- Genotyping vs Sequencing
- Which genotyping service is best?
- So what about sequencing?
- My opinion
If you’ve arrived here you’re probably somewhat aware of the various consumer genotyping kits available for people wanting to check their ancestry and more recently (at least in an official sense) their health. The 4th quarter of 2016 saw 1.6 million people gain access to their genetic data in one form or another, by far the largest number on record. With the surge in interest, more genetic testing providers have popped up to meet demand. And consumers are the one’s who benefit, especially as the FDA has eased some restrictions on health reporting. For example, 23andme can now tell its customers whether they have a version of the APOE gene that is associated with an increased risk for Alzheimer’s disease.
23andMe is by far the most well known of these companies, as they were the first to identify the niche in the market for consumer focused genomics, all the way back in November 2007. While, the technology wasn’t especially cutting edge, the way the data was packaged and presented was ground breaking, with Time Magazine accordingly naming their service the “Invention of the Year” in 2008
However, even though over 2,000,000 people have been genotyped by 23andMe (and many more by their competitors) there is still a lot of misunderstanding about what exactly these services offer, and how individuals can use this data. Before diving in it’s worth looking at our genetics 101 primer so your familiar with some of the terminology that follows.
Genotyping vs Sequencing
The first thing to understand is the difference between genotyping and sequencing. All the major players you’ve likely heard of, from Ancestry.com to 23andme, are all genotyping companies. As we explore below, they report on a tiny fraction of your overall DNA.
Below, I list the three basic ways you can have your DNA tested.
Whole genome – all your DNA
Whole Genome Sequencing (“WGS”) is exactly that. Every single base from all of your chromosomes is determined. Interestingly only about 2% of your genome is known as “coding DNA” that is DNA which codes for the proteins which make up all our cells and allow us to function as the unique humans we are.
The rest, known as “non-coding DNA,” was long thought of as junk DNA, but as we understand more about our genetics we now know these regions play a hugely important role in regulating the coding portions of our DNA. Our understanding of these regions and their interactions is relatively poor compared to our knowledge of the DNA coding regions.
To use a highway analogy, WGS represents every inch of the highway, including stretches of scrubland along the side of the road, far away from any exits or towns.
Exome Sequencing – just coding DNA
Whole Exome Sequencing (WES) sequences only the regions of DNA which code for proteins. This accounts for approximately 2% of the whole genome.
On the DNA highway, WES represents every known exit and town, even ones that are not thought of as important, or are as yet still unknown.
Genotyping – curated DNA
Then onto genotyping. Here information for a carefully selected number of bases is captured. These bases are usually selected because they represent locations where particular sequences associate with characteristics. But there are huge regions of the exome, let alone the genome which aren’t covered.
Genotyping picks up just the important stops on the highway that have activity.
Approximate regions covered by whole genome sequencing (WGS), whole exome sequencing (WES) and consumer genotyping.
23andMe, Ancestry.com and most other services are all genotyping companies. They look at select points of interest in your DNA, and look for variations (polymorphisms) giving rise to the term Single Nucleotide Polymorphism (SNP). But as you can see the amount of the genome they cover is tiny, approximately 0.03%!
Which genotyping service is best?
How long is a piece of string?
A bit of a blasé answer, but there really isn’t much to separate the major players, a fact which is summed up really nicely by this table (which I also summarise below). There will be some differences in how the data is presented to you within their site, and their particular focus i.e. Ancestry.com may be more relevant for those trying to trace relatives and construct a family tree, whereas 23andMe provides more “health” based information.
Ancestry.com – best for family tree searches
As the name suggests, Ancestry.com beats 23and me for those trying to construct a family tree, or find a distant relative. The company boasts a database of over 5 million from which users can “connect dots” with those who may be related. To be clear, this is an interface win, rather than a data advantage, because as we will see, both services are very comparable.
23andme – best for health research
23andme wins out on how they present health data to customers (although it’s important to point out that the Health plus Ancestry version of 23andme is more expensive). For example, 23andme users can access a “Genetic health risk” section which outlines the genetic risk for conditions like late onset Alzheimer’s and Age-related macular degeneration. The company has even included a new report providing risk factors for celiac disease.
