Mailund on the Internet

Yeah, I know I’m a day late with my list of the blog posts I found interesting during the week, but yesterday was my birthday and I didn’t spend it at the computer.

Human evolution

1. A burst of segmental duplications in the genome of the African great ape ancestor (Nature)
   1. Did burst of gene duplication set stage for human evolution? (Science Daily)
   2. A burst of DNA duplication in the ancestor of humans, chimps and gorillas (Not exactly rocket science)
   3. Is human uniqueness a matter of copy number? (Gene expression)
2. How diverse were early hominoids? (Greg Laden)

Neanderthal genome

1. Neanderthal DNA revealed (partially) on Darwin’s 200th birthday (Genome Canada blogs)
2. What makes us human? Neanderthal genome holds clues (Wired)
3. Neanderthal genome gets a first draft (Scientific blogging)

Teaching

1. The mystery of the $150 textbooks (Statistical modeling)
   1. The economics of textbooks (Me!)
   2. More on those $150 textbooks (Statistical modeling)
   3. Hey, nobody offered me $8000 (Statistical modeling)

Publishing

1. Impact factors and Physical Review Letters (Biocurious)
2. Hypocrisy inside open access journals (The secret microbe)

3. Commenting on scientific articles (Nascent)

4. Google Peer Review!? (A blog around the clock)

R Programming

1. Our new R package: R2jags (Statistical modeling)

2. Find information about R with Rseek.org (Revolutions)

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How do you calibrate the molecular clock — where you need a few known sequence divergence times — when you only know a few speciation times?

Yesterday at a meeting (I’m not sure I can tell you which meeting; I’m not sure how open it is supposed to be :-/) we discussed the divergence time of human-orangutan and human-macaque. We need the sequence divergence time to calibrate a CoalHMM model for figuring out some speciation and population genetics parameters of ancestral species.

No definitive answer came up at the meeting, but there was a short discussion by email after the meeting. This paper was sent around, where the divergence times were estimated to 25MYA and 13MYA, respectively, although the last of those numbers is actually the calibration point used in the analysis, so it is an assumption more than an estimate.

The problem is, the 13MYA used for the calibration is based on fossil evidence, and as far as I can see, that would make it an estimate for the speciation time between human and orangutan. We need the sequence divergence time. Speciation time and divergence time can vary with millions of years (if the effective population size is large enough).

If 13MYA is the divergence time between human and orangutan, we get a speciation time that is unrealistically recent.  If the divergence time is 18MYA instead, as we assumed in this paper, we would get a speciation time around 12MYA which would match the MBE paper.

But how do you figure out the divergence time needed to calibrate the clock?  Is there any way to get it, rather than the speciation time, from fossil evidence?

For our purposes, I suppose we can just as well work with speciation times for our calibration, but not everyone is using CoalHMMs for their analysis, so how do you deal with this problem?

Remember the “hobbits” (homo floresiensis)?

The debate over whether they are a separate branch of humans or not goes on.

• Fossil Science: Hobbits may be human after all
• John Hawks: Hobbit cretin FAQ

Yesterday I read the paper

Mapping human genetic ancestry I. Ebersberger et al.Molecular Biology and Evolution 2007 24(10):2266-2276

that addresses the same problem that we addressed in

Genomic relationships and speciation times of human, chimpanzee and gorilla infered from a coalescent hidden Markov model A. Hobolth et al.PLoS Genetics 2007 3(2): doi:10.1371/journal.pgen.0030007

although taking a different approach to the problem but using a lot more data.

Tracing the ancestry of the human genome

Human’s closest living relatives are the chimps and the closest relatives to human and chimps are the gorillas, but the species are so closely related that not all of the genome follows the species genealogy. Click on the figure on the right to get an illustration of this.The reason this happens is that as we trace the history of a piece of our DNA back in time, we will necessarily find the most recent common ancestor of humans and chimps further back in time than the speciation time of humans and chimps. If this time is so far back that it also precedes the speciation time of the human/chimp ancestor and the gorilla ancestor, then the most recent common ancestor of chimps and gorillas, or humans and gorillas, might be younger than the most recent common ancestor of all the species.Looking at the DNA of the three species we can infer the average time in the past where the DNA splits into the different species and using coalescent theory we can then infer the speciation times.In Hobolth et al. we approximated the coalescent process using a hidden Markov model which enabled us to efficiently analyse large alignments of DNA sequences and from this extract the parameters needed to infer speciation times, information about the diversity in ancestral species and to annotate the alignments with the most likely genealogy e.g. showing us in which part of our genome we are closer related to gorillas than to chimps.

