Mitochondrial DNA, "Eve", and Bottlenecks

She's the mother of us all - literally!

I received several questions that can be answered here - who was "Mitochondrial Eve"? If she's the mother of all of us, who's the dad? What is a population bottleneck, and what does it have to do with this genetic mother person anyway?

First, let's explore the science of mitochondrial inheritance.

Recall from class that DNA can be found in two separate organelles in the cell: the nucleus and the mitochondria. Mitochondria are the cell's powerhouses - they produce energy that the cell uses to perform all of its functions. To produce energy, the mitochondrion must go by its own set of DNA instructions. This set of DNA, called mtDNA for short, never mixes with nuclear DNA, which instructs the cell to make proteins and other stuff. Why not? They are essentially two different "animals", two separate life entities. The mitochondria are basically little symbiotic organisms living within our cells - our cells give them a nice, protected place to stay, and the mitochondria provide energy.

Ok, so we have "alien" life forms in our cells, but what does that mean for inheritance? Does it work the same way for mtDNA as it does for nuclear DNA?

No.

You inherited half your nuclear DNA from mom, and half from dad. But your mtDNA all came from mom! How? Remember that eggs are much bigger than sperm. They have to be, because they have to take on all cellular functions after the sperm inject their DNA package. Sperm do have their own mitochondria (it takes energy to swim, after all!), but these mitochondria don't make it into the zygote. So the mitochondria and the DNA in them gets passed though mothers- you have mtDNA from your mother, she got hers from her mother, and so forth.

mtDNA - the Genetic Clock Darlings
Geneticists have a special place in their hearts for mtDNA because it is not under the same selective pressures as nuclear DNA, so it probably accumulates mutations at a constant rate that aren't subject to many selective forces. Plus, while each cell contains only one nucleus, a cell may have many mitochondria, so there are many times more copies of mtDNA per cell than nuclear DNA, which makes it easy to find and extract from a sample, even one thousands of years old! mtDNA has only a fraction of the genes that nuclear DNA has, so it's genome was easily mapped. Put all of this together, and you have the ingredients for a potentially very good molecular "clock" - get a close estimation of the mutation rate, look at mtDNA from people around the world, then work backwards.

Did we all really descend from one woman in Africa 200,000 years ago?
Seems like it. How is this possible? Actually, with a little bit of math and some logical thinking, it's not too hard to see. Remember set theory from middle school math? Imagine that the mothers of everyone on the planet today constitutes a set. Now imagine their mothers - a set that cannot be larger than the original, but must either equal the original or be less than the original set. Since many mothers have more than one kid, set two is smaller than set one. Keep going in this fashion, and we can eventually come up with a set with only one member in it - that mother is so-called Mitochondrial Eve. Her mtDNA was left in her descendants, and those daughters that survived long enough passed it on to their kids, and those daughters to their daughters, and so on. For a more involved discussion, look here.

The Bottleneck - A natural disaster, not a beer container!
This does not imply that the entire human population of the earth 200,000 ya consisted of one pregnant lady! It simply means that the other women around at the time did not leave enough daughters, or their daughters did not leave as many daughters, and (rinse, wash, repeat). What it does imply is that the human population probably experienced a bottleneck - some kind of natural happenstance that reduced the number of members of the population quickly and randomly. Think volcanic disaster or some other more or less random event. A population bottleneck reduces the number of individuals, and reduces genetic variation - but the reason why some alleles survive in the population and not others is simply due to random chance alone - not selective advantage.

Is there a mitochondrial "Adam"?
Not as such. Since mtDNA comes from eggs, we're talking ladies only in this line. But it is possible to look at the inheritance of the Y chromosome with respect to accumulation of mutations in a similar way. Indeed, researchers have already done this (aren't they clever?) and found a Y-Chromosome "Adam", if you will. What is really interesting is that the ancestor of all male humans lived only about 59,000 years ago - much more recently than Mitochondrial Eve!

Picture Swiped From:

http://citruscollege.com/apps/pub.asp?Q=842

Announcement: Student Question Extravaganza!

Last week, I tried something a little bit different: on the genetics exam, one of the bonus questions was "Ask me a question about genetics and anthropology that I can answer on my blog". Of course, the response was a bit overwhelming(!), but I hope to answer all the questions in the next week or so here on ramidus.

