Counting Chromosomes
A blog of random musings on genealogy, genetics, science, and history

Virtually all of the more than 17 million direct-to-consumer autosomal DNA tests have been performed on microarray BeadChips made by Illumina. Living DNA opened their doors using the Illumina GSA chip, but are now the first major-tier DTC tester leaving Illumina.

Note: information updates obtained after this article was published are posted at the bottom of the page and we will attempt to add salient information as it becomes available.

Microarray

Living DNA announced yesterday, 22 October, that they are moving away from the Illumina GSA (Global Screening Array) genotyping array microchip they have used since the company opened, opting instead for an offering from Thermo Fisher Scientific under its Affymetrix brand, acquired by Thermo Fisher Scientific 31 March 2016. Living DNA is the first major direct-to-consumer (DTC) autosomal DNA testing company to cease using Illumina, and we can only make educated guesses at the reasons.

The industry has been watching closely for many months to see what the introduction of Illumina's GSA chip would mean to the genealogy marketplace. Living DNA launched 22 September 2016 selling its first test kits in the UK. It exclusively employed the GSA chip. As of September 2017, with its "v5" product, 23andMe had moved from the Illumina OmniExpress chip to the GSA chip, as well. The 800-pound gorilla in DTC genetic testing, AncestryDNA, continues to use the OmniExpress chip, as do large industry players Family Tree DNA and MyHeritage.

For genealogical matching, the wrench in the works has been that the OmniExpress and GSA chips—while both are testing over 665,000 of the approximately 10 million identified SNPs (single nucleotide polymorphisms; and to be precise, as many as 15 million SNPs may have been identified but only as many as 5 million have been used as yet in advanced genetics studies, so split the difference at 10 million) among the 3.2 billion base pairs of the human genome—look at only about 23% of the same SNPs. Almost 80% of the SNPs tested by each microarray product are unique and can't be directly compared.

SNP Venn Diagram
Venn Diagram displaying approximate in-common overlap of tested SNPs between the Illumina OmniExpress and GSA BeadChips

In other words, if you've taken a Living DNA test (or recent 23andMe test) and your cousin an AncestryDNA test, only one-fifth of the SNPs can be compared one-to-one. We were left with only two options: either omit the evaluation of non-tested SNPs (which reduces the genomic comparison to only about 135,000 total SNPs), or employ imputation algorithms—think of them as Wheel of Fortune math that use empirical probabilities to make best-guess determinations about missing DNA letters—to assume which nucleic acids would be at specific chromosomal loci, had those base pairs been tested.

If the goal is accuracy in genealogical matching, neither of those two options is exactly a stellar standout. Living DNA still has no production user-matching feature. Its Family Networks offering was announced last February at RootsTech but, eight months later, it is still in beta-only mode.

Not dissimilarly, GEDmatch introduced the Genesis Algorithm in late May 2017 as an intended matching accuracy enhancement in support of its mission to be testing-vendor neutral. This was begun as a beta test and deployed a second database, separate from the initial one some of us colloquially now call "Origin." While the Genesis database could accept raw data from GSA chip tests, the Origin database could not, and the two databases remained separate: kits in one could not be compared to kits in another. In what may be the longest public beta in the history of genealogy tools, the two GEDmatch databases are just now, 17 months later, beginning to share data.

This is in no way the fault of the GEDmatch developers; it's merely a testament to the difficulty of the task: attempting to work with the detailed correlation of two disparate sets of data. The verdict is still out as to the efficacy and accuracy of directly comparing GSA and OmniExpress results, and the Genesis side of GEDmatch is still labeled as a beta-mode product and requires a separate log-on account.

Speaking of the verdict being out, the only online offering that has declared itself production-ready for accurate comparisons between multi-vendor GSA and OmniExpress results is MyHeritage, and that functionality was brought online amazingly quickly, considering the challenges. We don't have any specifics regarding how MyHeritage was able to accomplish this feat, but given their use of haplotype imputation in what they referred to at RootsTech as a "stitching" algorithm—a way to identify two very small, proximal segments that should really be combined into a single meaningful segment for matching—I suspect we have a significant amount of assumptive math in play.

I have yet to see any experiential findings analyzing the accuracy of MyHeritage's combined comparison of OmniExpress and GSA chip data. If you've studied those results, or know someone who has, please drop me a note.

