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Lactase Persistence Study Offers Look at Past Migration, Pastoralism in Africa

NEW YORK (GenomeWeb News) – The ability to continue digesting the milk sugar lactose in adulthood — enabled by ongoing expression of the lactase enzyme — seems to have spread across Africa through a combination of convergent evolution and past population movement, an international team reported today.

The resulting lactose tolerance patterns coincide with a rise in pastoralism and cattle domestication in various parts of the continent, and the lactose-related alleles found in present-day populations are revealing past human migrations and interactions.

In a study published online in the American Journal of Human Genetics, the University of Pennsylvania's Sarah Tishkoff and colleagues described findings from an effort to track down new lactose tolerance variants in Africa. Through targeted sequencing on samples from more than 800 individuals from dozens of African populations and hundreds of non-African individuals, they unearthed both known and new SNPs associated with this process.

By tracing the allele frequency and haplotype patterns of these alleles, the team got a glimpse at the variable genetic patterns used to accomplish lactose digestion. But it also found instances of shared haplotype profiles pointing to past interactions within and beyond Africa.

"Because of this large dataset, and comparisons with a set of non-African individuals, we were able to get a better picture of the distribution of variants associated with lactase persistence in Africa," the study's first author Alessia Ranciaro, a postdoctoral fellow in Tishkoff's University of Pennsylvania lab, told GenomeWeb Daily News. "It's interesting how different variants can give the same final effect — the ability to digest the milk."

Lactose tolerance in adulthood, also called lactase persistence, has been documented in populations with northern European ancestry and a smattering of populations originating in Central Asia, the Arabian Peninsula, and Africa, the researchers noted.

In European populations, the ability to continue digesting lactose has been attributed to the presence of key variants in a gene neighboring the lactase-coding sequences. But a 2007 Nature Genetics study by Tishkoff, Ranciaro, and others indicated that those variants are not typically present in African populations. Instead, they found three alternative variants contributing to this process in parts of Africa.

For their new analysis, the investigators used targeted Sanger sequencing to interrogate regions suspected of influencing expression of the lactase-phlorizin hydrolase gene LCT in samples from 819 African individuals from 63 African populations and more than 150 non-African individuals from Europe, the Middle East, and Asia.

The team set its sites on three candidate regions: introns 13 and 9 of a LCT neighboring gene called MCM6, which house variants implicated in lactose tolerance in Europeans, and the promoter region of LCT itself.

Using an established blood assay that tracks lactose digestion to produce glucose and galactose sugars, researchers also assessed study participants' lactose tolerance patterns.

Because the team was dealing with much larger samples sizes than those included in past studies, it had far more power to look for lactose tolerance associations, particularly in populations in Northern Kenya and Sudan, Tishkoff told GWDN.

Along with known variants, the researchers narrowed in on two new lactose tolerance-associated variants in African populations. One fell in the LCT promoter and another appeared in intron 13 of MCM6.

More research is needed to determine whether one or both of the newly detected variants are causal, since they may also be in linkage disequilibrium with some previously described variants.

"We don't know yet, because we didn't do functional studies, if the [two new variants] are associated through their linkage with the other variants known to contribute to lactase persistence or if they themselves make a contribution," Ranciaro said.

For 252 of the study participants, the researchers also did genotyping at four variable microsatellite markers, which made it possible to assess the chromosomal context of the lactose tolerance alleles.

That approach "gives us a lot of information to trace the origins [of lactase persistence variants] and tracing history," Tishkoff said.

For example, the presence of a variant called G-13915, which appears to have originated in the Middle East, in populations in North Africa points to migration between the regions and coincides with known historical interactions between the populations.

On the other hand, their work turned up distinct lactose persistence variants that appear to have arisen in various parts of Africa through convergent evolution. For instance, one lactose tolerance variant was more or less exclusive to northern Kenya, Ethiopia, and northern Sudan.

Another lactose tolerance-linked variant was specific to populations in Kenya and Tanzania and to Bantu-speaking Xhosa and San hunter-gatherer populations in southern Africa. That hints at introduction of the variant from East Africa, perhaps indirectly via Bantu migration, Tishkoff said. She noted that populations in southern Africa that carry the allele today may also have had a much broader distribution at one time.

Interestingly, the researchers also detected classic European lactose tolerance alleles in some West- and North-Central African populations, such as the Fulani in Cameroon and Algeria's Mozabite population.

Even so, the variants detected so far do not explain all of the lactose tolerance detected in African populations so far.

"There are likely to be novel mutations that we haven't found yet and/or there could be bacteria playing a role in digesting [lactose]," Tishkoff said. "We're looking into both of those possibilities."

The team has already extended the study to look at additional individuals from other populations, especially Hadza hunter-gatherers, who are often lactose tolerant despite drinking very little milk.

So far, researchers have not detected known variants associated with lactase persistence in the Hadza. They speculate that that population may carry lactase-related variants that reflect the enzyme's role in breaking down other forms of carbohydrates, such as those found in plants, berries, or tubers, though that hypothesis requires further investigation.