The Eating of the Blondes - genes, that is!

No, this isn't a post about cannibalism!
Genophagy - literally the "eating of genes", is a discredited notion that was popular at the dawn of genetic science in the early part of the 20th century. Back then, it was believed that the dominant alleles for any given trait would eventually overwhelm the recessive ones - the dominant genes would seem to "eat" the recessive ones right out of the population. What is interesting to me is that this idea never really seems to be put to rest, at least in the popular perception of how genetics works, which helps to explain why so many news outlets (and very credible ones at that!) picked up the hoax story a few years ago about blondes going extinct in the near future.

Why aren't blondes going extinct? Aren't dominant genes "stronger" and more widespread?
Not really. Dominant just means that the allele gets expressed in heterozygotes' phenotypes. What's usually going on at the cellular and molecular levels is that both alleles are getting translated, but the dominant allele's functional product is obvious in the phenotype, whereas the other gets "hidden". A good example of this is the ABO blood system. Recall that both A and B alleles are codominant, but both are dominant to the O allele. This is because the A and B alleles code for a fully formed, functional antigen, whereas the O allele codes for a shortened molecule that does not function as an antigen, basically because it's missing a piece. Thus, in heterozygotes with one O allele, the other allele is making antigens, while the O is making non-antigen molecules. Phenotypically, only the antigens count.

The genes behind hair color are somewhat similar. Like the eyes and skin, hair color is all about melanin. More melanin = darker hair. So blonde people, like blue-eyed people, have few melanocytes. So dark hair is dominant just because dark hair genes actually code for melanin to be produced in the hair.

Dominant genes do tend to be more widespread, but not always. Take the case of "milk allergies", which are not usually allergies at all (a true allergy is when the body's immune defenses activate in response to common, non-disease causing things like pollen or peanuts). Most people who are "allergic" to milk are actually intolerant of the milk sugar lactose because they have lost the ability to produce the enzyme lactase, which breaks it down (digests it). Almost everyone in the world can digest lactose from birth to about 2 years old, but most people lose the ability to product the enzyme sometime between ages 2-6. The gene that causes this (it's a regulatory gene that "switches off" the gene that makes lactase) is recessive. In some populations, many people have inherited a mutated version of this gene, which keeps lactase production going into adulthood. This gene is dominant to the "switch off" gene. So, if most people in the world are lactose intolerant as adults, most people in the world are homozygous recessive.


Hardy-Weinberg to the rescue!
Yes, these two mathematicians can help us understand why Blondes aren't going away anytime soon. Or, probably, ever. These two gents actually proposed their equilibrium model as a way to disprove the genophagy theory. In most populations most of the time, most allele frequencies are fairly stable over time. There are only a few factors that can shift them around, those 5 forces of evolution we've been talking about (natural selection, genetic drift, gene flow, mutation, and assortative mating).
What about our world population of people and the gene locus for hair color - are we evolving?
If so, which force or forces are at work?
For blonde people to be selected out of the population, they'd have to have fewer babies that nonblondes (hey, that sounds like the name of a band!) This could happen if blonde people were somehow less able to have kids (blonde genes somehow related to problems with reproductive organs, perhaps?), if blonde people were less able to avoid predation (blondes more easily detected by bears?), if blondes tended to die before reaching child-bearing age (blonde hair = leukemia?) and so forth. Of course, none of my proposals above is really happening.
What about assortative mating - do gentlemen (or gentlewomen!) prefer blondes? If this were true, then we can imaging that blondes might have even greater reproductive success than other hair colors, thus increasing the blonde genes in the population!

At any rate, I don't think blondes are going anywhere anytime soon.

Are blondes on the fast track to extinction?

No.

More on this later!

What causes two different colored eyes?

In the context of discussing pedigrees, some great questions were asked in class concerning the inheritance of eye color: "Why do some people's eyes change color?" "Why is it common for some dogs to have two different colored eyes - one blue, one brown?" and "What are the genes that code for eye color anyway?"



