introgression

I'm going to point to Rex Dalton's piece today with relatively little comment:

"Neanderthals may have interbred with humans"

Genetic data points to ancient liaisons between species.

The researchers arrived at that conclusion by studying genetic data from 1,983 individuals from 99 populations in Africa, Europe, Asia, Oceania and the Americas. Sarah Joyce, a doctoral student working with Long, analyzed 614 microsatellite positions, which are sections of the genome that can be used like fingerprints. She then created an evolutionary tree to explain the observed genetic variation in microsatellites. The best way to explain that variation was if there were two periods of interbreeding between humans and an archaic species, such as Homo neanderthalensis or H. heidelbergensis.

I understand that there is more to come on this subject in the not-too-distant future, and in this case I don't have anything on paper to go on. As everybody knows, I very much expected to find a similar result. Besides that, others have published similar outcomes based on resequencing data.

I titled the post, "Multiregional evolution lives," for a reason -- this study and others have been looking at genome-wide evidence of interbreeding outside of Africa. It's a multiregional model. Even I haven't been talking about levels of interaction as high as they are outlining in these models -- here they're looking at a genome-wide effect on neutral genetic loci, something you're not going to pick up significantly with today's samples unless it amounted to more than a couple percent of the human gene pool.

These ongoing studies are concluding that present-day genetic variation is inconsistent with a simple model where a random-mating ancestral population gives rise to today's global population by means of a staged out-of-Africa dispersal. They next look at a model with some substantial (possibly complete) isolation between ancient human populations followed by a subsequent out-of-Africa dispersal. They show that this model fits the data significantly better.

So far, so good.

For a moment, I'm going to adopt a critical perspective. Previous results haven't yet been able to answer an important possible question: Can they distinguish the effects of intermixture outside Africa from an ancient population structure inside Africa? Increasingly it looks like population structure inside Africa may have been very important to the evolution of Late Pleistocene Africans. How can we distinguish these kinds of structure from each other?

The short answer is that maybe we can't, yet. Human population history was not simple. If we take a simple model and add more parameters, it will fit the data better. The question is whether there may be some even better model with the same number of parameters. Population structure within Africa, selection on some loci but not others, asymmetrical migration -- all these and more might be possible.

I take it as very likely that the strict out-of-Africa replacement without interbreeding is no longer credible. We've moved beyond it, and all these papers are testaments to that. They're valuable.

But there's a lot of work left ahead of us, finding better models and continuing to test them with the increasing body of human (and ancient) genetic data. There's an awful lot up for grabs. Were Neandertals really a different species, a subspecies, or what? How genetically distinct were the groups within Africa that gave rise to the Middle Stone Age? Was there time for all recent humans to get Neandertal genes (as Jeff Long suggests in Dalton's story), or do some have a lot more than others?

As Dalton's story notes, soon we'll have the Neandertal genome, which will give an additional perspective on this issue from a point 40,000 years in the past -- like an eyewitness at the scene. This year, we'll begin to see whole-genome data applied to these questions. There may be other ancient genomes that will surprise us. And maybe those of us on the population genetics side still have a trick or two up our sleeves.

(Thanks to readers who forwarded this link!)

Today I was looking through the online data files for the South African genome. Those online files are available from the Data Libraries entry of the Galaxy bioinformatics tool website.

I noted last week that some of the most interesting data -- in particular, the genotypes for new SNPs -- are not yet available to download ("Online toolkits -- the good and the frustrating"). But in the meantime there are some very interesting things there. In particular, the sequencing team has made available a list of amino-acid-coding mutations present in one or more of the five individuals (four Bushmen and Desmond Tutu) for whom the team obtained exome sequence.

If you look at the summary information for this list, it gives the position of amino-acid-coding mutations against the human reference genome (hg18), the position and identity of the amino acid change. It then gives a "prediction" of whether the mutation is damaging to gene function.

This kind of prediction can be very misleading. The categories of effects include "tolerated" and "damaging", but these are based on whether the site tends to be conserved in other mammal lineages, and whether the new amino acid is very different in affinity (and possible conformation) compared to the reference. There's no "beneficial" -- even though some fraction of these polymorphisms are probably retained because of selection on the mutant allele.

