The Whole Shebang!
NextGen Sequencing Comes to Genealogy
Cover photo: Ultima wafer used to process WGS samples for MyHeritage.
23andMe revolutionized the fields of personal genomics and genetic genealogy when they introduced the first direct-to-consumer autosomal DNA test in 2007. Back then, a kit would set you back $1000. Economies of scale and improvements in technology brought prices down to a tenth that amount, and the companies have updated their tests along the way, but the microarray has been a staple of genetic genealogy for nearly 20 years.
That may be changing!
First, Some Background
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Illumina microarray chip (https://www.illumina.com/science/education/genetic-analysis/causal-variant-discovery.html)[/caption]
Microarrays are technology that target roughly 600,000–700,000 units (called base pairs, or bp) of our DNA. That’s only a tiny fraction of the 3.2 billion base pairs that make up the human genome, but most of our DNA is identical to everyone else’s, so sequencing everything isn’t necessary. Microarrays selectively target some of the more variable spots, called SNPs. (SNP is short for single nucleotide polymorphism, which is just a fancy way of saying “DNA bits that are variable.”)
Even so, more than 600 million SNPs are known to exist in the human genome. Some are rare, some less so. There’s a lot more information in our DNA than microarrays are providing. How much? A scientific study published in 2014 estimated that sequencing the whole genome could improve relationship detection by 5%–15%. More on that below.
Next-Gen Sequencing
The first human genome to be sequenced took 13 years and cost more than a billion dollars at today’s prices.1
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https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost[/caption]
The Human Genome Project sparked a technological revolution that both increased speed—from 13 years to a few days—and lowered cost. Rather than “reading” the genome base-by-base in sequence, “next-generation sequencing” (NGS) approaches essentially skim the genome in tiny portions, then reassemble the short sequences using computer software.
Much like skimming a book, NGS can make mistakes or completely miss information. For critical applications, like cancer diagnostics, the lab might “skim” the genome hundreds of times. This is called coverage, expressed as, for example, 30x or 100x.2 The higher the coverage, the more accurate the results and the greater the cost.
Currently, one can purchase a 30x whole-genome sequence for about $400. Lower coverage may be fine for other applications.
NGS Is Coming to Genealogy
Both MyHeritage and FamilyTreeDNA recently introduced NGS technology for their autosomal DNA tests. Even better, the cost won’t change! The price for FamilyTreeDNA’s Family Finder test remains $79 and MyHeritage’s offering lists for $89 (although it’s almost always on sale). What’s interesting is that FamilyTreeDNA and MyHeritage are taking very different approaches to NGS.
MyHeritage is now doing low-coverage, whole genome sequencing. At 2x coverage, they aim to sequence every DNA position an average of twice. In reality, some will be sequenced more than that and others not at all. The missing data will be filled in using a statistical technique called “imputation.”
FamilyTreeDNA, on the other hand, is taking a different tack called “targeted enrichment”. Rather than trying to sequence all 3.2 billion base pairs at low coverage, they’re specifically targeting about 280 million base pairs at higher (10x–12x) coverage. Those targeted bases were chosen because they span the genome, are genealogical informative, and are back-compatible with the microarray results already in the matching database.
Which approach is better? I have no idea!
From a scientific standpoint, both strategies are valid for genealogy. We won’t know which is preferable for some time. That’s because most of the benefits won’t be apparent immediately.
Initially, a few NGS kits will be swimming in a sea of traditional microarray results, so we probably won’t see much difference. Both companies will need to build up their NGS databases with new testers (or re-testers like me), refine their matching algorithms and origin estimates, and ultimately create new tools to benefit us. Genealogy has always required patience.
As for myself, I did both tests while at RootsTech earlier this month and dropped them off at the venue on the same day. Neither should receive special treatment, so this should give us an initial comparison of how quickly these tests can be processed. I’ll update as soon as I know more!
1 For a more thorough discussion of the cost of the Human Genome Project, see here.
2 The coverage level doesn’t guarantee that every position in the DNA is read at that level; rather it’s an average. For example, at 10x coverage, some base pairs might be read 30 times and others not at all, with an average of 10 per position across the genome.
It's amazing how fast things change.
Interesting developments. Thanks for explaining.