Razib Khan One-stop-shopping for all of my content

January 16, 2012

The milkmen

Dienekes and Maju have both commented on a new paper which looked at the likelihood of lactase persistence in Neolithic remains from Spain, but I thought I would comment on it as well. The paper is: Low prevalence of lactase persistence in Neolithic South-West Europe. The location is on the fringes of the modern Basque country, while the time frame is ~3000 BC. Table 3 shows the major result:

Lactase persistence is a dominant trait. That means any individual with at least one copy of the T allele is persistent. As Maju noted a peculiarity here is that the genotypes are not in Hardy-Weinberg Equilibrium. Specifically, there are an excess of homozygotes. Using the SJAPL location as a potentially random mating scenario you should expect ~7 T/C genotypes, not 2. Interestingly the persistent individual in the Longar location also a homozygote.

HWE makes a few assumptions. For example, no selection, migration, mutation, or assortative mating. Deviation from HWE is suggestive of one of these dynamics. The sample size here is small, but the deviation is not to be dismissed. Recall that lactase persistence has dominant inheritance patterns. If the trait was being positively selected for you would only need one copy. The enrichment of homozygotes is unexpected if selection in situ is occurring here. It can not be ruled out that one is observing the admixture of two distinct populations. One generation of random mating would generate HWE, but when populations hybridize in realistic scenarios this is not always a plausible assumption. Rather, assortative mating often persists over the generations, slowing down the diminishing of population substructure.

Stepping back from speculation in this case what can we say? First, the LCT locus has a large mutational target. The trait of lactase persistence has arisen multiple times via different mutational events across the Old World. But, there does seem to be one particular variant which is found from Spain to Northern India. There is some circumstantial evidence that the allele had its origin somewhere in Central Eurasia, but currently its modal frequency is in Northern Europe, Scandinavia and Germany. The region in the genome around this mutation is characterized by a very long haplotype. It is one of the most definitive loci as a candidate for natural selection in the human genome. There is now a fair amount of ancient DNA evidence that lactase persistence in Europe is a feature of the last ~5,000 years or so. Among the modern Basques the frequency of the allele is 66 percent.

For me the key issue is teasing apart the role of migration and selection in each specific case. It does not seem to be correct that the frequency of the -13910T LCT allele in Basques and Punjabis is reflective of the frequency of recent common ancestry. That implies that natural selection is at work at this locus. On the other hand, the haplotype which is present in both the Basque and Punjabis is likely to be descended from a common set of individuals, implying that there is a genealogical chain connecting these two very distinct and distant Eurasian populations. Therefore, we can potentially make some inferences about the power of migration in spreading distinctive alleles. Often we partition selection from genealogical information, because selection so often serves to distort the signal. But the genealogical patterns may lay at the heart of the distribution of different natural selective events at the LCT locus.

Overall, I would say that the results from ancient DNA are disordering and clouding simple elegant models. One hopes and presumes that as sample sizes increase in this domain we’ll start to see more clarity as new paradigms crystallize.

Citation: European Journal of Human Genetics, 10.1038/ejhg.2011.254

September 8, 2011

The gift of the gopi

Krishna with milk-maids Unlike in some Asian societies dairy products are relatively well known in South Asia. Apparently at some point my paternal grandmother’s family operated a milk production business. This is notable because Bengal is not quite the land of pastoralists. In much of North India milk and milk-products loom larger, in particular ghee. [...]

April 1, 2010

Ancient “Swedes” were “lactose intolerant”

Filed under: Culture,Genetics,lactase persistence,LCT — Razib Khan @ 5:26 am

ResearchBlogging.orgMy recent focus on the lack of genetic continuity between hunter-gatherer and farming populations genetically and culturally is primarily due to the fact that we’re not in theory-land; the extraction of ancient DNA samples is steady-as-it-goes and is sharpening and overturning our understanding of the past. The relationship between culture and genetics is of particular importance in this case, genes serve not only as markers which we can track population movements, but genes themselves are embedded in dynamics which need not be connected to population movements.

Consider lactase persistence, which confers the ability to digest milk as an adult. In the 20th century “lactose intolerance” was assumed to be a pathology, but it turns out that most human populations can not digest milk sugar as adults due to the lack of production of the lactase enzyme. This is the ancestral type. Rather, different mutations which result in the persistence of lactase production into adulthood seem to have arisen independently in several regions of western Eurasia and Africa. This suggests that the mutational target zone here is large, that is, given particular selection pressures (cattle culture) mutants will arise in the background and increase in frequency which produce the phenotype of lactase persistence.

