DNA Technologies 101: Genotyping vs. Sequencing, and What They Mean For You

Flow cell

Flow cell used during our Next Generation Sequencing process.

We’re all interested in what’s in our DNA, the genetic code personalized to each of us. But… how many of us know anything about the technology that reads DNA? And more importantly, why should we care?

What you may not realize is there are many ways to decode DNA, and not all are created equal.

As a genetic counselor, I have helped thousands of people explore what their DNA can tell them and their families. What are they asking to discover? What do we know about translating their DNA to get them an answer? And what’s the best technology to use to answer that inquiry? These are important questions.

Our ability to read DNA has gone through nothing short of a revolution over the past decade. You may remember the announcement in 2003 that the human genome had (for the most part) been sequenced, more widely known as “The Human Genome Project.” It was an amazing accomplishment that took 10 years and about 3 billion dollars to achieve. Fast forward to the present and we can sequence all of your DNA in a matter of weeks or even days, at relatively low cost.

While all of this scientific progress is the kind of thing that gets folks in lab coats pretty excited, many of the lab coat-less out there might still wonder, “why does it matter to me?” It’s a fair question.

Let’s dive in. But first, let’s do a super quick recap of the basics of DNA.

DNA 101

DNA, the acronym for deoxyribonucleic acid, is the genetic code inherited from your mother and father that exists in almost every cell in your body. The code is made up of about 3 billion bases or letters, consisting of A, T, G, or C (which stand for adenine, thymine, guanine and cytosine), that spell out the personal biological instructions that tell your body how to function over time. You are born with this code, and it doesn’t change.

Genotyping vs. Next Generation Sequencing

Arrays. Sequencing. Exome Sequencing.

To explain the difference between the technologies that read DNA, think of a book. Imagine the string of letters that make up your genetic code are like words on a page, telling a story, chapter by chapter.

Genotyping is like reading a few scattered words on a page.

Sequencing reads whole sentences, paragraphs and chapters.

To sum it up quickly, genotyping gives you small packets of data to compare while sequencing gives you more data, with more meaning and context, today and down the road.

Genotyping looks for information at a specific place in the DNA where we know important data will be. Microarrays (or “arrays,” for short) are just one approach to genotyping but it has paved the way for understanding how common variations in our DNA may be associated with health conditions like diabetes and heart disease.

However, while identifying this specific point in the DNA — or “word” on the page — is incredibly important, it also signals to researchers that something in that “paragraph” could be even more significant or provide context. This is the equivalent to reading the word “knife” on a page, yet not knowing whether the book is a cookbook or a murder mystery.

This is what genotyping is good at: finding what we know today, where we know it will be. That’s a great tactic if you know what you are looking for. But what about what we don’t know? And what about context?

Sequencing looks at all the letters, in the order they’re spelled out in your DNA. In some cases, it looks only at a gene, a stretch of DNA that has the instructions for a specific protein. In other cases, the sequencing can look at the entire sequence, all 3 billion or so letters.

Through significant advances in technology, we’ve drastically decreased the time and labor costs it takes to do sequencing. The ability to look at the entire sequence of genes faster and cheaper through next generation sequencing (NGS) allows us to see beyond the commonly known variations in your DNA, thus enabling scientists to identify more of the unique variations from person to person. In turn, this leads to deeper discovery about the genetic underpinnings of your health.

Without sequencing, we simply miss these nuances to the story. We only know, “there’s an apple in this book.”

This is what sequencing is good at: uncovering the context, meaning, detail, and granularity.

What is the Exome+?

At Helix we use next generation sequencing technology (NGS) to analyze what we call the Exome+. It reads all 20,000 or so of our genes that are considered important because they code for proteins, the functional players in the body — known as the exome. The “+” means that we have added hundreds of thousands of other regions of interest, from data important to provide insights about ancestry to markers that are associated with a wide range of health conditions.

The end result is that the Exome+ provides 100 times the amount of information provided by existing genotyping or array technologies that are currently available to consumers. This is important for many reasons. With Exome+ sequencing, we can do a better job interpreting your data today, and we can find rare variations that cannot be found using arrays.

What Does All Of This Mean For You?

1. A more complete view: Consider you are planning a family. You want to know whether you carry certain inherited diseases that could pass along to a child. Let’s take cystic fibrosis (CF) as an example. The gene that is associated with CF is large — about 250,000 letters in total. To make matters more complex, there are over 1,700 known variations of the gene that cause CF. While genotyping or arrays may look for a handful of the more common variations, they could miss less common ones. Sequencing can read through the entire gene to identify all (or the majority of) letters that could have an important impact on family planning.

2. A cost effective way to keep informed: Since your DNA doesn’t change, it’s possible for us to read it once and refer back to it over your lifetime. On the first pass, we may not translate the meaning of everything in “the book.” Maybe the results include words or sentences we don’t understand (yet). So we store the book on the shelf to continue reading later as our translation abilities improve.

Imagine you paid for insights about your genetic predisposition for heart disease, or personalizing your approach to fitness and nutrition. What we know today is certainly valuable, but as we amass more knowledge about DNA over time, we can offer new insights. That means if you have had your exome or genome sequenced, it’s possible to return to it as new insights are discovered, without having to provide yet another sample or incur more lab costs.

3. Your unique code can help forward science. While we continue to benefit from genotyping, our understanding of the hereditary contributions to health conditions is still limited. Genetic causes of certain disease often derives from rare variations unique to individuals, and may exist only within a single person or family.

We really are as unique as snowflakes. A recent scientific publication that took a deep dive look at the genomes of 10,000 people found that each person had almost 9,000 variations in their DNA that had not been seen before (Telenti et al, 2016). Imagine what we’d find if we sequenced all 7 billion people on the planet. Each and every one of us has a part to play in these discoveries through our individual DNA.

The Future

As NGS has continued to become faster and cheaper, it also enables us to include more people in sequencing efforts. And because sequencing takes a close look at the code, we can also begin to compile deeper insight into how our DNA is similar and different across populations, and from person to person.

From family planning to fitness and nutrition guidance, the volumes of genetic data, in combination with other aspects of your health, will continue to yield greater and more personalized insights. We will continue to expand our understanding of how to interpret your genome, based on your unique variations.

With NGS, we have the power to provide a more complete picture, starting now and lasting through a lifetime as experts focus on translating the information to impact everyday lives.

To start your DNA discovery journey, visit helix.com.

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