I'm purposely not including 23andMe in that particular discussion because they don't allow the use of any other company's raw data in their comparison and matching tools.

I commented 6 September 2017 about imputation and the then-new GSA chip. At that time I had seen but, unfortunately, did not capture information that the introduction came with the announcement that Illumina would be phasing out the OmniExpress chip. I wasn't alone it that understanding: my friend T.L. Dixon mentioned the discontinuation of the chip in his blog as recently as last January, and on 5 September 2017 Roberta Estes wrote: "Illumina, the company that provides chips to companies that test autosomal DNA for genetic genealogy has obsoleted their OmniExpress chip previously in use, forcing companies to utilize their new Global Screening Array (GSA) chip when their current chip supply runs out."

Now, over a year later, there is no further word from Illumina about discontinuing the OmniExpress chip, and seemingly no alarm bells ringing at AncestryDNA or Family Tree DNA over the chip's imminent demise. Genealogy is not, by far, high on Illumina's balance sheet of revenue drivers. However, it just may be that the phenomenal growth in this marketplace (see my 9 August 2018 post, "New Data Show Dramatic Growth in Consumer DNA Testing") and the disparity between OmniExpress and GSA chip test data inspired Illumina to postpone retirement of the OmniExpress chip, at least for the time being.

We are excited to announce that we have developed an improved SNP genotyping platform that has been tailored to match the technical requirements of the different statistical methodologies we use to analyse your data. Sirius, the new chip, has been designed using the Axiom technology from Affymetrix / Thermo Scientific, which allows a great flexibility to match every feature of the chip to our methodologies/products. In other words, Sirius will allow us to make a better use of your genetic information and to use our methods more efficiently. New features include a higher overlap between the SNPs we test for our customers and chips used by other ancestry companies and a better SNP density and distribution across the genome.
     —Living DNA Blog, 22 October 2018

It should be noted that "Sirius" is not an Affymetrix or Thermo Fisher Scientific product name. Living DNA referred to its previous Illumina GSA chip as "Orion," but to be clear these are internal monikers and in no way imply that Living DNA manufactures their own microarrays. More on the "Orion" and "Sirius" names when we wrap this up.

The product line in question is almost certainly either based on, or is identical to, the UK Biobank Axiom Array. "Designed using imputation-aware SNP selection, this array provides optimized content modules for genome-wide association studies (GWAS) of common and low-frequency variants, biological function, and human disease in populations of European and British ancestry." This microarray is derived from the Axiom myDesign GW Array Plate, 675K-1.3M.

I might not be quite at the right address, but I'm fairly certain I'm in the correct neighborhood. Precisely how the chip aligns with Living DNA's operations and the other Illumina chips in use is yet to be seen. That said, the Axiom Array looks to be highly configurable and, using the UK Biobank version as a reference, would likely be testing at least some 821,000 markers, ergo the higher overlap described by Living DNA's announcement. The Axiom myDesign GW Array would have the capability of testing up to 1.3 million SNPs depending upon how it is configured.

This is perhaps already farther than speculation should have taken us. Living DNA, in their Facebook Group, has promised more details next week. But given the uncertain history the past year has brought regarding chipsets and genetic genealogy, I believe Living DNA's move has the potential to prove a bold one. It isn't just the chip that changes: the microarray is at the heart of an entire workflow, a whole system of procurement, programming, scheduling, handling, processing, analysis, and reporting. For a working laboratory, this is not a minor change.

But if Living DNA sets a precedent that moves toward a 1-million-marker test that can effectively bridge that chasm between the OmniExpress and GSA chips, might that begin to influence Illumina's product planning decisions? Or, if not in manufacturing, then decisions by the large players still on the OmniExpress platform, like AncestryDNA, Family Tree DNA, and MyHeritage? After all, if the 800-pound gorilla in the market eventually must make a decision that might move it backward by 50,000 tested SNPs while a competitor has increased the coverage by almost three times that amount, the marketing message might take a definite hit.

The "You Can't Make This Stuff Up" Department

To close with a bit of humor and irony, Living DNA refers to their new chip as "Sirius," and their previous GSA version as "Orion." The new chip is based on an Affymetrix product, which company was acquired by Thermo Fisher Scientific on the last day of March 2016.

It it almost certain that Living DNA has no intention of using Sirius or Orion as a trade name; they're simply internal identifiers the same way that new, significant updates to the Microsoft Windows or the Android operating systems have code names. But...