True value of genotype data is the raw data file
But the true power of your genotype data (at least for us with a health focus) comes with the raw data file, which can be analysed by third party providers (Genetic Genie, Promehease, Livewello, and now Gene Food with the launch of our custom nutrition plan) with a much clearer health focus. For example, if you’re curious about your MTHFR status, you will need to use the raw data to find if a mutation in that gene is present.
As both 23andMe and Ancestry.com provide access to this raw data there is very little difference between the two. Even the number of SNPs analyzed is remarkably similar with the most recent 23andMe kit analyzing ~670,000 SNPs and Ancestry.com covering ~700,000 SNPs.
|Major Focus||Physical and behavioral traits, and some information about genetic disorders.||Geographic interpretation of genome with advanced ancestry matching.|
|Health Information||Some, limited.||n/a|
|Ancestry Information||Paternal and maternal information. Geographic analysis. Some simple genealogy tools.||Geographic analysis.|
Advanced genealogy and DNA matching tools for family tree building and ancestry matching.
|Estimated Turnaround||3-4 weeks||4-weeks|
|Access to Raw Data||Yes||Yes|
So what about sequencing?
Personal sequencing is the next big step in personalised medicine. While the genotyping services described above are powerful, they are only looking at a fraction of the exome (the coding region of the genome) and a minuscule fraction of the entire genome.
Theoretically therefore getting access to your WGS or even WES would open up many more more doors. And there are services available which offer this. Two major players are Veritas Genetics and Gene by Gene; however, each is only available to researchers or clinicians, not consumers.
Direct to consumer WGS options
Moving, on I was able to find three companies who offer direct to consumer WGS. FullGenomes, Dante Labs and Guardiome (who seem to be in the process of starting up). All three offer WGS and will supply your raw data, for actually quite reasonable prices.
Interpretation of this raw data however will be very limited. While all three services offer curated analysis, this seems limited to the same information covered by the much cheaper genotyping companies. Additionally, automated analysis of the raw data using services such as Livewello is currently not supported.
So unless you’re a practicing bioinformatician who can analyze these huge datasets, you will be paying for further analysis, and this is where the costs can ramp up significantly.
Whole exome sequencing? Is Helix a good value?
Are things better with WES? Remember, the whole exome sequencers provide your coding DNA.
One option here is a recently opened startup called Helix, which is approaching WES in a different way.
With a low initial price of $80 they will perform WES, you can then access a variety of analysis packs through their store. Sounds great? $80 is a steal compared to the genotyping companies, let alone the other WGS and WES offerings…
UPDATE: Data export is now available for an optional $499, which is in line with what you may expect to pay for a WES service.
Why we don’t recommend Helix
I’m sure you’ve spotted the rub however. Helix don’t provide your raw data, so in effect you’re locked into their system forever. For some this will be fine, but for me personally I struggle to see the benefit… By the time you’ve performed the same sorts of analyses offered by the genotyping companies you’ll have spent many times more and you won’t have access to a single byte of your raw data.
For me this one is a definite avoid.
Based on the ability to download your data now this is somewhat more appealing. I would still recommend genotyping for most individuals based on the cost and evidence available right now. However, if the cost listed isn’t prohibitive to you this service will provide you everything genotyping does, and future proof you as well.
While WGS and WES are going to be the future of personalised medicine, and are already providing great information to researchers and healthcare professionals, the framework just isn’t there for personal consumers… yet!
But if you rewound the clock back to October 2007 you could say the same thing about consumer genotyping. So for me personally, I would still currently go for the genotyping option over either WES or WGS.
However, if you’re comfortable paying more now for a similar level of curated analysis, while being happy holding onto your data ready for some clever company to unlock (or feel confident analyzing this yourself), then WGS is the way to go!
So, bottom line, we recommend either having your whole genome sequenced, or going with one of the genotyping options, all of which are comparable.
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