"Mysteries of DNA" image courtesy Mark H. Adams. Full-size version.

As anyone who follows this blog knows, I recently took a 23andMe genetic test and have been blogging about it ever since. Today I thought I would focus on one of the fun parts of the service: traits.

Lots of our traits are at least partly dependent on our genes. So a genetic test should be able to tell me a bit about what I’ll look and even be like in the future. It may even tell me what I can expect for my kids.

Here is what is available on the 23andMe test (click on the image for a larger version):

As you can see, some of this is pretty obvious…I know my eye color for example. It is kind of cool to see my blue eyes written in my DNA but not necessarily that helpful. When I click on eye color, I find out that people with this particular bit of DNA have a 72% chance for blue eyes, a 27% chance for green and a 1% for brown. (Incidentally, this 1% brown is probably a big reason why blue-eyed parents can have a brown-eyed child.)

What would have made this report more interesting for me is what it meant for my kids’ eye color. Does it mean I’ll have blue-eyed kids? This of course depends on my wife’s genes but it would be cool to have the option of including my wife’s data to find out.

Other less obvious traits were very interesting to me. The results say that like most mammals, I should be lactose intolerant. Which I am not—I’m fine drinking milk. So did 23andMe get it wrong?

Probably not. The science is pretty good on this topic. People with a certain difference in their lactase gene almost always lose the ability to make lactase as adults. No lactase means lactose intolerance.

When I dug deeper on the website I got some hand waving about other genetic influences or the environment. A better explanation is that I will probably become lactose intolerant at some point in my adult life—it just hasn’t happened yet.

Losing the ability to make lactase is a gradual thing. It happens to some people early in adulthood and others later on. I am probably one of the “later ons.” Something to look forward to…

One trait that I’ve always been a bit interested in is HIV resistance. Some people are more resistant to infection by HIV (the virus that causes AIDS). If these people do become infected, they tend to develop AIDS symptoms much more slowly as well.

In Europeans at least, this resistance has been tied to a DNA difference called CCR5-delta32. The people who are resistant to infection and who develop AIDS more gradually tend to have two copies of this DNA difference.

This DNA difference has been proposed to have become common in Europeans because it also makes people resistant to either the plague or smallpox. If true, my ancestors must have died like flies from the plague or smallpox because I don’t have the DNA difference.

I also now know about what my DNA tells me about my earwax, how I respond to a certain bitter chemical, and whether I flush from alcohol. These are sort of interesting but not very.

This part of the 23andMe experience is kind of fun though. I really enjoy it when genetic theory matches up with what I can see about me. It sort of validates genetics…

What can genetic testing tell you?

A while back I took a 23andMe genetic test that looks at over 600,000 different spots on my DNA. The last few blogs I have been going over my genetic test results with an eye on how useful they are. And how well the results are explained.

Last blog I wrote about how current genetic tests aren’t that great at predicting your risk for common, complicated diseases like diabetes or Alzheimer’s. This time I thought I’d focus on what today’s genetic tests can be very good at and whether or not 23andMe does a good job with these.

Current genetic tests are very good at predicting your risk for rare, simple genetic diseases like cystic fibrosis (CF) or Huntington’s disease (HD). And at predicting the chances that your kids will get these diseases too.

Genetic tests for these diseases work because most of them are caused by a single gene gone awry. Testing for a single gene is relatively easy.

For example, most cases of CF happen because of known differences in the CFTR gene. A genetic test can look for these differences and tell you if you and/or your spouse have any of them. If you both do, they can also give you a pretty good idea about the chances that your kids will get them too.

Of course, we don’t know all of the differences in the CFTR gene that can cause CF. And some differences only cause CF some of the time. And there are people with everyday, run-of-the-mill CFTR genes who get CF because of differences in different genes.

Still, as genetic tests go, these are pretty good. If a test comes up with a known CFTR difference that causes CF, then you have a pretty good idea of what your chances for developing CF are. If your spouse gets tested too, then your kids’ chances can be determined as well.

So how does 23andMe do? OK, I guess…

First off, they look at eight of these sorts of diseases under a category called Carrier Status. The diseases they look at are shown in this image:

For me, the first big result is that I am a carrier for a variant that can lead to hemochromatosis. This isn’t surprising since 1 in 8-12 people of Northern European descent in the U.S. are too, but it is definitely something to watch out for. It may be important for my wife to be checked too so we can make sure none of our kids got two copies. (Luckily hemochromatosis is easily treated by giving blood on a regular basis.)

