Report from the LI Conference, part 9

With the overview talks done, we finally get to the meat of the conference.

The first section was devoted to the question: What Is the Prevalence of Lactose Intolerance, and How Does This Prevalence Differ by Race, Ethnicity, and Age?

Population Genetics: Evolutionary History of Lactose Tolerance in Africa
Sarah A. Tishkoff, Ph.D.
Associate Professor
Departments of Genetics and Biology
David and Lyn Silfen University
University of Pennsylvania

Holy smoke. That Sarah Tishkoff?

For the fans of population genetics out there, yes, I got to hear from Sarah Tishkoff herself. Why is this a big deal? Let's go back in time, to a post I made in 2006, quoting Scientific American.

According to University of Maryland biologist Sarah Tishkoff, the lead author of a study appearing in today's Nature Genetics, the mutation allowing them to "get milk" arose so quickly and was so advantageous that "it is basically the strongest signal of selection ever observed in any genome, in any study, in any population in the world."

What this means is that despite the nonsensical statements that "humans were never meant to drink cow's milk," lactose tolerance or lactase persistence is such an overwhelmingly positive mutation in humans that multiple populations, totally independent from one another, selected for that version of the gene. Being able to tolerate milk products must have significant advantages. The exact nature of those advantages are still not completely certain. The nutrients that dairy provide are "obvious," to use her word. But even the fact that milk is a drinkable fluid, containing water, may have been of critically importance in areas like Africa, where supplies of potable drinking water were often rare.

Some Sensible Writing About Lactose Intolerance

Getting is right shouldn't be a news story any more than "Nobody Killed as People Go About Ordinary Day" should be the headline in a newspaper. Correcting wrongs is a more urgent business and one that I spend probably half my time at.

Every once in a while it's nice to recognize correctness, though. When two correct halves of a large and more complete correct whole come together, well, that's news I can and should write about.

A few days ago I posted about a new computer model study looking at The Origins of Lactase Persistence in Europe. That study also got a nice write-up in USA Today, which started its article, by Elizabeth Weise, with an overview of lactose tolerance and intolerance.

First off, most people who have bad reactions to milk aren't actually allergic to it, in that it's not their immune system that's responding to the milk.

Instead, people who are lactose intolerant can't digest the main sugar —lactose— found in milk. In normal humans, the enzyme that does so —lactase— stops being produced when the person is between two and five years old. The undigested sugars end up in the colon, where they begin to ferment, producing gas that can cause cramping, bloating, nausea, flatulence and diarrhea.

If you're American or European it's hard to realize this, but being able to digest milk as an adult is one weird genetic adaptation.

It's not normal. Somewhat less than 40% of people in the world retain the ability to digest lactose after childhood. The numbers are often given as close to 0% of Native Americans, 5% of Asians, 25% of African and Caribbean peoples, 50% of Mediterranean peoples and 90% of northern Europeans. Sweden has one of the world's highest percentages of lactase tolerant people.

Being able to digest milk is so strange that scientists say we shouldn't really call lactose intolerance a disease, because that presumes it's abnormal. Instead, they call it lactase persistence, indicating what's really weird is the ability to continue to drink milk.

All true, and all things that I've said myself in the past.

But not the entire story, something difficult to pull off in the confines of a single article that's designed to lead to a particular point.

Skip the now 520[!] comments attached to the story, most of which will make you despair of the notion that intelligence is also an evolutionary result and turn to the letters to the editor page.

There we find a comment from a person who - unbelievable as it might seem - actually knows what she's talking about. Theresa Nicklas, professor, Children's Nutrition Research Center, Baylor College of Medicine - Houston, wrote:

It's important to recognize that the lack of the lactase gene does not mean people can't enjoy milk and milk products. The limited ability to digest lactose (lactose maldigestion) does not necessarily result in any symptoms (lactose intolerance).

Although different people can handle different amounts of lactose, your readers should understand that even people who have a limited ability to digest lactose can enjoy dairy foods, often without any symptoms.

This has significant public health implications because it is difficult to get the recommended calcium and potassium in the diet without including dairy. A large percentage of Americans 2 years old and older are not consuming adequate amounts of calcium and potassium.

One against 520. Those aren't good odds. I'm happy to back Dr. Nicklas, making it 520 to 2. That's still bad, but heck, it's twice as good as before. I'd like to think that two people who are knowledgeable and right beat out the 520 who are neither. It's my fantasy of the day.

The Origins of Lactase Persistence in Europe

Most of the world's population is lactose intolerant, with the latest estimates that a minimum of 60% are. Being lactose intolerant means that you are born with a gene that turns off the production of the lactase enzyme that digests the milk sugar lactose at some point in your life.

Most Northern Europeans and their descendants, which means most Americans, are not lactose intolerant. That makes them a unique population, given the size and numbers and uniformity of the ability to drink milk without symptoms as an adult.