We applied this to five large alignments, but covering only a small fraction of the entire genome.In Ebersberger et al. they construct a large number of (smaller) alignments covering the entire genome and consider the same problem in analysing this data.The statistical model they use is slightly less sophisticated than what we did, but that is probably more than compensated for by the much larger data-set. What they do is construct a single tree for each alignment, by picking the most likely phylogeny of all the possible, discarding alignments when there is no clear winner.They then use coalescent theory to infer the diversity of the ancestral species measured as the parameter N_e (effective population size) — essentially doing the same as we did — but as far as I understand they equate DNA divergence time with speciation time which strictly speaking is incorrect (I might be wrong here, I didn’t check in detail how they inferred the time interval between human/chimp divergence and their divergence from the gorilla).

A plot of diversity is shown on the bottom half of the figure on the right. Click to enlarge.

Their estimates of N_e are pretty close to ours (65,000 ± 30,000). This is pretty good news, considering that the results come about using different methods (although based on the same underlying theory).

However, the assumptions we put into the analysis differs. To calibrate the molecular clock in the analysis we both use the divergence time from the orangutan, but where we used 18 million years (Myr) ago they use 16Myr ago. The generation time is also very important in estimating the divergence and where we used 25 years as the average generation time they used 20 years. Our estimate of generation time is a bit on the high side — Ebersberger et al. calls unrealistically high — but we really had no idea what to use here when we did our analysis.

How much have these assumptions affected the results?

With help from Julien Dutheil — who has just re-written the entire CoalHMM software — I got the numbers our analysis would have obtained had we used the assumptions from Ebersberger et al. The human-chimp divergence we estimate is 5.1 Myr (as opposed to their 5.7) and the divergence with the gorilla we estimate to 8.4 Myr (as opposed to their 7.8). This is reasonably close enough to be the same. When we then estimate the speciation time — where the generation time assumption is important — we get 3.6Myr for the human/chimp speciation and 5.7 Myr for the (human/chimp)/gorilla speciation. These look very recent to me, and I don’t fully trust them. I have seen numbers around 4 Myr for the closest distance between human and chimp, but the fossil record just doesn’t match that.

For the N_e estimate, the new assumptions give us a whooping 81,000 for the human/chimp ancestor. I’m not really sure why. Using their assumptions moves us further from their estimates. This is probably worth looking into.

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Citations, for Research Blogging:Ebersberger, I., Galgoczy, P., Taudien, S., Taenzer, S., Platzer, M., von Haeseler, A. (2007). Mapping Human Genetic Ancestry. Molecular biology and evolution, 24(10), 2266-2276.Hobolth, A., Christensen, O.F., Mailund, T., Schierup, M.H. (2007). Genomic Relationships and Speciation Times of Human, Chimpanzee, and Gorilla Inferred from a Coalescent Hidden Markov Model. PLoS Genetics, 3(2), e7. DOI: 10.1371/journal.pgen.0030007

During some random surfing I stumbled upon these two blog posts:

• Did Gen Suwa just save paleoanthropology?
• Miocene hominids and a crisis of confidence

both by John Hawks.

I found these interesting not least because he refers to a paper that we published earlier this year:

Hobolth A, Christensen OF, Mailund T, Schierup MH. 2007. Genomic relationships and speciation times of human, chimpanzee, and gorilla inferred from a coalescent hidden Markov model. PLoS Genet 3:e7. doi:10.1371/journal.pgen.0030007

That paper was mainly on a new statistical method for analysing speciation. A method that combined comparative genomics with population genetics through a model that joined hidden Markov models with coalescence theory. Of course, that is not really what caught people’s attention. What we did in the paper was to apply our new method on data from human, gorrilla, chimp and orangutan, and one result that came out of that was a very recent split between human and chimp; a split only 4.1 million years old.

We get a very resent speciation split between human and apes exactly because of the combined population genetics and genomics. If we only look at the genomic sequences, the distance between these will necessarily be larger than the distance between the species — it takes a while from the time a piece of DNA is in the same individual until it is two different individuals in separate species — and our method is able to estimate the speciation split from the genome split.

I’m not sure how well I am explaining this here. I gave a (not too technical) talk in the computer science department some months ago, maybe that explains it better:

(sorry about the quality of the slides here, it looks like slideshare messed up the fonts)

A few other studies of genomic data before our own also reported more recent speciation times of human and chimp than previously believed — moving the time from about 6-8 million years ago down to maybe 4-5 million years ago — so a recent divergence between human and chimp might not be too far fetch after all, but still, I think our estimate is a bit too recent.

This is also what John Hawks writes.

Why do we get such a recent divergence, then?

It is hard to say. The 4.1 million years is what comes out of applying our method on the (admittedly small) data we had. It is a very new method, however. There is a lot we do not take into account in it and there might be biases in it we haven’t fully understood yet.

We are currently working on improving the method and once we get more data — the orangutan has already been sequenced and is now being assemblied and the gorilla genome is in the process of being sequenced — we will redo our analysis. It will be interesting to see how that turns out.