Some of the other results are less illuminating. For example, I do not carry the CF difference they test for (delta F508). This is of course great news. Unfortunately, this variant only accounts for about half of the CF cases out there. Which means I could be a carrier for CF, just not a carrier of the most common variant that they happen to test for.

The same thing goes for most if not all of the other carrier status diseases (sickle cell anemia is an exception). Some like BRCA (breast cancer) are as poorly covered as CF while others like Bloom’s disease cover a larger percentage of cases.

23andMe is pretty upfront about the limitations of their testing once you dig a bit into the results. But still, if they’re going to look at 600,000 different parts of my DNA, you’d think they could add a few more to give me a stronger answer about whether or not I am a CF carrier.

Could a genetic test have told me I was at a higher risk for developing type 2 diabetes? Image source: aldenchadwick

Metabolic syndrome isn’t quite as scary as it sounds.  Basically I am on my way to type 2 diabetes.  But if I eat better and get off the couch, I should stave off the disease and get better.

My question, naturally, is whether or not a genetic test could have told me I was at a higher risk for developing type 2 diabetes.  And whether I would have done anything with that result.

As you know if you’ve been following my blog, I took a 23andMe genetic test and have been writing about it since.  The image below shows what the front page of my clinical report looks like (click to enlarge):

According to the DNA checked in this test, I am in the average risk range for type 2 diabetes.  This doesn’t really seem to line up with my reality.  But I might not expect it to since these genetic tests are so limited right now.

This kind of test can be informative with the yes answer—yes I carry a certain version of a gene that might lead to a disease.  But the no answer isn’t that useful.  It doesn’t mean that they've looked at all the possible genetic differences that can lead to a disease and I don’t have any of them.  Basically it means that they didn’t find the specific genetic difference they were looking for.

Now I wouldn’t necessarily have predicted that any genetic test available right now could tell me a lot more than that.  Type 2 diabetes is too complicated for that and a whole lot more research will need to be done to get a genetic test useful to lots of people.

But still, this is probably what people are looking for with these sorts of genetic tests.  Will I get cancer, type 2 diabetes, Alzheimer’s, Parkinson’s, etc.?  For most of these cases, the tests can tell you a lot about rare forms of these diseases but little about the more common forms.

So the no answer didn’t really help me much.  Here I am on my way to being a diabetic and the test said I was at average risk.  Of course, I suppose I didn’t even need to take a test… all four of my grandparents came down with type 2 diabetes.  Like lots of these complex diseases, family history is the best predictor.

The second part of my question is a hypothetical one.  Let’s say they had a perfect genetic test that said that I was at an increased risk for type 2 diabetes.  Would it have changed my behavior?  I’m not sure but probably not.

I certainly wouldn’t have changed any of my behaviors when I was young.  I was invincible, remember?

Now that I’m a bit older, such a test might have influenced my behavior a bit.  I already knew about my risk because of my grandparents but my thought has always been that maybe I got lucky and didn’t inherit their tendencies towards diabetes.  But if they were tested and we shared the same genetic differences that led to type 2 diabetes, then I might be worried enough to change what I was doing.

Most likely though, my behavior modification wouldn’t be perfect.  What I’d probably do is keep watching TV and eating Twinkies but get my blood sugar tested more often.  Once I was headed for diabetes, then I’d modify my behavior and keep it at bay.  (I’m sure doctors scream into their pillows at night because of patients like me.)

This is different than some people’s reactions to other genetic tests.  For example, some women who find out they have the version of BRCA1 that greatly increases their chances of breast and ovarian cancer have a double mastectomy and/or a hysterectomy before there are any signs of cancer.

I might react much more strongly with a valid cancer genetic test.  Cancer is scary, nasty and not really reversible.  Type 2 diabetes is different.  You can start down the road, modify your behavior and then nip it in the bud.  Carpe diem and then pay the piper.

Are they related to me? I still don't know…

In my last blog post, I showed how the two most powerful ancestry tests, mitochondrial DNA (mtDNA) and Y chromosome, were useless to me in my hunt. Now I want look at the rest of my DNA.  So here we go!

