNA, a business division of Houston-based Gene by Gene, and Rockville, Maryland-based Full Genomes introduced their Y chromosome sequencing tests in the fall of 2013, though Family Tree DNA officially launched its test several months later in March 2014 following an introductory period. Full Genomes' test, called Y Elite 2.0, currently sells for $750, according to CEO Justin Loe. Family Tree DNA CEO Greenspan said that the cost of Big Y is now $575.

Though the services differ in terms of coverage and enrichment methods, both rely on Illumina next-generation sequencing to provide comprehensive analysis of the genetic variation of a customer's Y chromosome. Both firms use Illumina HiSeq 2000 instruments to process user samples. Customers submit saliva samples by mail, and the companies analyze the samples on the HiSeq. Turnaround time is between 10 weeks and 12 weeks, several times longer than the array-based autosomal DNA testing services, which typically take about a month to process.

While technology is one aspect of the services that set them apart from other offerings in a consumer genomics industry that relies heavily on SNP arrays, the purpose of Y chromosome sequencing differs from array-based autosomal DNA tests.

Those services use chips to genotype a customer's DNA across hundreds of thousands of SNPs, generating data that is used to determine the biogeographical components of one's ancestry, as well to match clients with relatives based on shared DNA segments. Y sequencing, in comparison, can be used to resolve specific questions about male lineage only.

Big Y is a "product designed to help people discover their personal SNPs on the Y chromosome," noted Greenspan, "and to potentially date those SNPs for genealogical purposes."

Family Tree DNA for years has offered microsatellite Y chromosome genotyping products to customers to serve the segment of the consumer genomics market that is interested in Y tests.

In November 2013, though, it rolled out Big Y, which allows users to explore around 13 million basepairs of the Y chromosome, including 30,000 known SNPs, at an average coverage of between 55X and 80X.

Family Tree DNA was not first to market with an NGS-based Y test, though. A few months earlier, Full Genomes launched Y Elite, promising coverage of the Y chromosome comparable to whole-genome sequencing for $1,499, a price that was later reduced to $850.

Full Genomes later expanded its services menu to include a test called Y Prime, priced at $589, as well as a whole-genome sequencing service that costs clients $1,850. The company also began offering analysis of BAM-formatted aligned sequence data files for $50, including those generated by rival Family Tree DNA.

Full Genomes' Loe, however, said this week that the company has recently decided to roll its Y Elite and Y Prime tests into the new Y Elite 2.0. It continues to offer both whole-genome sequencing services and BAM file analysis. The newest test covers 13.2 million megabases, at a read length of 250 basepairs at 30X coverage.

Representatives for both companies portrayed the market for these services positively, and believe they are poised for future growth, especially as prices fall and their services improve.

"It's been about one-and-a-half years since we launched the Big Y product and sales and new SNP discoveries have both exceeded my expectations," said Greenspan.

Family Tree DNA's current Big Y customers can be broken down into two groups, he said: academic researchers associated with universities and the most interested and active Y chromosome advocates among the general public.

"Frankly, I've been surprised by the purchasing interest from both groups," Greenspan said.

"I think the core customer for the Y targeted sequencing is a highly-engaged genetic genealogist who is interested in pushing the frontiers of the science and better understanding their own paternal lineage," said Full Genomes' Magoon. "Many of them coordinate or are otherwise active in research projects often involving hundreds or even thousands of participants focused on better understanding Y haplogroups of interest to them," he said.

The availability of such services has also provoked the creation of third-party analysis service providers. Just as the array-based autosomal DNA testing market has spurred the creation of numerous do-it-yourself analysis tools, many of which are housed at GEDmatch, a free, online community resource, so have tools for Y chromosome sequence data become available.

"If the past is an indicator, third parties will fill niches that we don't fill, which in general is not something that we fear," commented Greenspan. "Competition keeps us all on our toes."

Full Genomes is now serving the market for third-party analysis by offering interpretation of Big Y BAM files, but YFull, a Moscow-based informatics company, has been offering for $49 an analysis of NGS-generated Y chromosome data for four years. Vadim Urasin, a team member at Y Full, said at the tail end of last year that the company is now processing files for hundreds of clients a month, thanks to the advent of Family Tree DNA and Full Genomes' services. Urasin did not respond to a recent email seeking an update on the company.

