Genome comparison 101

Over at The Loom, Carl Zimmer tells us that a group of academics and a Conneticut biotech company are about to begin sequencing the Neandertal genome. Sequencing the Neandertal genome gets them all of the possible "Damn, that's cool!" points, but it's also got the potential to greatly increase our understanding of human evolution - particularly if it's the start of a project to sequence more ancient hominids.

Sequencing the Neandertal genome is one of those things that would have been pure science fiction just a couple of years ago. If they manage to pull this off, it will be an absolutely spectacular technical achievement. Sequencing ancient DNA is quite difficult. DNA degrades over time, even when preserved in bone or amber. The result is DNA that is extremely difficult to amplify using conventional techniques. The scientist who is heading up this effort, Svante Paabo, has been working with ancient DNA for years, and is one of the (if not the) most respected authorities on extracting, amplifying, and sequencing ancient DNA. His involvement in this project makes me much more willing to believe that it will work.

If it does work, it will probably do more to help us identify the areas of our genome that were critical to the development of modern humans. We've already sequenced chimps - our closest living relatives - and we've sequenced the human genome. Comparing those two genomes has already helped a great deal, but adding Homo neanderthalensis to the mix will make it much, much easier to figure out which of the differences between chimps and humans were important to the development of modern humans.

Here's why this one genome will would be such a big deal:

When we compare genomes, we see the similarities and differences between the two genomes. That's a no brainer, of course, but let's look at what the comparison tells us.

Hypothetically, let's say that we have these two sequences:

Chimp: ATTCAGCATCATAGGGAG
Human: ATTCAGCTTACTAGGGAG

By itself, that tells us relatively little. We know that the sequences differ between humans and chimps, but we don't know whether the change took place in the chimp lineage or in the human lineage. (Remember, the chimps didn't stop evolving after we went our separate ways.)

How can we figure out which lineage changed, and whether the change is likely to have been important to our development? We could try to study each of the differences individually, and figure out what if anything each of those changes does, but that would be labor intensive, expensive, and inefficient. Most of the changes probably didn't have a substantial effect, and in other cases it might be that it is the interaction of two (or more) changes that has had the biggest effect.

Additional genome comparison can help us identify which lineage changes occurred in. Let's add gorillas to our hypothetical:

Gorilla: GTTCAGCATACTAGGGAG
Chimp: ATTCAGCATCATAGGGAG
Human: ATTCAGCTTACTAGGGAG

That helps a bit. If we look at the two sites where chimps and humans differed, we can see that in one case, the chimp and gorilla sequences are the same and the human sequence is different while in the other case the human and gorilla sequences are the same, and the chimp sequence is different. The most likely explanation for these patterns would be that the first difference was caused by a mutation that took place in the human lineage after it diverged from the chimps, and the second was caused by a change that took place in the chimp lineage after it diverged from humans. (I also threw in a change in the first base position, where humans and chimps are the same and gorillas differ. That change could have taken place in either the gorilla lineage or in the chimp+human lineage. To figure out which, you'd need to add yet another sequence to the comparison.

Adding Neandertals to this mix gives us a lineage that falls in between chimps and humans. This is good, because it will let us identify areas in the genome that have changed in humans since we split from the Neandertals (about 400,000 years ago). Identifying those differences will greatly narrow down the areas of the genome that were critical to the development of modern humans, while identifying areas that are the same in humans and neandertals (but different in chimps) will help identify areas that may have been important earlier in human evolution.

All of this will be good, but it will be even more helpful if it is just the beginning of a broader program of paleogenomics. There are human remains that are contemporaneous with the Neandertals that are being sequenced. Adding those to the mix will help even more, particularly when it comes to identifying any areas in the genome that might have been under selection recently.

All in all, this particular genome project really looks like one that's worth following closely. Any results will definitely be interesting.

More like this

This week, Science published two papers about the genetics of Neandertals from a team of scientists based at the Max Planck Institute of Evolutionary Anthropology. The first (which is the only one anyone seems to really care about) gives a draft version of the entire Neandertal genome - a whopping…
Good news! The gorilla genome sequence was published in Nature last week, and adds to our body of knowledge about primate evolution. Here's the abstract: Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution.…
Well, some of you! And maybe me! Last year, scientists combed through Neanderthal and Denisovian DNA sequences (yeah, those exist!) and found fourteen ERVs that were in Neanderthals and/or Denisovians, but NOT humans. Neandertal and Denisovan retroviruses SUMMARY: Modern humans (Homo sapiens) last…
Comparing living chimpanzees to living humans, in reference to the species that gave rise to these two closely related species, is one way to frame questions about the evolution of each species. Generally, it is useful to address evolutionary questions by comparing two living species with the…

Since, as you say, sequencing ancient DNA is quite difficult, does that mean that there is no hope of ever being able to sequence any hominids older than Neandertals?

So does this mean that a billionaire will open up a theme park on some Costa Rican island with cloned homonids?

By Jeff Matzke (not verified) on 20 Jul 2006 #permalink

My question is if it's possible to sequence the genomes of older fossils? I'm assuming that the older a fossil is, the more the DNA degrades over time?

Sequencing has to have DNA available to work with, preferably uncontaminated by more recent (or bacterial/viral) cells.

The other problem, of course, is that that have to have *cells*. Mummified or frozen cells will do. Fossils, where the bone has been turned into stone, won't _have_ any cells, hence the need, in Jurassic Park, for "Amber" encased "fossils"...

By Jack C Lipton (not verified) on 05 Sep 2006 #permalink