The Y chromosome and mtDNA are a small fraction of my DNA—something like 0.8% of the total DNA in one of my cells.  But they are incredibly useful because they change very little from generation to generation.  The mtDNA I got from my mom is probably exactly like hers.  Same with most of the Y I got from my dad.

The other 99.2% of my DNA is a lot trickier to look at from an ancestry perspective because it has changed a lot from generation to generation over time.  For example, the chromosomes I inherited from my parents are not the same as the ones they have.  I got a mix of their chromosomes

For example, my mom had two copies of chromosome 1 (and two copies of her other 22 chromosomes too).   As you know, she passed one chromosome 1 to me (my dad gave me my other one).  But, through a process called recombination, her two copies of chromosome 1 swapped DNA so that I got a hybrid of her two copies.  I inherited a unique chromosome never before seen.

This is all well and good from a survival of the species point of view, but it is a problem for ancestry testing.  Imagine that instead of my mom, we look at my Cherokee great-great grandmother.  She has just had a child who inherited a mix of her chromosome 1’s.  This chromosome will look Native American and the child would appear half Native American.

Actually, the test isn’t perfect yet and so there isn’t yet a “Native American” set per se.  Instead, here is how 23andMe describes Native American DNA in their tests:

“…people who identify themselves as Native American exhibit fairly consistent Ancestry Painting proportions of about 75% Asian and 25% European, plus or minus 10%.”

This means the chromosomes the child got from his or her mom won’t look Native American but instead will look 75% Asian and 25% European.  (See a realted post of mine elsewhere for why it looks like this.) Now imagine that this half Native American child grows up and has my grandfather as his or her son.

My grandpa will inherit a mix of his parents’ DNA too.  In this case the Native American DNA will mix with the European DNA to create a hybrid.  On average, you would now see something along the lines of 37.5% Asian (this is a simplification but it gets us into the ballpark of the number we might expect).

Each generation would see, on average, a continued dilution of this Asian part.  My dad would have 18% Asian, I would have 9%, etc.  Here are my ancestry results (click the image to enlarge):

Not a hint of Asian.  Looks like my great-great grandma wasn't Cherokee.  Or was she?

There are lots of ways she could still be Cherokee.  First off, I don’t know how solid the 75% number is for all Native Americans.  I don’t know how many Native Americans are in their database.  I also don’t know how much variation there will be tribe to tribe.

Secondly, you may have noticed that I was very careful to always say, “on average.”  This is because the recombinations don’t have to be a 50-50 swap.  It is true that if you look at a large number of recombination events, the average will be 50%.  But individual recombination events can be biased towards one or more chromosomes.  Occasionally you’ll get mostly one chromosome and sometimes mostly the other.

Sort of like flipping a coin—do it enough and you’ll get pretty close to half heads and half tails.  But if you flip a coin twice, you might get one head and one tail.  And you might not.  Half the time you’ll get two heads or two tails.

This is less a problem than you might think with our chromosomes since the recombination is spread over 23 pairs with each pair being independent of the others.  But it can still throw a monkey wrench into the works.  23andMe actually has a nice chart that hints at this by giving the most likely range of possibilities.  Unfortunately, this chart didn’t come up with my results and I had to stumble on it while I was playing around.

Using the chart, I can see that the bottom end of my expected results in 0.24% “Native American” (if I am reading the chart correctly).  That is pretty low and it seems like a pretty minor mistaken assumption at the beginning might knock this down to zero.

So where am I after this?  Still in the dark.  This is actually how many genetic tests end up.

The positive result tells you a lot.  Had there been Native American DNA, that would have been a slam dunk.  (This isn’t always the case with genetic tests but it would be here.)  But there wasn’t.  Which means, given that I was on the edge of detection, that she may or may not have been Cherokee.

Now, this isn’t 23andMe’s fault.  The test itself couldn’t be conclusive given how far back we need to go and the DNA tests that 23andMe offers.  In fact, 23andMe does an excellent job of presenting the data.  There are pretty chromosome paintings, graphs superimposed on world maps, etc.  All very nice.

I am still worried that the explanations that go along with these images assume an awful lot of knowledge that most people might not have.  Without that knowledge, it can be hard to assess the significance of a certain result.  Next blog that’ll become even more important as I tackle health conditions.

