What is lactase persistence?

Lactase. It’s that amazing enzyme which allows us to chug down a gallon of milk on a daily basis without having constant diarrhea. Well, some of us, at least. Lactase persistence, meaning the persistance of the lactase intestinal enzyme among adults, has a dramatic variation depending on where you come from and what your genetic profile is like. While many Northern and Central Europeans may take the lactase persistence trait for granted, lactase persistence is actually not a luxury given to all adults worldwide. Percentually speaking, adults with LP are a clear global minority. Among Europeans, the SNP that is most strongly associated with LP is C/T*−13910 (C standing for ancestral allele, T standing for the derived allele). It is also the first one that was identified. -13910*T reaches its highest frequencies among present-day Northern Europeans. Among Africans, G/C*-14010 and C/G*-13907 are more strongly associated with LP. Generally speaking, it can be said that LP among Africans seems to be dependent on multiple SNPs, while LP among Europeans appears to be more strictly dependent on -13,910*T.

Abbreviations:

LP= Lactase persistence

LBK = Linearbandkeramik culture

EEF= Early European Farmers

MNF = Middle Neolithic Farmers

WHG = Western-Hunter-Gatherer

FBC = Funnelbeaker culture

GAC= Globular Amphora culture

PWC = Pitted Ware culture

NBA = Nordic Bronze Age

WSH= Western Steppe-Herder

Tishkoff et al, 2009, suggested that while the SNPs that are believed to be responsible for LP among Europeans are not the same as those that cause LP among African people, we all developed LP convergently. Meaning, there was a similar genetic “demand” for this trait and we likely developed it much through the same process. Namely, through the domestication of animals combined with an increased consumption of dairy products among adults as well as selection for LP.

From an evolutionary perspective, the benefits of lactase persistence are obvious. It’s a (relatively) low-risk, low-energy expending source of calories, protein and minerals. It may have provided massive advantages for populations living in areas with low sunlight exposure, where milk and other dairy products not only provided an increased amount of dietary vitamin D, but also favoured the intestinal bioavailability of calcium through the help of lactose (lactose has been shown to increase bioavailability of calcium). Just like milk and dairy is a great and easy source of protein and calories for gym-goers wanting to bulk up, they were an excellent help in nutritional acquisition for the physically active ancient populations.

Middle Neolithic farmers? Steppe pastoralists?

Now, in which European population (or populations) did LP originate? It makes sense that it would be pastoralists, right? Maybe the people of the Yamnaya culture? Well, it doesn’t seem that way. Allentoft et al. (2015) may have put the final nail in the coffin to that theory. Among Yamnaya people, who carried the ancestry component known as Western Steppe-Herder (WSH) LP was practically non-existent or at very low frequencies. Thus, it doesn’t seem like European LP has its origin in pastoralists from the Pontic-Caspian steppe. The results of Allentoft et al. (2015) were largely corroborated by more recent studies such as Linderholm et al. (2020), which sequenced genomes from the early Corded Ware culture in Poland and found that they had no LP. Additionally, a massive 2022 study by Allentoft et al. concluded that lactase persistence started being heavily selected for before the introduction of steppe ancestry in Europe.

The Origins of Lactase Persistence in Europe by Itan et al, 2009, suggested that −13,910*T first underwent selection in the Linearbandkeramik culture in Central Europe. The LBK people were mainly of EEF ancestry, with small but varying amounts of WHG admixture depending on the region. They practiced cattle-raising alongside their farming and that might just have been what triggered this initial selection for LP. However, we know that LP was by no means widespread in this ancient population. Rather, we have to assume that this trait was very rare everywhere in Europe at this time. Studies like Burger et al, 2007, show that this must have been the case. The selection likely happened in such a way that LP continuously became more and more common through a slow gradual selection that lasted well into the Iron Age.

Given the data currently available to us, it seems quite likely that a moderate selection for LP took place in cultures such as the Funnelbeaker culture and possibly the Globular Amphora culture, which are both known to have practiced dairy farming. The former much more so than the latter, I should add. A dissertation from 2008 by Anna Linderholm at Stockholm University found that the FBC population had a significantly higher frequency of the lactase persistence allele than the hunter-gatherers of the Pitted Ware culture who preceded them in Scandinavia. The near complete abscence of the LP allele among the Pitted Ware culture population was later elaborated on in the study “High frequency of lactose intolerance in a prehistoric hunter-gatherer population in northern Europe” which noted that the LP allele frequency only reached about 5% among the Pitted Ware foragers from Sweden. The authors of the study noted that this is in stark contrast to modern Swedes, who along with the Finns and the Dutch, have the highest frequencies of the LP allele in Europe (Kuokkanen et al, 2005, Malmström et al, 2010, Vuorisalo et al, 2012, Kretchmer 1972, Witas et al, 2015). This is yet another case where we can observe a very dramatic difference in LP when comparing Mesolithic and Neolithic populations with modern populations. Taking into account that the PWC hunter-gatherers didn’t practice animal husbandry, it doesn’t exactly come as a surprise that they were lactose intolerant. A study by Beja-Pereira et al, 2003, also highlighted the correlation between the regions that were inhabited by the cattle-pastoralist Neolithic Funnelbeaker culture and present-day high levels of lactose tolerance. In addition to that, the publication found a substantial geographic coincidence between high diversity in cattle milk genes and areas that were inhabited by the FBC people during the Neolithic. What this implies, as the authors of the study so neatly put it, is that there is a “gene-culture coevolution” between humans and cattle. Isn’t that just amazing?