In its annual report for the year 1999 Sirius Group International reported holdings of over US$1.6 million in Affymetrix Inc. Evidently Sirius was serious about Affymetrix for several years. And the Thermo Fisher Scientific acquisition of Affymetrix Inc. was not easily won. Its final competitor? Origin Technologies. As of 22 March 2016 Origin had upped its cash-purchase bid for Affymetrix from $16.10 to $17 per share of common. It was a week of uncertainty and on 28 March Affymetrix's stock took a dive because shareholders weren't thrilled with the company's decision to rebuff suitor Orion and accept Thermo Fisher's bid that was $3 per share lower. The deal closed three days later, on March 31; Affymetrix stock ceased trading; and the company became part of a $20 billion global enterprise...and now a new player in our genetic genealogy world.

Recent Updates

  Living DNA has established a thread on their Facebook page where they are fielding questions about the change in the microarray chip and, specifically, what it means to existing customers: https://www.facebook.com/livingdna/posts/2149559351960395.

  A companion topic to this blog post has been opened on the WikiTree G2G Forum. Specific questions for Living DNA should be directed to their Facebook page, but general discussion about the change in chipsets, and possible implications, can be engaged at WikiTree.

  Living DNA's co-founder, David Nicholson, confirmed on the company's Facebook page that Living DNA was, as I'd remembered, advised by Illumina well over a year ago that the OmniExpress chip was being discontinued and that Living DNA needed to use the GSA chip instead.

  Steve Evans replied to my post in Blaine Bettinger's Genetic Genealogy Tips & Techniques Facebook Group with some specifics about the SNP coverage of the new Living DNA Affymetrix chip. He notes that it includes testing for 759,727 autosomal SNPs, 15,227 X-chromosome SNPs, 34,216 Y-chromosome SNPs, and 3,982 mtDNA SNPs, which is a significant increase in autosomal SNPs and an increase on the Y-chromosome. In total, this would mean that 813,152 SNPs are tested, or about 147,000 more than with the current Illumina GSA BeadChip.

In truth, I'm not entirely certain what to call the microarray. Living DNA, of course, refers to it as "Sirius," but that's clearly an internal name that really has no comparative relevance outside the company. As a microarray manufacturer, One advantage Illumina has is that it is much easier to write than Thermo Fisher Scientific. If not specifically the "Axiom myDesign GW Array" product, we at least know that the chip is part of the Axiom family. And while "Illumina GSA" works in casual conversation, "Thermo Fisher Scientific Affymetrix Axiom myDesign GW Array" certainly does not. Until we see a consensus among genetic genealogists, I'll keep my references to the "Axiom chip" in the same way we refer to the "OmniExpress chip."

  The morning of 24 October, Living DNA published another blog post available at this link. The post is due in part to the volume of questions and responses about the introduction of the Axiom chip, but also contains the interesting news that Living DNA has been working for a year to find a processing laboratory in the U.S. with which to partner. Following 29 October 2018, all U.S. residents purchasing a test from Living DNA will send samples to this U.S. laboratory, not to the UK. The name of the laboratory was not disclosed.

The blog post contains a short list of FAQs about the change to the Axiom chip gleaned from the previous 36 hours of questions received, and it also affirms Steve Evans's (above) statement about SNP coverage, with a tiny difference in autosomal markers. Per Living DNA, their "Sirius," Axiom chip will include tested loci for:

  • 759,757 autosomal SNPs
  • 34,216 Y-chromosome SNPs
  • 15,227 X-chromosome SNPs
  • 3,982 mtDNA SNPs
  • 813,182 total loci investigated

  Approximately 3:30 a.m. Eastern (10:30 a.m. BST) 25 October, Living DNA posted on Twitter that their offices had lost all telephone and WiFi services, preventing them from accessing email in addition to phones. Don't panic! This has nothing to do with the change to the Axiom chip!

But I couldn't resist a little humor leading into another day a series of which, I'm sure, have seen a volume of "retest for free" cries from Living DNA customers that the company could never have anticipated...because there has never been such a response when other companies changed the versions of their microarray chips. Best wishes to the Living DNA IT staff on getting those office services up and running again.

  Thursday evening, 25 October, Dr. Ann Turner offered the clarification that 23andMe was part of the original consortium that help design the Illumina Global Screening Array BeadChip. See the Global Screening Consortia Participants page at Illumina's website.