How could this possibly come about? The origins of drinking milk had to come after milkable animals were domesticated in large numbers. That appears to have happened for the first time in the Middle East around 10,000 years ago. That's a very short time in human history. We do know that the mutation that never sends out the signal to stop producing lactose is one that keeps cropping up - in fact, scientists have found 43 separate versions of the mutation - so it must be fairly common. Even so, getting a chance mutation, even a dominant mutation as this one is, to spread completely throughout a population is extremely unusual. No other mutation like lactose tolerance is known today.

Exactly when and where the mutation took hold in a population that would spread it across Europe has been fiercely debated for years. In Milk Mutation "Strongest Signal of Selection", for instance, I reported that:

Tishkoff's team determined the date range when the mutation likely occurred: 3,000 to 7,000 years ago, which matches up well with the archaeological record that places pastoralization coming to East Africa about 5,000 years ago. The European trait dates back about 9,000 years.

A new computer model developed by a group of UK scientists make the time and place much more specific:

We infer that lactase persistence/dairying coevolution began around 7,500 years ago between the central Balkans and central Europe, probably among people of the Linearbandkeramik culture.

Oh, c'mon, everybody knows the Linearbandkeramik culture. They were the first farmers in Europe.

The Linearbandkeramik Culture (also called Bandkeramik or Linear Pottery Ceramic Culture or simply abbreviated LBK) is what German archaeologist F. Klopfleisch called the first true farming communities in central Europe, dated between about 5400 and 4900 BC. Thus, LBK is considered the first Neolithic culture in the European continent.

The word Linearbandkeramik refers to the distinctive banded decoration found on pottery vessels on sites spread throughout central Europe, from south-western Ukraine and Moldova in the east to the Paris Basin in the west. The LBK people are considered the importers of agricultural products and methods, moving the first domesticated animals and plants from the Near East and Central Asia into Europe.

If lactose tolerance is associated with milking and milking is associated with farmers, then the first farmers in Europe are a logical place to look for a beginning. It all seems to come together.

When I was doing the research for Milk Is Not for Every Body, I had to struggle through dozens of articles from medical and archaeological journals, but for sheer total unreadability nothing compared to articles on the math of population genetics. So I was pleasantly surprised to see that the introduction to this particular article from PLoS Computational Biology is written in more or less accessible English. Here goes.

Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG, 2009 The Origins of Lactase Persistence in Europe. PLoS Comput Biol 5(8): e1000491. doi:10.1371/journal.pcbi.1000491

Abstract

Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (1−13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the −13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on −13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the −13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

Author Summary

Most adults worldwide do not produce the enzyme lactase and so are unable to digest the milk sugar lactose. However, most people in Europe and many from other populations continue to produce lactase throughout their life (lactase persistence). In Europe, a single genetic variant, −13,910*T, is strongly associated with lactase persistence and appears to have been favoured by natural selection in the last 10,000 years. Since adult consumption of fresh milk was only possible after the domestication of animals, it is likely that lactase persistence coevolved with the cultural practice of dairying, although it is not known when lactase persistence first arose in Europe or what factors drove its rapid spread. To address these questions, we have developed a simulation model of the spread of lactase persistence, dairying, and farmers in Europe, and have integrated genetic and archaeological data using newly developed statistical approaches. We infer that lactase persistence/dairying coevolution began around 7,500 years ago between the central Balkans and central Europe, probably among people of the Linearbandkeramik culture. We also find that lactase persistence was not more favoured in northern latitudes through an increased requirement for dietary vitamin D. Our results illustrate the possibility of integrating genetic and archaeological data to address important questions on human evolution.

One final technical point. The evolution of "white" skin has usually been explained by the need for northerners to get more vitamin D from the sun in the relatively limited time available. "Black" skin reduces the uv absorbed and vitamin D made, but this isn't a problem in the tropics. Calcium sources were also more limited in the north, making milk a dietary necessity and vitamin D helps calcium absorption. So why isn't there the expected correlation between the people who were drinking more milk and therefore getting more calcium which therefore required more vitamin D? Two reasons. One is that the model found that the coevolution of dairying explained enough so that an additional explanation wasn't needed. The second was that this particular effect wasn't included in the model in the first place.

That's the problem with computer models. They are excellent at checking whether the data meets expectations. Putting every possible variation and explanation into a model exceeds what our computers can do at this point.

The whole article is a fascinating read and a good summary of much of what is known or suspected today on the spread of dairying and lactose tolerance. It's not as difficult a read as most, at least until the equations start taking over.

The history of lactose tolerance is the history of western civilization in many ways. Northern Europeans couldn't have survived the north without milk and dairying. Their aggressive societies took over the rest of the world, taking their milk-based culture with them. Most Americans grew up thinking that dairy was the norm and have been surprising to find themselves a minority in the world. This is history well worth the study and the time and difficulty in tackling it. It's the story of us, tolerant and intolerant alike.

More on the History of Lactose Intolerance

Everything old is new again, as the ancient phrase goes. (Or is it ancient? I got sidetracked to do a search on that phrase's origin and I didn't find anything earlier than the song written by Peter Allen and Carole Bayer Sager in the film All That Jazz, which came out in 1979. Then I found a 1975 song on Anne Murray's Together album. And a search of Newspaper Archive reveals absolutely nothing before that? Shouldn't the phrase be far older?)

