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Tuesday, August 26, 2008

More Neandertal mtDNA stuff...

Has anyone read Hawk's latest blog about Neandertal mtDNA? He answers some emailer's questions and goes on a long explanation.

His "Drift" section has me confused. If someone could read what Hawks wrote, and then maybe explain the concept to me like I'm a college freshman who barely understands this stuff, that would be excellent. Basically, I don't understand how his explanation shows that drift probably didn't happen. Instead it seems like a lot of mathematical mumbo-jumbo, ending with Hawks stating that "contamination" might just be proof that neandertals and humans shared DNA. I'm concerned because I'm not even sure which part of it I find confusing: the concept of drift, the population genetics involved, what mtDNA tells us, or all three!

His other explanations make sense, if I assume his Drift-stuff is true. Please help!

Saturday, August 9, 2008

Neandertal mtDNA genome sequenced

A neandertal mtDNA genome has been sequenced (Green et al. 2008), the specimen coming from the Croatian site of Vindija, some 38 kya. The paper’s verdict: “Neandertal mtDNA falls outside the range of variation of modern humans.” So though they don’t explicitly say it, it sounds like the conclusion is that, based on mtDNA, neandertals were a separate species from the humans that inhabit the globe today. Is this the end of the story? Hardly.

First, a technical note. The team used the “high-throughput 454 sequencing technique”, and since I am not a geneticist and could barely understand what the technique involves when I looked into it, all I can gather is that the method creates more sequence copies than traditional PCR (polymerase chain reaction). Perhaps a colleague can enlighten me and other readers on this technique? Also, the team took strong precautions that pretty much ensured that the sample wasn’t (significantly) contaminated with modern human mtDNA. Cool beans, the future today.

Anyway, what’s important is that this complete sequence (from a single individual) allows researchers to do whole mtDNA comparisons of neandertals with modern humans, to try to answer a riddle that is hotly debated in Paleoanthropology—whither Neandertals? Was there admixture between the archaic humans endemic to Eurasia (Neandertals) and the immigrating modern humans coming from Africa?

Now, in general I don’t care that much about neandertals. In my mind, they’re just a form of H. sapiens, albeit probably a homely form. But what I do care about (lately) are patterns of speciation in primates and human origins, so the question of modern-human-neandertal admixture is an interesting one to me. Green and colleagues inferred from the Vindija mtDNA that humans and neandertals were distinct (i.e. probably separate species)—a level of separation I don’t know I can agree with. When the team compared sequence differences between the neandertal and 53 modern humans from around the globe, they found that there are more differences between the neandertal and each human than there are between any pair of humans. This is in contrast to previous studies that looked only at the HRVI and HRVII regions of mtDNA, which found more overlap (less difference) between humans and neandertals. So this underscores the importance of using whole genomes for analysis, rather than a few genes.

Next the team estimated the human-neandertal divergence, assuming a molecular clock with a Homo-Pan divergence of 6-8 mya. This yielded a divergence date of 660,000 years, with the 95% confidence interval of 800,000 to 520,00 years. I suppose this is not too unreasonable. Some 600 kya is roughly the time when H. heidelbergensis is running around Europe and Africa. Their Homo-Pan divergence estimate is not so much to my liking, however. They based this estimate on the fossil record, 8 mya being based on the ~7 my-old Sahelanthropus tchadensis cranium and 6 mya based on the ~6 my-old Orrorin tugenensis material. I might have just stuck with the 6 mya divergence, because Sahelanthropus is not convincingly a hominin or “pre-hominin,” really it’s not convincingly anything but an ape. And 5-6 mya is when we start seeing fossils that really look like hominins, be it the Orrorin femora or the dental and mandibular fossils from E. Africa.

Now, as I asked before, is this the end of the story? No. For starters, this paper only looks at mtDNA, which is only maternally inherited. So we could deduce from this paper that perhaps no neandertal females interbred with modern humans. What will be more informative is a look at nuclear DNA—which the team hopes to have sequenced by the end of this year. Moreover, this single neandertal falls outside the range of variation of modern humans. There are several human mtDNA haplotypes—different lineages of mtDNA (again, I’m not a geneticist, so I don’t know how many or how different—a little help, anyone?). From this single individual we cannot get a good picture of neandertal mtDNA variation (haplotypes). Plausibly if we had more samples of mtDNA from archaic humans (are there any from any Upper Paleolithic modern humans?) we may well see the gap between humans and this neandertal bridged. Of course, on the other hand, we might not. So this paper demonstrates considerable difference between human and neandertal mtDNA, but the case is anything but closed.