When talking about genetic pre-disposition to a condition, make sure you understand both the increased risk factor and the general risk.

What I try to do in answering these questions is give them a feel for what the disease is, how genes are involved and then give them some links to some reliable websites on the topic.  I always try to emphasize that for a lot of diseases, genes are just one part of the story and that speaking with a genetic counselor in person might be a good idea.  I also warn them to look very carefully at the risk numbers.

Very often risks are given in how much more likely someone is to get a disease compared to the general public.  So, for example, if you have a brother or sister with schizophrenia, then you can be up to 9 times more likely to end up with the disease too.  Sounds like a scary number!  But it may not be…

If the general risk is 1 in a million, then 9 times is pretty insignificant.  It means that your risk is 1 in 110,000 or so.  This is worse than the chances of dating a supermodel (1 in 87,000) or of winning the lottery if you buy 50 tickets (1 in 77,000).  So if this were the case, a 9 fold increase means you still probably aren't getting the disease.

For schizophrenia, the general risk is 1 in 100.  This means that if you have a parent or sibling with the disease, your chances go up to about 1 in 11.  Unfortunately 9 times more likely looks pretty significant here…

Sometimes, though, a smaller risk can be even more significant.  For example, women who have a sister, mother, or daughter with breast cancer are twice as likely to develop breast cancer themselves.  Since about 12% of women will develop breast cancer in their lifetime, this means the risk is actually 24% or about 1 in 4.

So when investigating these sorts of risks, get both numbers.  You want to know what your increased risk is because a relative has the condition AND what the general risk is.  These two numbers together will give you a better feel for your chances.

An important note here is that these risks are averages.  Your actual chances will depend on the genes you have, how you live your life, etc..  For example, some of the women is the breast cancer example carry certain versions of the BRCA1 or BRCA2 gene.  These women are 5 times more likely to develop breast cancer pushes their risk to around 60%.

This is one of the many reasons why a sitdown with a genetic counselor is so useful.  Your risk depends on your specific situation and not an average risk you find on the internet.  A genetic counselor can take the time to carefully go over your family history and let you know what tests are available so you can better calculate your odds.

Shows like CSI can increase the public's awareness of genetics

They also give me a feel for what is going on with science in popular culture.  I can tell this by looking at Google Analytics data and seeing which of our previous answers has had an upsurge in visits.  (We post around one new answer online per week.)

For example, whenever PBS airs a show on how a mutation called CCR5-delta 32 may have made people resistant to the plague, I get an uptick in the hits on the answer that deals with that topic.  When House (a show on Fox) had a character say that of course someone was adopted because he had a cleft chin and his parents didn't, I got an uptick on the Chimeras start out as fraternal twins that fuse together at a very early stage.  What this means is that chimeras have two sets of DNA.  Some of their cells have the DNA from one twin and the rest of their cells have DNA from the other twin.

As you can imagine, these folks can wreak havoc with a police investigation!  What happened in the CSI episode was that the DNA from the crime scene did not match the DNA from the most likely suspect.  In the end we find out that the suspect is a chimera and that the evidence left behind at the crime scene had one set of DNA and that the blood they tested had a different set of DNA.  From the same person!

It is great that there is so much science starting to seep into popular culture.  If the science is accurate, it is a great way to get people involved in science.  I just wish it was accurate more often.

Credit: Deutsches Bundesarchiv (German Federal Archive)

And this is probably a good thing. I am not sure this is a road we want to go down– it smacks a bit too much of Hitler and a perfect race.

Of course, we've started down this road a ways already. We aren't able to shape anyone's DNA yet. We don't have the technology to do this in any safe or reliable way and frankly, it'll probably be a long time before we can.

But we can take a peek at an embryo's DNA if the egg has been fertilized outside of the body. The process is called preimplantation genetic diagnosis or PGD. Using PGD, scientists can look through a number of embryos' DNA and pick the one(s) the parents want.

Right now we can't scan all of an embryo's DNA. We have to pick and choose what part of the DNA to look at.

For example, PGD is often used to make sure that an embryo has all 46 chromosomes. This service increases the chances for a successful birth for women who are going through repeated miscarriages.

Of course, if we can look at the chromosomes, we can also tell whether the embryo is a boy or a girl. Often this is done to select for girls in families that carry male specific genetic diseases like Duchenne muscular dystrophy. But it is also done for the less life threatening goal of an even number of boys and girls in a family (gender balancing).

