Types of DNA Tests - Which is right for you?

In this video I’m going to compare three common methods for checking a persons DNA: whole genome sequencing, whole exome sequencing, and genotyping arrays. Each of these methods are common types of consumer DNA tests.

I’m going to compare them on: how much of the genome they cover, how they work, their cost, and what they can tell us. Stick around until the end to hear which companies are actually offering which kind of test.

First, we need to do a quick review. The human genome is 3.2 billion base pairs long. 1.2% are sequences that code for proteins, also called coding DNA . The rest is non-coding DNA that sits between coding sequences. Genes are actually composed of coding dna and non-coding dna. When the dna of a gene is transcribed, the non-coding pieces are removed, then the coding sequence is translated into a protein. Proteins are the workhorses of the cell. Which is why if there’s a problem in a gene sequence, there will likely be a problem with the protein that the gene codes for. That protein may not do its job correctly, which sometimes gives the carrier a sign or symptom.

So you might think, ah, then only the coding dna matters, we can just focus on that. Which would be great, but the genome is more complex than this. Nature didn’t just stick all that intergenic non-coding DNA in our genomes for fun. Many non-coding DNA sequences help regulate how, when, and how much specific genes are transcribed. Other pieces of non-coding DNA are crucial for how DNA physically folds, which in turn affects how genes are read. And we are learning more everyday about the many roles non-coding DNA plays.

This brings us to the primary way these three genomic tests differ: their coverage of the genome

Coverage

Whole genome sequencing delivers the entire 3.2 billion base pairs of an individual. Whole exome sequencing delivers only the coding sequences of an individual (so about 1.2% of the genome or about 38 million base pairs). And genotyping delivers information on a few hundred thousand base pairs which is about .01% of the genome.

How they work

In terms of how these test actually work. Whole genome sequencing and whole exome sequencing are quite similar. First DNA is isolated from the sample, then it is broken into little pieces. In WGS, all the DNA fragments of the right size get little ends called adapters stuck to them so that they can stick to the flow cell in the sequencing machine. However in WES, the exons, or regions that code for genes, are isolated from the sea of DNA fragments and then have adapters attached to them for sequencing. Thereafter the sequencing process is nearly identical.

However genotyping works very differently. Instead of sequencing the DNA base by base to discover the sequence, genotyping starts with a device called a microarray. A microarray, which is about 10 centimeters long, has hundreds of thousands of tiny wells. Each well has a bead in it. Stuck on the surface of the beads are many copies of the same DNA sequence. This DNA sequence stops one base before the base of interest. In this picture I’m just drawing one for simplicity. The sample DNA is then broken into small pieces and washed over the array. When the sample dna complements the dna sequence on the bead, they stick to each other. Then the base where the SNP is in incorporated and emits a laser excited light signal where its color tells the scientists which base it is.

So what are these bases of interest that the microarray is testing for? They are called SNPs (or single nucleotide polymorphisms). A SNP is a single base at at a particular location in the genome that varies in humans. For example some people might have a T, whereas other people have a G. A genotyping array, also called a SNP microarray, can test for hundreds of thousands of SNPs in a persons genome. However, if you have a genotyping array done on your genome, its likely that for most of the SNPs, you will have the reference base, which is the base we expect most humans to have and is more or less uninteresting. So its not like you are going to find hundreds of thousands of interesting SNPs in your genome when you get a SNP microarray done, you may only find a hundred or so.

If you want to learn in more depth about how a genotyping or SNP array works, checkout this video.

But when you start to think about all the variations in the sample DNA has that weren’t on the array lawn, it kind of makes you sweat. Considering that we know of about 350 million human SNPs, and that an array can only test about 600K variants at most, its clear that the amount of information an array yields is minimal.

Cost

Now the genome coverage (or how much of the genome sequence they deliver) affects the price. As you can imagine, WGS is the most expensive at about $1000 per genome for clinical grade quality for 99% accuracy. Whole exome sequencing on the other hand is around $400 and genotyping is anywhere from $50 to $200. Also its worth noting that the prices of sequencing continue to drop as sequencing technology advances.

Usability

At the end of the day, we usually do a DNA test because we have questions about your DNA that we want answered. Naturally these tests vary in how effectively they can address these questions. First lets say you want to know where your ancestors are from. In this case, the more of your DNA sequence we have, the more accurately we can tell you what your ancestry is. So whole genome sequencing would be the best, followed by whole exome sequencing, followed by genotyping. Here is why. Ancestry is a very complex. Stay tuned for another video where I go in depth into the challenges and strategies for determining genetic ancestry. A population of people doesn’t differ from another by having a variant that the other population doesnt have. This almost never happens. Instead two populations differ by how common a variation is in their population. For example, variant X might occur in 20% of population A, but 60% of population B. Therefore if you have variant X, you are slightly more likely to come from population B than population A. The more variants like this that can be considered to determine ancesty, the more statically powerful the ancestry prediction becomes. This is why, genotyping for determining ancestry can be inaccurate, because only a small number of your variants are being considered.

Now lets say you have a very specific variant in mind and you want to know if you have it. Then a genotyping array would work just fine as long as long as it includes the variant you are interested in. The catch would be that, lets say this variant is related to breast cancer. New mutations and genes important that play a role in cancer are discovered everyday. And so by the time you get your genotyping results, its possible that there are 20 more equally consequential variants for breast cancer that have been discovered, and now you’re back to where you started. You’ll have to get genotyped again with an array that includes those twenty additional variants. And this process sort of never ends.

After this experience, let’s say you got smarter. You talk to your doctor and they tell you, usually people who get breast cancer have one of these 3 genes mutated. You say great, I’ll order whole exome sequencing so I can see if I have variants in any of these genes. Whole exome sequencing gives you the exact sequence of each of these genes. You may find a harmful mutation that would increase your risk for breast cancer on one of these genes. Or you may not. But either way, this is already way more comprehensive than genotyping. However, its possible your gene sequences are just fine, but that you have a varaint outside one of these genes that cause it to be expressed 10 times more than it would normally, making your cells to grow and divide uncontrollably, leading to cancer. Do you know if you have one of these mutations? You do not. And will not until you have whole genome sequencing done.

Now lets say your fed up, you only want to have one more genetic test done in your life. You want this test to cover everything. You buy whole genome sequencing. Finally there are no more unknowns. With the right help and software, thre is no place in your genome you cannot check. Not only do you have a list of every single variant that in unique to you (your VCF file) but you also have your complete genome sequence in order and the raw jumbled up sequences that the sequencing machine spit out. At any time in the future you can have a bioinformatician, researcher, or clinical lab re-analyze your raw data with the latest tools. This means you will always be able to apply the lastest science and discoveries on your genome and turn that into valuable knowledge that will shape your lifestyle choices.

And this is why I recommend whole genome sequencing over alternatives. Software will change, discoveries about the human genome will be made, but your genome sequence is literally timeless. Checkout Guardiome if youre interested in completely private high quality whole genome sequencing. If you still have questions, checkout these other videos where I focus on what a genomics consumer should know before buying. Please like and subscribe if this was helpful. Wishing you a healthy and happy day.