Linderholm’s dissertation is far from being the only academic literature that brings up the connection between the FBC and LP. Studies such as Grasgruber et al 2014, also mentions the remarkable similarity between the areas with the highest frequencies of LP in modern times, and the regions inhabited by the Funnelbeaker culture of old.

So, the first population of an Indo-European culture where LP shows up in any kind of significant frequency is the Corded Ware culture. The CWC people just so happened to have been formed through the admixture of Yamnaya-like people from the Yamnaya cultural horizon (carrying WSH ancestry) and Middle Neolithic farmers from the GAC and FBC cultural horizons. The FBC and the GAC people were a mix of EEF and WHG, with the WHG component reaching very high percentual levels in some individuals. The EEF component in the FBC mainly came from LBK farmers, but also from EEF who lived in France and had EEF ancestry from both LBK and the Cardial Pottery culture. It is likely from these Western farmers (Michelsberg culture, for example) that the high WHG component in the FBC people came. Going back to the CWC: if we assume that it was in the CWC, a population formed through WSH mixing with Middle Neolithic farmers that LP first started picking up speed, that still doesn’t give us the full picture. Even among the late CWC populations, LP was at relatively low frequencies in comparison to that of modern Northern Europeans. This means that the selection was indeed slow and may have increased even further during the Bronze Age and the Iron Age. Allentoft et al, 2015 showed that the people of the Nordic Bronze Age had the highest degree of lactose tolerance in Europe during their time.

It is not audacious to assume that this selection that was ongoing in the NBA population, and in neighbouring populations, simply kept going and reached its peak during the Iron Age, where it probably landed at similar frequencies to those of present-day Northern Europeans. In any case, despite the fact that some Bronze Age populations like those of the NBA had already developed fairly high allele frequencies of LP , we also know that there were Bronze Age populations in Central Europe that hadn’t. For example, Burger et al, 2020 showed us that the warriors from the Bronze Age Tollense battlefield in Germany had a low prevalence of lactase persistence, again suggesting that selection during the last 3,000 years has been significant. Perhaps more so in Central Europe than in Northern Europe (the latter which already had a somewhat high degree of LP as shown by the Nordic Bronze Age DNA samples).

Conclusion

Lactase persistance in Europe is something that is both old and new. It existed as early as in the LBK around 7,500 years ago, but was initially only selected for on a very small scale. Due to a process of gradual selection it became more and more common and seems to have reached its modern frequency due to a strong final selection that likely ocurred in the late Bronze Age and/or early Iron Age.

What we see when we look at the development of lactase persistence in Europe is not only the result of intense and relatively recent selection pressure. It is also proof of co-evolution between humans and cattle. This is evidenced by the cattle breeds from regions that were inhabited by the Funnelbeaker people having the highest diversity in milk genes, and the humans inhabiting these regions having the highest LP allele frequencies. The LP phenomenon can truly best be described as a fascinating interlinkage of culture and genes.

References:

Beja-Pereira, Albano (2003): Gene-culture coevolution between cattle milk protein genes and human lactase genes https://www.researchgate.net/figure/Geographic-coincidence-between-milk-gene-diversity-in-cattle-lactose-tolerance-in-humans_fig1_8993180

https://www.nature.com/articles/ng1263

Tishkoff, Sarah (2007): Convergent adaptation of human lactase persistence in Africa and Europe https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672153/

Vuorisalo, Timo (2012): High lactose tolerance in North Europeans: a result of migration, not in situ milk consumption https://pubmed.ncbi.nlm.nih.gov/22643754/

Linderholm, Anna (2008): Migration in Prehistory : DNA and stable isotope analyses of Swedish skeletal material https://www.diva-portal.org/smash/record.jsf?pid=diva2%3A198368&dswid=1823

Kuokkanen, Mikko (2005): Lactase persistence and ovarian carcinoma risk in Finland, Poland and Sweden https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.21130

Itan, Yuval (2009): The origins of lactase persistence in Europe https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722739/

Burger, Joachim (2007): Absence of the lactase-persistence-associated allele in early Neolithic Europeans https://www.pnas.org/content/104/10/3736

Fang, Ling (2012): The human lactase persistence-associated SNP -13910*T enables in vivo functional persistence of lactase promoter-reporter transgene expression https://pubmed.ncbi.nlm.nih.gov/22258180/

Burger, Joachim (2020) Low Prevalence of Lactase Persistence in Bronze Age Europe Indicates Ongoing Strong Selection over the Last 3,000 Years https://pubmed.ncbi.nlm.nih.gov/32888485/

The importance of lactase in food https://proquiga.es/en/lactase/importancia-de-la-lactasa-en-la-alimentacion/gmx-niv44-con25.htm

Malmström, Helena (2010): High frequency of lactose intolerance in a prehistoric hunter-gatherer population in northern Europe https://bmcecolevol.biomedcentral.com/articles/10.1186/1471-2148-10-89

Witas, Henryk (2015): Hunting for the LCT-13910*T Allele between the Middle Neolithic and the Middle Ages Suggests Its Absence in Dairying LBK People Entering the Kuyavia Region in the 8th Millennium BP https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122384

Allentoft, Morten (2022): Population Genomics of Stone Age Eurasia https://www.biorxiv.org/content/10.1101/2022.05.04.490594v2

Linderholm, Anna (2020): Corded Ware cultural complexity uncovered using genomic and isotopic analysis from south-eastern Poland https://www.nature.com/articles/s41598-020-63138-w

© Genomic Atlas 2021