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Lactase Persistence

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Soft serve

The trait of lactase persistence (lactose tolerance) is probably one of the better schoolbook examples of natural selection in human populations. The reasons for this are probably two-fold. There is a very strong signature of selection within a specific gene known to associate with the trait in question in many populations. And, there is a very compelling historical narrative which explains rather neatly how this particular functional change could have undergone such strong selection within the past ~5,000 years across these populations. But the elucidation of the origin and spread of this genetic adaptation is also interesting because it looks as if it was not a singular event. Populations as disparate as Arabians, Danes, and Masai seem to carry different alleles around the locus of interest which confer the ability to digest milk. This illustrates the fact when selection pressures have a viable target, there is a rapid response on the genomic level. At some point during the maturation of a mammal the regulatory pathway which produces lactase enzyme shuts down. Yet within numerous human populations this gradual shutdown process has been short-circuited.

The variety of response in relation to this adaptation was brought home to me as I read Diversity of Lactase Persistence Alleles in Ethiopia – Signature of a Soft Selective Sweep, in the latest issue of The American Journal of Human Genetics:

The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (−13910∗T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (−13907∗G, rs41525747; −13915∗G, rs41380347; −14010∗C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, −14009T>G (ss 820486563), is significantly associated with lactose-digester status, and in vitro functional tests confirm that the −14009∗G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep.

To some extent the paper was written rather confusingly for my taste. Importantly, they did not even consider the results of Pagani et al. (in the same journal!) from last year in their analysis. The big picture result is that whereas in Eurasia and East Africa it looks as if lactase persistence spread through populations via “hard” selective sweeps, in Ethiopia it may have been propagation through “soft” sweeps. The former are cases where a single new mutant confers a beneficial phenotype. In the absence of allelic competitors this variant sweeps up in frequency extremely rapidly, and flanking regions of the genome generate a long haplotype block. In Europeans this has resulted in a strongly homogenized region of the genome around LCT.

The situation in Ethiopia is a touch paradoxical in light of the above model. Instead of one allele, it looks as if several are segregating. And, the lactase persistence haplotypes exhibit more, not less, genetic diversity than the non-persistent variants. As noted in the article it may be that there are strong selective constraints against lactase persistence. Apparently there is a long non-persistent haplotype in Horn of Africa populations, explaining the reduced diversity of this subset of the sample. Whereas in a hard sweep a single mutation can rise in frequency against disfavored ancestral variants, in this situation you have a soft sweep where alternative variants with similar fitness values are presumably increasing in frequency.

But all this needs to be considered in light of Pagani et al., which indicates a very recent admixture in Ethiopia. The discussion above seems to suggest in situ selective events within the Horn of Africa, but the possibility is that the sweeps may have initiated among the Eurasian ancestors of the Ethiopians (perhaps some admixture mapping would be useful?). Ultimately this is going to be a complicated story. It doesn’t take away from the bigger picture that lactase persistence is an excellent model for natural selection, but the sketch has more details to be filled in, though I’m not quite sure about the specific character of this from this paper

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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

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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. People don’t tend to consume what makes them ill, and even accounting for some processing in the form of butter, most researchers have assumed a substantial number of South Asians must be lactase persistent. That is, they can extract nutritive value out of the lactose sugar present in milk (in addition to fat and protein). Additionally, many South Asians have the well known -13910 C>T common in Western Eurasia. How do I know this? Because I share my genetic information with lots of South Asians, and some of them, especially Punjabis, come up as “lactose tolerant” on that allele.

A new paper in Molecular Biology and Evolution confirms this with a larger data set, over 2000 samples from South Asia. The geographical pattern is exactly what you’d expect:

-13910 C>T is modal in Northwest India, where cattle culture is most widespread across society. It drops off as one moves south, east, and north, into zones where milk production and products are less integral, or lacking, in the cultural toolkit. The ability to digest lactose as an adult is interesting and nice because it’s a perfect illustration of the power of natural selection to reshape traits. Relatively genetically close populations can be very different depending on whether the trait is favored, or not.

What’s the case here? There are many statistical genetic tricks that they used, but I’ll spare you that. First, remember that lactase persistence has emerged multiple times. There’s a mutation which is very common in Northern Europe, which extends into Central Eurasia. This is the same one discussed in this paper. Other mutations are localized to the Arabian peninsula and East Africa. The convergent evolution suggests some combination of:

1) Strong selection pressure for this trait in dairying cultures

2) A large mutational target, in that a wide range of changes seem to effect the appropriate shift

3) Low levels of gene flow which allow for different variants to flourish. If gene flow was too ubiquitous than the earliest variant would sweep all the others before it

It turns out that the overwhelming majority of detected variants known to allow for lactase persistence in India is the West Eurasian one. This is interesting, because there are various genetic and cultural reasons to connect South Asia to West Eurasia (even Europe). There is some genetic evidence to imply that the West Eurasian mutation derives from the Volga region. Though the word does not appear in the text of the paper it does not take a rocket-scientist to infer that this allele may have been introduced by Indo-Aryans. The main counter-argument against this is that it seems that their statistical corrections imply that geography predicts the variation of the trait more than linguistic affinity (i.e., if there was a sharp difference between Indo-Europeans and Dravidians who were neighbors it would be of great interest) by and large (the Austro-Asiatics and Tibeto-Burmans are exceptions, language is a good predictor of the lack of lactase persistence). These results make me less skeptical of the possibility that most of the recent admixture from West Eurasia in South Asia was due to the Indo-Europeans. Perhaps they did push south in a continuous manner gradually, and culturally were discontinuous? This is theoretically not implausible. On the other hand, I do wonder if perhaps the West Eurasian mutations pre-dates the Indo-Europeans. The authors of the paper observe that pastoralism has a 7,000 year history in South Asia. Not as long as Europe, but a long time indeed.

But these results don’t tell us just about ancestry. The region around LCT in Europeans shows a lot of evidence of natural selection. What about in South Asians? It seem that some of the signatures do persist in India. Additionally, there is a strong correlation between pastoralism and lactase persistence. This stands to reason, but it is nice to have that confirmed. This suggests that we need to be careful about inferring too much in regards to ancestry from this locus: it is not a neutral proxy, as it is subject to positive or negative natural selection. The aggregate frequency in their pooled sample is ~0.20, with high bounds in the range of ~0.75. Based on earlier Y and mtDNA work the authors suggest that it is more likely that these frequency variations and the overall level is a function of natural selection more than ancestry. In other words, a small group of pastoralists brought the favored allele, which spread rapidly to ecologically favored niches.

🔊 Listen RSS My 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

• Category: Science • Tags: Culture, Genetics, Lactase Persistence 
Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"