Serial founder effects, again

5 minute read

A flush of papers this week (two today in Nature, one tomorrow in Science) describe new analyses of SNPs across the genome. Two of the papers sample SNPs in global samples numbering more than 500 individuals.

This Reuters story by Maggie Fox is typical of the press coverage:

Gene studies confirm 'out of Africa' theories
WASHINGTON - Two big genetic studies confirm theories that modern humans evolved in Africa and then migrated through Europe and Asia to reach the Pacific and Americas.
The studies, published in the journal Nature on Wednesday, paint a picture of a population of humans migrating off the African continent, and then shrinking at some point because of unknown adversity.
Later populations grew and spread from this smaller genetic pool of founder ancestors -- a phenomenon known as a bottleneck.

These studies have very, very exciting potential. Here in my lab, we will be immediately using the data from these papers to test hypotheses about recent human evolution.

But it is beyond me to understand why anyone thinks that the "serial founder effect" story is news!

For one thing, the idea is based on 12-year-old research demonstrating that human diversity declines for some genetic loci with distance from Africa. This observation was replicated for genome-wide STR loci in a well-publicized paper three years ago. This paper clearly demonstrated how a model involving a chain of bottlenecks could result in a cline of diversity -- one population leaving Africa, a small group from this population moving to Jordan, another small group moving from Jordan to Mesopotamia, another small group from Mesopotamia to the Zagros, etc.

In other words, there's nothing new here. It's no surprise that genome-wide SNPs and copy-number variants (CNVs) should replicate the pattern already shown for genome-wide STRs.

What's worse, all these papers from the Stanford school of genetic orthodoxy fail to even test the hypothesis! I pointed out this problem three years ago:

The data that the paper attempts to explain are (1) the correlation of genetic distance and geographic distance among human populations, and (2) the decrease in genetic diversity in populations farther from Africa. We may ask, what other hypotheses would explain the same data? And what kind of evidence could test these hypotheses, instead of just asserting that they "match" the pattern of evidence.
One scenario that matches the evidence is multiregional evolution with a recent African dispersal of some adaptive genes. This is the hypothesis presented by Eswaran (2002). The idea is that human populations interacted for a long time in Africa and Eurasia, and that during the Late Pleistocene, adaptive changes within Africa allowed those populations to spread alleles into existing populations in Eurasia. The strength of the "founder effect" in this scenario depends on the genetic structure and selective advantage of the new African adaptive complex. Ramachandran et al (2005) actually cite Eswaran (2002) as an example of a serial founder effect. So the idea that there was widespread genetic movement out of Africa does not necessarily imply an out-of-Africa population replacement. The data do not require a replacement, and some -- even many -- of the genetic variants outside of Africa may have nothing to do with recent genetic movement out of Africa.
A second hypothesis is presented by Templeton (2002), who proposed that several founder effects happened at different times in the Pleistocene, each carrying one or more genetic variants out of Africa. The pattern of genetic variation appears to indicate that some genes left Africa during the Lower or Middle Pleistocene, while others dispersed later, during the Late Pleistocene. For Templeton (2002), this pattern indicates multiple dispersals, none of which was sufficient to wipe out the genetic contribution of earlier dispersals. This scenario also would lead to a pattern of correlation of genetic and geographic distance (because most genes have been affected by isolation-by-distance for a long time), while the recurrent dispersals would explain the decline in genetic variation outside of Africa.
A third hypothesis is that population size was simply greater within Africa than within Eurasia. The smaller population size (along with isolation-by-distance) would explain the difference in genetic variation; the correlation of genetic and geographic distance would be explained by isolation-by-distance. We may consider a fourth hypothesis also: that natural selection has tended to create slightly more genetic uniformity within Eurasia and slightly more genetic diversification in Africa. Such a scenario might be justified on ecological grounds: African populations cover a wider range of ecologies and have historically had a greater exposure to zoonotic disease, for example.
Except for the serial founder effect with population replacement, none of the other hypotheses are mutually exclusive. In other words, some genes might have been influenced by natural selection, most might have been somewhat influenced by differences in population size, but the largest effect might have been recurrent population dispersals.

Reading over the whole post, I think it did a good job of laying out the situation with serial founder effects in 2005, and there is little reason to change it now. Still nobody has tested the model! Again, this is a case of science by consistency -- the results of simulations generate the same kind of correlations as the observed data, so the authors claim support for their hypothesis.

But the necessary test should be carried out by dating haplotypes, finding the ages of "founder mutations" and eliminating the possibility of introgression from ancestral Eurasian populations. One of the key points in my earlier post is that the model proposed by Eswaran (2002) would generate exactly the distribution expected for serial founder effects -- despite the fact that it describes a wave of genetic change within an already-established pan-Old-World population.

This study doesn't support an out-of-Africa migration; it merely assumes it. Now, I'm one who thinks that there was an important trend of strong gene flow out of Africa in the Late Pleistocene. But data showing a correlation between diversity and distance from Africa just cannot show the critically important facts about the timing and magnitude of such gene flow.

Somebody will eventually straighten all this out. What I wonder is why it never seems to be the reviewers!


Jakobsson M and 23 others. 2008. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998-1003. doi:10.1038/nature06742

Eswaran V, Harpending H, Rogers AR. 2005. Genomics refutes an exclusively African origin of humans. J Hum Evol 49:1-154.

Ramachandran S, Deshpande O, Roseman CC, Rosenberg NA, Feldman MW, Cavalli-Sforza LL. 2005. Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc Nat Acad Sci USA 102:15942-15947.

Templeton AR. 1998. Human races: a genetic and evolutionary perspective. Am Anthropol 100:632-650.

Templeton AR. 2002. Out of Africa again and again. Nature 416:45-51.