One of the most popular features offered by Family Tree DNA, Full Genomes, and YFull, is being placed on the companies' so-called "Y Trees." Y Trees are essentially Y chromosome pedigree charts where each branch, differentiated by certain mutations, is named with a letter and deeper branches are labeled with numbers and letters to reflect their relationship to each other. By being placed on a firm's Y Tree, clients can learn about their specific line of ancestral descent, with hints to their geographical origins.

The continued adoption of Y chromosome sequencing testing, though, has meant that these Y Trees have evolved dramatically in the past two years. Greenspan said that Family Tree DNA's Y Tree has expanded in a "near crazy way" since it launched Big Y. "I think the total number of SNPs on the tree has quadrupled to well over 120,000 in the past two years," Greenspan said.

"Next-generation sequencing has enabled a significant improvement in resolution for the Y Tree," agreed Full Genomes' Magoon. "It has also allowed robust growth of the tree into more recent time scales — the past few hundred years," he noted.

Magoon said that Full Genomes will continue to invest in "staying on the cutting edge of the science in the Y chromosome sequencing space." He noted that the company has recently upgraded to a longer read length of 250 basepairs, compared to the 100-basepair read length of the initial Y Elite test that the company launched in 2013.

Seeking more information

The feedback from genetic genealogists to the Y chromosome sequencing services has in general been positive, though some would like the companies to deliver back more information on detected structural variation that could help them to answer specific genealogical questions.

Doug McDonald, a professor of chemistry at the University of Illinois, who is the data curator for the Clan Donald Y-Chromosome Project, said that the group has ordered 100 Big Y tests and two Full Genomes Y tests since they became available.

He credited the enrichment primers used in Family Tree DNA's Big Y service with helping to deliver to users high-quality results, and said that while Full Genomes' Y Elite service did turn up a few additional SNPs, the offering was, in his opinion, "not worth the money."

"The two people we selected for Full Genomes were particularly critical ones in the known genealogy," said McDonald. "We hoped that Full Genomes might find a useful SNP to differentiate them that Big Y missed," he said. "It didn't."

In comparison, he said that Big Y has allowed the group to resolve 85 percent of the questions it has sought to answer so far. To answer additional questions about the clan's lineage will require it to test members for structural variations that have so far been reported as unreliable SNPs in the Big Y chromosome sequencing test reports. He noted that Family Tree DNA now offers direct testing of these specific variations, which should allow the group to test more members and answer more questions about its lineage.

Addressing the issue, Greenspan acknowledged that the market wants every SNP scored, even when the slightest chance of a positive is shown" but said that the company would "prefer to just call SNPs with the highest confidence level." With next-generation sequencing, he added, there are some regions of the chromosome that are covered to a greater extent than others, a fact that has led the company to be cautious about the information it reports back to its customers.

"It's a damned if you do, damned if you don't situation," said Greenspan. "We take accuracy quite seriously and are happy to look into a call if someone questions the results in the BAM file."

Blaine Bettinger, author of the blog The Genetic Genealogist, said that he has had some success with the new Y testing services.

"Of course, I purchased a Big Y test from FTDNA, which has turned out to be extremely valuable for my haplogroup project, the R1b-L1/S26 Y-DNA Haplogroup Project," Bettinger said. "We've discovered several new SNPs as a result of Big Y that will help us further breakdown this group."

Bettinger also tried Full Genomes' interpretation of his Big Y results and was "extremely happy" with the firm's service. "The instructions for interpreting the results are very clear, and the variety of results was terrific, including the comparison to others."

Tim Janzen, a genetic genealogy community leader and co-founder of the Institute for Genetic Genealogy, said that the companies that offer Y chromosome testing services will likely need to reduce costs and tweak their performances before more customers will be willing to take a chance on them. He noted, like McDonald, that companies have "not always been able to deliver all of the SNPs that are positive in the results conveyed to the customer," issues that may confound users who are trying to better understand the lines of descent in their lineages.

But, in addition to questions about SNP reporting, it remains the price that constrains Y chromosome testing services from becoming more popular, Janzen maintained.

"From my perspective, the cost of these Y chromosome sequences deters most casual genetic genealogists," said Janzen. "If the price of complete genome sequence ever drops into the $100 to $200 range then I think a lot more people will do it," he said.

Additionally, Janzen predicted that microarray-based autosomal DNA testing will continue to be "much more popular than Y chromosome sequencing … in part due to the fact that autosomal testing will be for the foreseeable future less expensive," and because array-based autosomal DNA tests "deliver more of value to genealogists than does a Y chromosome sequence as a general rule."

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