Also, as paper commentator A. Clark noted, there are many genes in modern human nuclear DNA that appear to be over 1 my old (Clark 2008), and this may suggest that modern humans and archaic populations (including neandertals) may have interbred at least sporadically. He notes, “The long period of coexistence of modern humans and Neanderthals, as well as the great depth of common ancestry of modern human nuclear genes, make it quite plausible that there was opportunity for interbreeding . . . If there had been admixture, say 100,000 years ago, giving modern humans small segregating pieces of our genome with Neanderthal ancestry, it would be nearly impossible to identify them as such, even with full genome sequences.” When two populations intermingle, their offsprings’ genomes will not necessarily simply be a mix of ½ one parent, ½ the other. Rather, often only adaptive genes are able to ‘sneak’ into the other population’s gene pool—a phenomenon known as introgression. It looks like the human FOXP2 gene may well be an example of introgression, and in fact may have introgressed from an archaic population into modern humans (Coop et al. 2008). On an interesting aside, geneticist Chung-I Wu has formulated the “genic species concept,” in which species are formed when they can still interbreed and exchange genetic material, but adaptive regions are not exchanged; obviously this intriguing concept is also controversial (Noor 2002).

A final point to consider that didn’t come up in Green et al.’s paper is the growing body of evidence that human evolution is accelerating, and has been for the past 40 ky, but especially in the past 10-20 ky (Hawks et al. 2007). This is interesting as the neandertal specimen is 38 ky-old, and other neandertal DNA has come from even older specimens (Krause et al. 2007). I’m not sure at the moment how to interpret this in the context of mtDNA and recent sequencing of neandertal mtDNA. But it should be very important when the team (or someone else) analyzes ancient nuclear DNA, especially given that neandertals (arguably) 'disappeared' before human adaptive evolution really began to sprint.

This is an exciting time for anthropological genetics. Techniques are being developed for the extraction and analysis of ancient DNA, which will help shed light on the nature of the emergence of modern humans, and their interactions with archaic populations. At the same time, I am always wary of papers in genetics because of the numbers of assumptions/parameters required by their models.

Clark AG (2008) Genome Sequences from Extinct Relatives. Cell 134(3):388-389

Coop G, Bullaughey K, Luca F, Przeworski M (2008) The Timing of Selection at the Human FOXP2 Gene. Mol Biol Evol 25(7):1257-1259

Green RE, Malaspinas A-S, Krause J, Briggs AW, Johnson PLF, Uhler C, Meyer M, Good JM, Maricic T, Stenzel U, Prüfer K, Siebauer M, Burbano HA, Ronan M, Rothberg JM, Egholm M, Rudan P, Brajkovic D, Kucan Z, Gusic I, Wikström M, Laakkonen L, Kelso J, Slatkin M, Pääbo S (2008) A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing. Cell 134(3):416-426

Hawks J, Wang ET, Cochran GM, Harpending HC, Moyzis RK (2007) Recent acceleration of human adaptive evolution. Proceedings of the National Academy of Sciences 104(52):20753-20758

Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S (2007) The derived FOXP2 variant of modern humans was shared with neandertals. Current Biology 17

Noor MAF (2002) Is the biological species concept showing its age? Trends in Ecology & Evolution 17(4):153-154

Wednesday, August 6, 2008

Centigenarians

I love Nova. They had a special on "centigenarians," which are people who live easily to 90-100 years old. Specifically, they were looking at a group of genetically similar (same ethnic background) individuals who are all in the 90+ range but are still active, mobile, and in most cases look like they're in their 70's or younger (one looked like he was in his early 50s!).

But these old folks didn't reach that age by being health nuts. Oh no, one claims to have eaten "french fries every day," while another smoked for 46 years (he was the 101-year-old guy). So the show turned to scientists at Harvard and some other places to explain how this might be possible.

One group of scientists are studying a gene (Sir-something) that when activated or present (in multiples), will turn a low-calorie diet into a longer lifespan in yeast, flies, worms, mice, and other lab fodder. Another group of scientist found a gene that, when damaged, would also turn a low-cal diet into more years (well, days in the fly's timeframe). Why low cal? Well, they say that decreasing calories turns on the body's "survival mode" and these genes, which affect things like insulin production and high good cholesterol, are part of that.

This all caused one of the scientists (I think he was in the first group) to try a low-cal diet. Apparently to be affective, it has to be a diet 30% less than one is "needed" (the camera visual on this took a healthy layout of a day's food for a 2,000-calorie/day individual and turned it into two small sandwiches and a salad). The scientist says he lasted a week before deciding that this was not a way to live.

So now he's looking for a pharmaceutical way to get the body to respond with longevity without actually having to starve it. He says that the very optimistic view would have such a drug in production in 5-10 years! OK, so even if it takes them another 30 years to perfect this, we might be in a position to benefit from it still!

Apparently he's looking into the same stuff that is supposed to make red wine so healthy for you. Unfortunately, the segment ended with a note that for people to get the same longevity results from red wine as the lab rats did, they would have to consume 1,000 glasses of red wine a day! Now, I like red wine, but that's a bit extreme. I'm also not willing to starve myself, so I hope they come up with a pill form soon. It would be sweet to look like I'm 50 when I'm 101!

To quote the end of the show: "Please drink responsibly".