Let's start with the basic genetics first. Color in your body, regardless of whether it's in the skin, hair, or eyes, is caused by the production of melanin. Melanin is a dark pigment produced by special cells called melanocytes. Within these cells are special organelles that actually product the melanin. What determines color is not how many of these organelles are present, but rather their activity levels. With the exception of albinos (people who have inherited two faulty copies of the genes for melanin production), we all have melanin producing cells, but some produce more melanin than others, resulting in darker hair, eyes, or skin.



Genetics of Eye Color

Eye color isn't a simple one-gene-locus-two-allele system like the conditions we've been discussion so far. In fact, scientists aren't entirely sure which genes are involved in eye color, but a recent paper just published seems to have located one gene that may be involved in making eyes blue or brown (called OCA2). There is almost certainly another gene that codes for green or blue eyes (called gey). What do these genes do? They tell the cells in the stroma of the iris (the part that actually has color!) to make melanin. If the OCA2 gene is working properly, lots of melanin is made, and you get brown eyes. If you have one working OCA2 gene and one broken gene, melanin still gets made. It takes inheriting two nonworking copies of OCA2 to get blue eyes. It appears that this mutation causing improperly functioning OCA2 probably popped up in a person living about 6-10,000 years ago.

But wait, what about green eyes? Well, we have to take into account what's going on with that gey gene too. It probably works like this: Let B = functional OCA2, and b = nonfunctional OCA2. Let G = functional gey, and b = nonfunctional gey. Remember, G makes eyes green. The two genes work together to produce pigments for the eyes. Take a look at how this is likely to occur with the table below relating genotypes to phenotypes.

BB bb = Brown
BB Gb = Brown
BB GG = Brown
Bb bb = Brown
Bb Gb = Brown
Bb GG = Brown
bb GG = Green
bb Gb = Green
bb bb = Blue

Notice that both B and G are dominant to b, but B is dominant to G. (See this post from Ask a Geneticist for more about how this works).

How to get two different colored irisis (Heterochromia Iridis)
Having two differently colored eyes is fairly rare in humans (there are a few famous cases, like David Bowie and Keiffer Sutherland), but more common in dogs and cats. How does this happen? Basically, something goes wrong and one iris does not get the "signal" to turn its melanin production on. Trauma is a pretty common cause for this - which accounts for David Bowie's heterochromia (he was hit in a fight). So the genes are still there, they just aren't getting the signals to function anymore. If trauma occurs during development, the specialized pigment cells, melanocytes, may die off and not be replaced.

Another way is to have a condition which prevents the melanocytes from migrating to the right place. Waardenburg's is a well known condition in which this happens. There are 4 genes responsible for this syndrom, and they control for development of the face and ears, among other things. If these genes aren't functioning properly, melanocytes that are produced in the fetus don't get the proper directions to migrate into the eyes, or even into hair follicles. People with this condition also usually have a lock of white hair and hearing loss. It turns out that because of inbreeding in dogs, Waardenburg's is fairly common, hence the typical association of different colored eyes and hearing loss in dogs.

Last, but perhaps most intriguing, is the possibility that one has two different functioning genes in each eye. There are two ways this can happen: Mosaicism and Chimerism. I had guessed in class that mosaicism may be responsible: this is when a gene mutates (a mistake occurs during DNA replication) early on in development. All the mitotic daughter cells of that mutated cell will also contain the mutation, but other cells will still have the normal gene. Hence, the body contains a "mosaic" of cells with normal genes and with mutated genes. Sounds weird, but it's extremely common - in fact, we're all mosaics! Our body has trillions of cells, and every time they divide, there's a chance for mistakes in replication. Some environmental factors can actually cause mutations, like sunlight or chemicals. But even so, mutations are pretty rare, and there'd be only a few mutated cells in your body at any one time.

Chimerism is really fascinating, and pretty rare: this is when the cells of two different people fuse! So a chimera is actually two people's DNA in one body! How can this occur? If a mother releases two eggs instead of one at a time, and both are fertilized by dad's sperm, you normally get two different people developing - fraternal twins. Occasionally, those two fertilized eggs (zygotes) will fuse into one, but both sets of DNA are still there. Because this happens so early in development, for the most part, the slight differences in DNA won't cause big differences in the person's body parts (one leg won't be significantly longer than the other!) since the cells are being coordinated with the same signals. A very famous case involving chimerism and paternity disputes can be read here.