The region of the world where lactase persistence is at highest frequency and greatest extent is northern Europe. It turns out that the region around LCT, the locus functionally implicated in variance of the trait of lactase persistence, has an enormous region of linkage disequilibrium around it. In other words, recombination hasn’t chopped up correlations of genetic variants along DNA strands. As you know this implies several possible evolutionary events, and may be a telltale signature of natural selection in the recent past.  In much of western Eurasia it seems that one SNP, -13910*T, is responsible for the shift from ancestral to derived state in regards to lactase persistence. In other words, one gene copy which had a mutant from C to T rose rapidly in frequency from northwest Europe to northwest India (there are different alleles among Arabs and various populations in the Sahel).

There has already been suggestive data that ancient European populations lacked the -13910*T variant. A new study seems to confirm this. High frequency of lactose intolerance in a prehistoric hunter-gatherer population in northern Europe:

Here we investigate the frequency of an allele (-13910*T) associated with lactase persistence in a Neolithic Scandinavian population. From the 14 individuals originally examined, 10 yielded reliable results. We find that the T allele frequency was very low (5%) in this Middle Neolithic hunter-gatherer population, and that the frequency is dramatically different from the extant Swedish population (74%).

We conclude that this difference in frequency could not have arisen by genetic drift and is either due to selection or, more likely, replacement of hunter-gatherer populations by sedentary agriculturalists.

The sample size here is small. But they ran some simulations and it seems unlikely that so few hunter-gatherers would have the derived frequency which is extant at high frequencies among modern Swedes. Additionally, we know that this locus shows signatures which might indicate recent natural selection. That is, it rose in frequency recently in many populations. And there are a other studies from Germany which suggest a similar transition, whereby ancient populations lacked lactase persistence.

gotlandmapThe samples were from the island of Gotland, and date from 2,800-2,200 BCE. In other words, contemporaneous with the Sumerian civilization and Old Kingdom Egypt. This might be prehistoric in Europe, but not on a worldwide scale. They were from the Pitted Ware Culture, and predated agriculture in this region by about ~1000 years. Here’s what Wikipedia says about the PWC:

The Pitted Ware culture (ca 3200 BC– ca 2300 BC) was a neolithic Hunter-gatherer culture in southern Scandinavia, mainly along the coasts of Svealand, Götaland, Åland, north-eastern Denmark and southern Norway. It was first contemporary and overlapping with the agricultural Funnelbeaker culture, and later with the agricultural Corded Ware culture.

Some sources seem to suggest that the in the zone of the Funnelbeaker culture which succeeded the PWC  we invariably see contemporary high frequencies of lactase persistence. So these results are not inexplicable or a total shock. The main question is this: did the genetic variant spread to Scandinavia through positive selection, or population movement, or a combination? A reasonable guess would be some of both, but the real answer lay in establishing the proportion. In other words, how many of the hunter-gatherers were assimilated? The high fitness benefits conferred by LCT means that even in an admixed population it would rise in frequency. The main suggestive aspect here is the one individual who is a heterozygote. Phenotypically they should express lactase persistence. Who was this individual? Unfortunately they didn’t get more of the total genome, but this person might have been of mixed origin, and so illustrate the complex dynamics of how farming spread.

A few years ago I would have assumed that LCT spread in Europe by natural selection, introgressing into the hunter-gatherer substrate as they adopted farming and cattle culture. Today I am not sure. It is clear that lactase persistence has been subject to natural selection, but that does not entail that it spread only through individual level dynamics. On other words, population replacement is now a serious possibility. That opens up the likelihood that much of the population of northern Europe are relatively new settlers in the context of human history, that they even post-date the civilizations of Egypt and Mesopotamia. Interesting times.

Helena Malmstrom, Anna Linderholm, Kerstin Liden, Jan Stora, Petra Molnar, Gunilla Holmlund, Mattias Jakobsson, & Anders Gotherstrom (2010). High frequency of lactose intolerance in a prehistoric hunter-gatherer population
in northern Europe BMC Evolutionary Biology : 10.1186/1471-2148-10-89

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