I say that because one of the five individuals (TK1) has an amino-acid-coding mutation in FOXP2.

Yeah, that surprised me when I found it.

As you'll remember the coding sequence of FOXP2 is pretty strongly conserved in other mammals. Two amino-acid-coding substitutions in humans separate us from other primates, an additional one separates primates from the mouse genome (Enard et al. 2002). This area of the genome looks like it had undergone a recent sweep in human populations, with relatively little variation and a strong excess of rare mutations surrounding the gene. Coop and colleagues (2008) gave a point estimate of the time of a sweep in humans as 42,000 years ago, which I wrote about at the time ("FOXP2 is really recent, it really did introgress (if it's not contamination)"). That estimate has to be massively too young -- it's not plausible that a sweep could be that recent and fixed worldwide.

Meanwhile, last year, Ptak and colleagues (2009) followed up on my suggestion that there might really have been a recent sweep, but one near FOXP2, instead of involving one of the two human amino acid substitutions. They found statistical linkage between flanking sites immediately around the gene, which would be unlikely after a fixed sweep of FOXP2 itself. That linkage is quite likely if the human-specific substitutions were already fixed, and much later another nearby site underwent a partial sweep. It remains to be demonstrated, however, what nearby site is a plausible candidate for a recent partial sweep.

So, finding variations near FOXP2 is very relevant to the history of this gene region. If there is an ongoing sweep involving some site near the gene, we should expect that some human populations haven't undergone the sweep yet, or have the selected haplotype at a lower frequency than others. The existing datasets from Africa -- mainly HapMap and HGDP sets -- are insufficient to test the hypothesis because they include only common SNP variants at low density. But sequence data from South Africa can give us a direct estimate of the nucleotide diversity around FOXP2, thereby letting us test for the presence of a recent sweep.

The amino acid coding variant in one of these Bushman genomes came to me as a total surprise. Using the alignment with hg18, the location of the mutation is at position 114089380 on chromosome 7. The mutation changes a leucine in the wild-type sequence to a proline in the mutant, and the algorithm classifies it as "damaging" -- probably because the two residues are very different in their hydropathy. This position is not one of the two human-specific amino acid substitution sites. In fact it is in the forkhead box domain of the protein itself, which is the DNA-binding motif. Without going further into the biochemistry, I really can't guess what the effect of the mutation would be. I'm not really sure it's relevant -- after all, if it is a singleton in the population it might well be a recessive with no effect on the carrier phenotype.

Still, the mutation could be common in the Bushman population. Our point estimate of the mutation's frequency is one in eight. Maybe it's a new variant that confers some advantage; maybe it's a result of a founder effect tens of thousands of years ago. It could even be widespread within Africa. We won't know until we have more genomes.

The mutation is not in any of the regions sequenced by Krause and colleagues (2007) in the Neandertals from El Sidrón. I wouldn't expect it to be there -- as a derived variant, it would be unlikely to evolve in parallel in Neandertals and southern African populations. But who knows what else we'll find?

References:

Coop G, Bullaughey K, Luca F, Przeworski M. 2008. The timing of selection at the human FOXP2 gene. Mol Biol Evol 25:1257. doi:10.1093/molbev/msn091

Ptak S, Enard W, Wiebe V, Hellmann I, Krause J, Lachmann M, P&aauml;&aauml;bo S. 2009. Linkage disequilibrium extends across putative selected sites in FOXP2. Mol Biol Evol 26:2181-2184. doi:10.1093/molbev/msp143

Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Bertranpetit J, Hänni C, Fortea J, de la Rasilla M, Rosas A, Pääbo S. 2007. The derived FoxP2 variant of modern humans was shared with Neandertals. Curr Biol 17:1-5. doi:10.1016/j.cub.2007.10.008

Enard W, Przeworski M, Fisher SE, Lai CSL, Wiebe V, Kitano T, Monaco AP, P&aauml;&aauml;bo S. 2002. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418:869-872. doi:10.1038/nature01025

Schuster SC and many others. 2010. Complete Khoisan and Bantu genomes from southern Africa. Nature 463:943-947. doi:10.1038/nature08795