For more information, try these:

about heterochromia iridis: http://www.thetech.org/genetics/ask.php?id=226

OCA2 in the news: http://www.msnbc.msn.com/id/22934464/wid/11915773

Mosaicism and Chimerism: http://www.thetech.org/genetics/ask.php?id=172

Sex, Gender, Identity, and Diversity

There never seems to be enough time during class to discuss some of the really interesting aspects of genetics, but now with *internet technology* (cue cheesy trumpet fanfare) we can continue the conversation outside of class!

Diversity
One of the reasons why I went into anthropology in the first place was because I've always been fascinated by the conundrum of humanity's great diversity and unity, how we can find connections with each other despite having so many differences. This is, I think, the best place from which to launch into a discussion of one of the most important aspects of our diversity: Sex and Gender.

First, to recap my earlier post on sex: sex is a biological category, while gender is a social construct. How do biologists define male and female? Simple: whoever makes the smaller gametes is male, and whoever makes the larger gametes is female. In complex organisms like mammals, there are all sorts of body parts whose job it is to help the two kinds of gametes meet up, and being mammals ourselves, we're pretty familiar with and usually very interested in these bits of ourselves and others (the first question everyone asks a new mom -"Is it a boy or a girl?"). But because we humans have complex societies as part of our developmental environment, we tend to associate certain modes of behavior (frequently learned behaviors) and dress with one's sex, so it's easily identify our roles in society. Gender is this social identity, which may or may not be based on one's "plumbing", as it were. See my discussion below of societies where having 3 genders is normal.

Biological Diversity: Intersex Conditions
I found this website to be very helpful and interesting:

http://www.isna.org/faq/what_is_intersex

The ISNA is the "Intersex Society of North America", a group for individuals who anatomically do not fit neatly into the categories of "male" or "female". According to their homepage,
"Our Mission:
The Intersex Society of North America (ISNA) is devoted to systemic change to end shame, secrecy, and unwanted genital surgeries for people born with an anatomy that someone decided is not standard for male or female."

As you probably know, the common thing in Western European-North American culture is that our sexual and gender categories overlap, and male and female are somewhat rigidly defined. Have a penis and testes? You're male. Have a vagina? You're female. But here's the really interesting thing: if there's potential for variability, there will be variability, and plumbing is not immune from this. So yes, there are people born with clitorises that are longer than average, penises that are shorter than average, scrotums that may be divided in such a way as to resemble labia, vaginas but no uteruses, and so on. Development is a complicated thing, after all! Before you were born, you had parts that were precursors for both male and female plumbing. In a sense, we were all "hermaphrodites" at a certain stage of development, because it isn't until 9 weeks after conception that the genitals begin to differentiate.

This is a great topic, but a huge one - I could fill pages with this discussion, but I want to hear from you: what do you folks think?

Question: What causes hermaphrodism?

I was asked this question in class the other day, and did not know the answer. So I looked it up, because it's really interesting to me to learn about genetic anomalies and issues related to sexual identity.
Google found me this link:
http://www.emedicine.com/ped/topic1492.htm

First of all, there are apparently many kinds of intersex conditions. Having a complete set of both male and female bits is one of a range of five similar conditions.
Here's an interesting quote from the site:

The internal ducts and external genitalia may vary in development, since
the presence of apparently male or female gonads does not necessarily correlate
with the patient's gender identity.

What does this mean?

Let's step back and look at this not through medical eyes, but through anthropological eyes. What can anthropology tell us about what makes men, men and women, women?

There is a distinction between sex and gender in science, and this is important. Sex is your plumbing, which is usually related to what set of sex chromosomes you've inherited, while gender is a social identity. While there are normally two basic biological sexes (remember - males are definied by being the ones with smaller gametes!), any culture can create as many categories of gender as they need. In Native North American cultures, there are frequently three genders: male, female, and two-spirit. A two-spirit individual may (often) have male plumbing, but will identify in all other ways as a woman, or the other way around - female plumbing, male clothes and behavior patterns.

And this is just the simple part.

What about those people who have bits of both sex's plumbing?

These individuals are commonly labeled "intersex". But plumbing is only part of an individual's overal gender identity. The mind, the behavior patterns, all of these are as important, if not more important, than the actual ducts and pipes a person is born with.

What do you think?