PGD can also be used to make sure an embryo did not inherit specific diseases like cystic fibrosis or sickle cell anemia that might run in the parents' families. These diseases can be screened for by looking for specific DNA differences in certain genes. Which is what this fertility clinic wanted to do for hair, skin and eye color genes.

Let's say a parent wants a redhead with brown eyes. The clinic would screen for certain versions of the HERC2 gene that mean brown eyes and certain versions of the MC1R gene that indicate red hair. When they found an embryo with the right combination of traits, then that embryo would be selected for implantation.

Remember, the people at the clinic can't change the DNA of the embryo. They can only sort through the genes that are already in the pool. So if one parent doesn't carry a red hair version of MC1R, then the parents can't have a red haired child.

Even without this ability, the furor over the fertility clinic's service raises a very important discussion point– where do we draw the line with PGD? And who should draw that line?

Obviously eye color is going too far (or is it?) and preventing an early death from a genetic disease is OK. But is it OK to look at gender for family balancing? This is allowed in the U.S. right now but is not permitted in most other countries.

What about conditions like high cholesterol? Or diseases that kill later in life like Huntington’s disease? Or traits like height, weight, or intelligence? Who gets to decide?

This former free living bacterium now supplies our cells
their energy.

The hijacked cell has over time become the mitochondrion. This organelle is responsible for making our energy. But it still has the marks of having once been a free living bacterium.

First off, mitochondria still have remnants of their old DNA. There isn’t much there in human mitochondria but there is enough to still get us into trouble. A big part of aging might be due to damage to this mitochondrial DNA (mtDNA). Some genetic diseases are also caused by mutations in mtDNA.

The DNA in mitochondria is also much more like bacterial DNA compared to the rest of our DNA. In fact, the mitochondrion has its own bacteria-like machinery for reading its DNA. This means that mitochondria can’t read the genes in our nucleus and vice versa. Mitochondria are so similar to bacteria that some antibiotics can damage them too.

Even though it was once free living, the mitochondrion doesn’t have a lot of its original DNA left. Over time, most of our mitochondrion’s original genes have traveled to the nucleus. These genes now work in the nucleus to make most of a mitochondrion’s proteins which are then transported back to the mitochondrion.

After all these years, human mtDNA is now only around 16,000 bases long and has only 37 genes left. This is a far cry from even the simplest of bacteria, Mycoplasma genitalium, with its 582,970 bases and 521 genes.

Humans are not unique in having mitochondria. Every plant, animal, and fungus cell in the world that has been looked at has mitochondria. But the DNA in these mitochondria is all wildly different.

The size of mtDNA can range from just 6000 base pairs all the way up to 2 million base pairs. Sometimes the mtDNA is a circle like ours. Sometimes it is spread out over lots of little circles. Sometimes it is one long, linear piece of DNA. Sometimes it is lots and lots of little pieces of linear DNA. And sometimes it is too weird to describe in a short blog like this.

Mitochondria from different species also have different numbers of genes. Some species have mitochondria with nearly 100 genes. While others have as few as 5.

With up to 2000 mitochondria/cell, evolution has had a free hand in tinkering with mtDNA. If a mutation or change in mtDNA causes a problem, that mitochondrion simply goes away. If there is some advantage to the new DNA structure, it is free to sweep through and take over. It is amazing what evolution has done to this bacterium!

Of course, evolution has made the mitochondrion a shell of what it once was. But we could argue that it is one of the most successful beasts ever.

It has gone from humble bacterium to being part of every eukaryote in the world. If humans die out, mitochondria will still be around somewhere else. Mitochondria will outlive us all.

More information on mitochondrial genomes: http://dx.doi.org/10.1016/j.tig.2003.10.012

Maybe a clone of this guy will wander the Earth one day.A new study shows that scientists can clone a mouse that has been dead and frozen for 16 years. If they can apply what they've learned to a mammoth that has been dead and frozen for over 10,000 years, then maybe my kids can ride a mammoth one day. Or at least my grandkids can.

You Need More than DNA to Clone

Cloning isn't as simple as was shown in Jurassic Park. You can't take DNA and make a clone from it. Instead, you need an intact nucleus. And ideally, an intact nucleus in an intact cell.

