“Why do you want to do
this?”
My wife, immediately after I
tell her I'm going to sequence my own exome.
There are a few times in life where you
want to do something so badly, but find it difficult to convey to others why. This was one of those times. Such a
simple question, but so many different answers. And each answer as valid as all
the others. All of them coming together to explain why I would want to do
something so, well, unusual.
I could frame a whole dissertation on
the reasons behind wanting to sequence my own exome. (And I will.) But first,
the simple answer:
I’m
curious about myself.
I want to see if I can figure out why I
am the way I am. And by that I mean both physically and mentally. For some
people, this isn’t something they’ll ever think about. For others, they might
see very clearly that they are this way because God made them this way, or
because their parents raised them like this, or because they had bad luck. They
may simply accept that they have specific features that make them who they are
and aren’t concerned with why.
For me, those answers are not good
enough.
I know that there are mysteries to be
solved in my genetic code. It comes with the territory of being a geneticist.
That said, though, almost everyone thinks this way, usually without even
realizing it. We can all look at our own families as a proxy for genetics. If
your mom had type 2 diabetes and your sister has type 2 diabetes and your uncle
has type 2 diabetes, you’re pretty sure you have a higher chance of getting type
2 diabetes. You’ll hear all sorts of people saying that—“guess I got my mom’s
bad genes” and “guess he took after his father” and so forth. If you’ve ever
known somebody who got old enough, you might have heard her tell you about her
mother lived to a ripe, old age and her mother before her, and so on. That’s
what I call thinking genetic.
The difference for me is that I’m thinking genetic at a different level. I actually want to look at
my genetics to try to explain these types of things. I don’t believe in fate
without reason. If my mom lives to be 90, and my grandmother lived to be 90, I
want to know if I got the mutations that helped them get there. Could I just
shrug my shoulders, say, “I probably did,” and move on? Absolutely. But that’s
just not good enough for me.
And really, it’s not good enough for anyone. We’re no longer
entering the era where we can do better than that. We’re already there. Exome
sequencing represents that first major step into the era.
I think, to make a case for exome sequencing (and by the
way, whole genome sequencing is basically just an expansion and improvement
upon exome sequencing—more on that later), I first need to explain what we can
learn from it. And to do that, first you’ll
need to know what an exome is. For those readers who already know all about
this, feel free to skip down.
What is an exome,
anyway?
To understand what the exome is, you first have to
understand what the genome is. There are massive tomes on the details of the
subject, but to describe the genome succinctly:
The genome is the
blueprint for every cell in your body.
Every single protein in every one of your cells is encoded
on this massive blueprint. In order to create and maintain a cell (and
therefore, your body and very being), your cell quite literally reads the
genome and generates certain amounts and types of various proteins to fit the
particular cell it’s trying to become or to fulfill a particular function.
The exome is a subset of the genome that contains the
instruction to create the proteins themselves. The exome makes up about 1-2% of
the whole genome. If the genome is the blueprint, then:
The exome is the
instructions for making every protein in your body.
Therefore, being able to read those instructions means we
can figure out if differences in them will result in different protein
structures.
What can I learn from
the exome?
Identifying variations in the exome that lead to differences
in proteins (which we call mutations) can give us a direct way of determining
if a protein might have altered function in us compared to other people.
Significant protein mutations will manifest themselves as traits. To bring up
an example from a previous post, the earwax trait is a result of a variation in
the exome that leads to a mutation in a protein that results in determining if
your earwax will be wet or dry. But it goes far beyond that type of
“interesting” trait. Mendelian disorders (which this blog derives its title
from) are disorders resulting from mutations in a single gene, which we can
detect in the exome (and, in fact, quite a few Mendelian disorders have been
“solved” through exome sequencing now).
By sequencing the
exome, we can directly assess every line of the “instructions” and identify
those lines that differ from the norm.
But that’s not the only way to use this information. We can
hunt for mutations that damage our proteins, and that is the first obvious
thing to do when looking at the exome. But we don’t know how every mutation
will affect a person. To the contrary—there are very few mutations for which we
understand the effect.
In fact, the current standard in personal genomics testing
(such as that from DTC companies like 23andMe or through-physician companies
like Navigenics) is actually an approach that dominated the field for about a
decade before next-generation sequencing really became a reality. Using
microarray technology, these approaches measure specific sites known to harbor
variants in the genome that are associated
with a trait or disease but typically not causative
for the trait or disease.
For example, right now if you were to do a standard 23andMe
test, you’d have genetic variations assessed at about a million sites across
your genome. These variations would then be compared to a database that tells
how strongly particular variations associate with particular traits or
diseases. So 23andMe can tell me that I have a collection of variants that
associate with type 2 diabetes, and it can calculate how that increases my risk
of getting the disease compared to the average person.
This is more of a science than people often think. This is thinking genetic at a slightly more
advanced level. I could simply turn to my family history and guess that I’m at
an increased risk for type 2 diabetes. However, the fact that my genetics
confirm the increased risk makes it much more “real” to me. Not only do I have
a family history, I actually inherited some of those genetic factors. My risk
is real.
Knowing my exome sequence takes that to the next level.
Rather than simply having associations, I may be actually able to go into the
regions of association and identify mutations causing these problems.
Moreover, as more and more information regarding the genetic
causes of various traits and diseases are discovered, my exome sequence will
always be at hand for me to cross-reference. Imagine that tomorrow a study is
released identifying a gene that tells you with complete confidence whether or
not you’ll get type 2 diabetes. I would check that gene in my own exome for mutations
immediately!
That may sound unrealistic, but when it comes to conditions
like cancer, these kinds of studies come out all the time. I may identify a
random mutation in a gene that pre-disposes people to getting a particular type
of cancer in my own genome, and then I will know that I need to have my doctor
monitor for that. Having worked closely on brain cancer for a few years, it
struck me that the reason it’s the deadliest type of cancer is because by the
time we detect it, it’s already at a very advanced stage. But if we have a gene
or set of genes that we know predisposes people to get malignant brain tumors,
we could look in our own exomes for mutations in those genes and then get
ourselves MRIs starting at a particular age to try to detect them earlier and
hopefully allow effective, long-term treatement.
I think anyone can see how powerful that type of diagnostic
and predictive tool can be.
And that brings up a major reason to sequence one’s genome:
This information is immutable. Your exome is not changing. On the day you die,
you’ve got pretty much the same exome and genome you had when you were born. If
a major discovery is made tomorrow, I’ll have my exome to look at for it. If
another discovery is made in ten years, I can take that same exome sequence and
look for it. There’s no “expiration date” on that information.
And that’s what really sold me on the whole thing, actually.
My intimate knowledge that my exome is always going to be a part of me, and
that our understanding of genetics and diseases will always be expanding. That
means my investment now is going to pay off for my whole life. Or at least
until I sequence my whole genome.
I hope that conveys my major reasoning behind why I would
want to do this. Of course there are other factors as well. For one thing, I am
a geneticist. Genetics is not just my job, it’s my hobby. I love it. And over
the years I’ve become increasingly interested in my own genetics. But that’s
honestly not the only reason. At this point, I see it as a choice that will
help me keep myself healthy throughout my life.
I think there will be a shift
generally towards that thinking in the medical community at large in the very
near future as well. It may only be a couple years before your doctor suggests
you get your exome sequenced as well. In a society where I feel most of us already think genetic, I think it's only a matter of time before we stop simply guessing that it's genetic and instead actually prove it. And beyond that, we actually figure out that there's something we can do about it. That is empowering right there.
