Monday, December 11, 2006


Study Detects Recent Instance of Human Evolution

A discovery by an international team led by University of Maryland researcher Sarah Tishkoff* identifies, for the first time, genetic mutations in East Africans that are associated with the ability to digest milk as adults.

Tishkoff's study of DNA, described in the journal Nature Genetics [1], found that the mutations evolved at the time in history when some Africans were beginning to raise cattle, and they evolved independently from the mutation that regulates milk digestion in Europeans.

The findings are not only evidence of how genes and culture co-evolve, says Tishkoff, associate professor of biology at Maryland, "they reveal one of the most striking genetic footprints of natural selection ever observed in humans."

Lactose Intolerant Humans

Human adults were not designed to digest milk. It took a genetic mutation to enable humans to tolerate lactose (see lactose intolerance), the main sugar found in milk. But not everyone has the mutation. Most northern Europeans, whose ancestors domesticated cattle, do. Descendants of cultures that did not raise cattle for milk - many southern Europeans, most Asians and many Africans - do not have the mutation and can't digest milk products.

Then there is the mystery of why some African people who raise cattle and successfully digest milk do not have the mutation that allows Europeans to digest milk.

Tishkoff's study appears to have solved that mystery. By resequencing DNA samples that her team collected from a number of different ethnic groups in remote regions of Africa and testing whether genetic variation is associated with the ability to digest lactose, Tishkoff discovered that, indeed, a distinct genetic mutation to allow digestion of milk occurred in Africa independently from the European mutation and arose at the time that African populations started raising cattle.

The mutation has gone undetected until now because it appears to be in a different location than the European mutation, and appears to be restricted to East African populations that herd cattle.

Got milk?

When humans were hunter-gatherers, before some began to domesticate cattle, they were able to digest milk only until they were about four years old. Lactase-phlorizin hydrolase (LPH), the enzyme that lets humans digest lactose, the main carbohydrate in milk, works in the small intestine to help the body absorb the sugars found in lactose. But LPH levels decrease rapidly after weaning and are at low levels in adults

When milk became a human food source, evolution went to work. Says Tishkoff, "The ability to digest milk as adults, called lactase persistence, appears to be an excellent example of gene-culture co-evolution. In this case, it is the development of technology - raising cattle - and the genetic mutation - the ability to digest milk - that becomes common."

By looking at the rate of decay of association of genetic variants over a three-million base pair region, Tishkoff and collaborators were able to estimate when these genetic mutations occurred in human history. The mutation for lactose tolerance began to show up in Northern Europeans at about the same time they began to raise milk cattle, around 9,000 years ago. A distinct mutation for lactose tolerance became common in East Africa beginning around 7,000 years ago. These dates correlate with archeological evidence for the origins of cattle domestication in these regions.

Got Genes?

For Tishkoff, who has been doing genetics research on disease and human origins among African populations for more than ten years, there were clues that some groups of Africans had adapted due to a distinct genetic mutation for lactase persistence- they have a history of cattle domestication, they consume milk- yet they don't have the mutation associated with lactase persistence in Europeans.

"Archeological evidence suggests that cattle domestication originated in southern Egypt as early as 9,000 years ago," said Tishkoff. "The ability to digest milk as adults was likely to be adaptive, because of the nutritional benefits from milk, and also because milk is an important source of water in arid regions. During the dry season, many pastoralist populations are fully milk-dependent."

Tishkoff's group selected specific African ethnic groups to study, those with and without a history of cattle domestication. Driving across rugged terrain in Land Cruisers, traveling to remote villages, and setting up collection stations under trees, they collected DNA samples from almost every major pastoralist population and some hunter-gatherers in regions where no one else had looked before: the Arusha and Dodoma provinces of Tanzania; Rift Valley, Eastern, and Nyanza provinces of Kenya; and the Khartoum and Kasala provinces of the Sudan.

The researchers also asked volunteers to consume lactose, then measured their blood sugar levels to determine if they were able to digest the lactose found in milk. "This ability was then compared to the specific genetic variants found in these individuals to identify the genetic basis for the ability to digest milk," says Tishkoff.

Location, Location, Location

Five hundred field samples of DNA went to Dr. Panos Deloukas' lab at the Sanger Institute in Cambridge, England, for genotyping of the new African variants identified by the Tishkoff lab. The lab also did genotyping of 123 genetic differences over a three-million-base pair region of chromosome 2, which encompasses the gene that regulates lactose digestion.

It was on that chromosome, near the gene coding for the enzyme"lactase" that the genetic variations for milk digestion in the African populations turned up - not just one, but three distinct mutations that evolved at different times, in different geographic regions. The most significant variant, the C-14010 allele, was common in East Africans. Two other mutations, not as common, were G-13907 and G-13915, found among Beja (North Sudan) and North Kenyan populations.

Studies of gene expression in small intestine cell lines that contained these new mutations, led by Dr. Greg Wray at Duke University in collaboration with the Tishkoff study, also indicated that these mutations regulate expression of the enzyme "lactase," that enables digestion of lactose.

Based on computer simulations of the strength and age of selection, done in collaboration with Dr. Jonathan Pritchard and Benjamin Voight at the University of Chicago, they estimate the most common mutation, C-14010, evolved over a 7,000-year time span, when different groups of Africans were moving from being hunter-gatherer to pastoral cultures.

"If a mutation provides a strong benefit, it will become common in the population," says Tishkoff. "This mutation was so important for adaptation that it rapidly swept to high frequency in East Africa.

"Furthermore, positive selection was so strong that a huge region of chromosome 2 near this mutation rapidly swept to high frequency as well," Tishkoff said. "The area of the chromosome affected by this adaptive event, more than two million nucleotides, is larger then any region ever reported in any human population, making this one of the most striking examples of recent natural selection in humans."

Implications for Disease

"Without resequencing, we wouldn't have found this," said Tishkoff. "Our results point to the importance of studying genetic variation in different ethnic groups. Even though we weren't looking for disease mutations, it demonstrates that mutations, including those that result in disease, can be geographically restricted."

Other University of Maryland researchers involved with this study include NIH postdoctoral research fellow Floyd Reed and graduate students Alessia Ranciaro, Holly Mortensen, Kweli Powell and Jibril B. Hirbo.

Source (Adapted): University of Maryland PR "UMd-Led Team Discovers Gene Mutation for Milk Tolerance in Africans" December 5 2006


[1] Convergent adaptation of human lactase persistence in Africa and Europe

Sarah A Tishkoff et al.

Nature Genetics - 39, 31 - 40 (2006)
Published online: 10 December 2006; | doi:10.1038/ng1946


A SNP (single nucleotide polymorphism) in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending greater than 2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past approx 7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits - animal domestication and adult milk consumption.


*Excerpt from Sarah Tishkoff's webpage about the African Genetic Diversity Project:

"Despite the fact that Africa plays a central role in human evolution, African populations have been greatly underrepresented in the study of human genetic diversity. Our goal is to establish a large database of genetic diversity among geographically, linguistically, and culturally diverse African populations. The study of African genetic diversity will be important for reconstructing modern human origins as well as recent African and African American population histories. The study of African genetic diversity will also be important for the identification of the genetic basis of diseases prevalent in African and African American populations (e.g. hypertension, diabetes, prostate cancer).

To achieve this goal, we and our collaborators have made several field expeditions to Africa to collect 9ml blood samples from greater than 4000 individuals from greater than 80 ethnic groups (most previously un-sampled) originating from Nigeria, Cameroon, Tanzania, the Sudan, and Kenya, from which we have extracted DNA."

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