The nucleus is where DNA is kept in our cells. The DNA is stored and packaged there in a way that only Mother Nature can do (for now). We can’t take our 6 feet of DNA and cram it into the tiny space of the nucleus.

Cloning 101.As I said, right now cloning uses intact cells. Here's how it works:

1) Take a cell from the animal to be cloned
2) Remove the nucleus from an egg (this is called an enucleated egg)
3) Fuse the two cells and let it divide a few times in a Petri dish
4) Implant the growing embryo into a surrogate mother
5) If everything goes well, a clone is born

This procedure requires living intact cells to be used. The problem with a frozen animal cell is that it is dead and ice crystals have torn it apart. It is not possible to fuse a beat up dead cell with an enucleated egg.

Cloning Using Frozen Cells

What the researchers in this new study did was change the protocol a bit. Instead of fusing two cells, they harvested nuclei from the frozen cells and injected them directly into the enucleated egg.

When they tried to clone the mouse that had been frozen for 16 years this way, it didn't work. But they managed to get 4 clones by adding an extra step. What they did was to make embryonic stem (ES) cells from the frozen mouse and use those cells to make a clone.

Basically they cloned the mouse but then instead of putting the embryo into a surrogate mother, they harvested its ES cells. Then they used the nuclei from these cells to create a clone in the usual way.

So we can now clone a long frozen mouse. The next step will be to try to clone an extinct animal like a mammoth.

Cloning a Mammoth is Trickier than a Mouse

Mammoth cloning will be no walk in the park. First off, we don’t have any mammoth eggs or cells to use. We'll have to use elephant ones. Hopefully, elephant eggs and/or cells will be compatible with a mammoth's nucleus. ( But there is some concern they they might not be compatible.)

Second, elephants are a lot harder to work with than mice. The experiments in this study used thousands of eggs to get a few clones. I don’t know enough about elephant biology but it seems like you'd need a lot of elephants to get that many eggs.

But this is definitely the first step in resurrecting long dead animals. For now we'll have to focus on the frozen ones. Maybe in the future researchers can figure out how to clone animals stored in formaldehyde. Or from pelts. Then we can start reviving species we humans have managed to kill off over the years.

Having extra copies of certain genes helps fish live in Antarctica

What I like is learning how these beasts have adapted to their incredibly harsh environment. More specifically, what changes have happened in their DNA that allow them to live where no other animal could.

In this blog I'll focus on those poor fish living in the waters off Antarctica. These waters are icy cold and the fish aren't warm blooded. Which means their body temperature is the same as the water around them.

Most biological processes do terribly under these conditions. Proteins don't fold right, enzymes work incredibly slowly, fats glob up. It is astonishing that these fish survive at all.

Scientists figured out back in the 70's that these fish evolved a special antifreeze protein to keep their blood from freezing. Since then they've done other experiments that show other adaptations to the cold too.

In a new study, scientists from the University of Illinois and the Chinese Academy of Sciences decided to take a look at as many genes and as much of the DNA of these fish as they could. What they found was that lots of genes are turned up in these fish compared to relatives that live in warmer waters. And that many of these genes are turned on higher because the Antarctic fish have extra copies of them.

The genes they found that were different made sense. For example, there are a bunch of genes that make proteins called chaperones. Chaperones help other proteins fold up right. In this cold, proteins need all the help they can get!

Also they found that there were more of the proteins that scavenge reactive oxygen species (ROS) in these fish. This makes sense because colder water has more oxygen.

O2 is a pretty nasty molecule that tends to create even nastier chemicals (ROS) that beat up on DNA and proteins. We all have proteins whose job it is to defuse these chemicals. These fish make more of these proteins.

A few years ago it would have been surprising to find that the way these genes made more proteins was by duplicating themselves. Not anymore.

As we look closely at the DNA of various creatures, we are finding that gene duplications (and deletions) happen a lot. Even in people.

For example, people from cultures that eat a lot of starch have extra amylase genes. (This gene makes amylase, a protein that helps breakdown starch.) Some people are resistant to HIV (the virus that causes AIDS) because they have extra copies of the CCL3L1 gene. And so on.

Our DNA is much less stable than we thought. Which is one way we can better adapt to our surroundings. I can't wait to see what they learn about those tubeworms!