Geneticists have been plunging deep into the DNA of humans and multiple other species to search for the historic information that is encoded there.

Dave Munger, for example, wrote about the history of lactose tolerance in his new column in Seed magazine.

The researchers say the lactase gene evolved in Europe because Europeans don’t get enough sun to produce Vitamin D, which in turn is needed for humans to take in calcium. Since lactose also assists in the uptake of calcium, adult milk drinking helped northern Europeans meet that deficiency.

Gerbault’s team developed a computer model demonstrating that, in order for the adaptation to persist, lactose-tolerant northern Europeans would need to have 1.8 percent more children. In other words, milk drinkers would need to be more successful in reproducing—and this is indeed what is observed there.

That's cool, right? A startling bit of history revealed in our genes. A new understanding of the world.

Except it isn't. That "discovery" is merely an affirmation of knowledge that is now more than 30 years old. I wrote exactly the above scenario in my 1996 book Milk Is Not for Every Body, based on academic work existing and easily findable. Everything else covered in Munger's column is in my book as well. All I did was read the literature, which nobody today seems to bother to do.

DNA evidence is a marvel. Many roads to the truth exist, though, and even the crude methods of the past managed to ferret out some relationships that hold true today.

Never forget the past when you cast your eyes toward the future.

The History of Lactose Tolerance

Evolution is the most powerful idea in science. Scientific American Editor in Chief John Rennie said that. He's right. We don't have to spend much time thinking about quantum mechanics or relativity. We are, and need to be, obsessed about our bodies, the food we eat, bugs spreading infectious diseases, all the animals in the world, the floral environment, medicine, surgery, everything we do and experience every hour of every day of our lives. The only way that life in all its ramifications can be understood is to study the basics in terms of evolutionary systems. As seminal biologist Theodore Dobzhansky once wrote, "Nothing in Biology Makes Sense Except in the Light of Evolution."

My point of entry into the world of evolutionary history is always lactose tolerance. People who can drink milk as adults display the most recent major mutation in the human body. Scientists are fascinated by the utterly amazing fact that 30% of the world's population shares a mutation that is less than 10,000 years old.

John Rennie and Steve Mirsky devoted part of a podcast to this bit of amazing genetics.

Steve: For example, our ability of, some of us, to digest milk, the lactose in milk as adults, it's a very recent adaptation in evolutionary history.

Rennie: Well, right, because really until we started to develop agriculture, until we started to herd animals and collected milk as a good source of protein, mammals don't continue to breast-feed throughout their lives; so the young have the ability to digest breast-milk and then after they stop drinking it, they stop making that lactase enzyme that allows them to breakdown the lactose sugar in the milk. But we kept drinking milk: We raised cows and milk was a ready source of protein and other nutrients, and we would keep on drinking that throughout our lives. And so evolution started to act on the human populations and in populations that traditionally drank a lot of milk, we have this ability to keep making the lactose throughout our lives, or lactase throughout our lives.

Steve: Let's just explain a little bit mechanistically. I mean, its likely that the mutation that enabled adults to digest lactose cropped up now and again, you know, throughout the history of human evolution; but there was never any selection pressure to keep it around until we had agriculture and were starting to try to use milk as a nutritional source, as a food, as adults.

Rennie: Right.

Steve: At that point in human history, all of a sudden those individuals who happen to have this genetic mutation have a big advantage over their comrades who can't digest the lactose, and so the combination of the environment and that genetic influence makes that genetic construct get selected for and preserved in the population. And all of a sudden, you know, within a couple of thousand years, the majority of Europeans can digest lactose.

Rennie: Right. You know, that's a good point, because it's always important to remember, you know, people always have these sorts of arguments about nature versus nurture and are there genes for various traits; you know, discussions about genes for intelligence and so forth are always notorious about this sort of the thing. But the reality is, you can't really discuss a gene, the idea of a meaning of a gene outside of the environment in which it's going to be expressed. You can't really talk about the meaning that it has, what it will do, whether it has any sort of positive or negative value in that way. Ultimately, you know, we talk about genes as though they are building blocks for some sort of complicated traits, even a trait like, say, being able to drink milk. But of course, the reality is, the molecular biological reality is, that the gene is just a stretch of DNA that happens to make a protein that breaks down a sugar that is in milk. So only under a number of different circumstances in which people happen to have exposure to, they happen to have easy access to, a lot of milk that happens to contain a lot of lactose that they can't digest very easily unless they happen to still make a lot of the lactase enzyme that they all made as children. All of these circumstances come together to make something like that beneficial. Anything that breaks down that set of circumstances, it's just another little stretch of DNA that may not prove its worth and as you said, it vanishes back in as random noise again.

It's exactly this idea that DNA changes just happen, without direction or outside influence or intention or for the good of the body, that seems so threatening. If we are nothing more than a collection of random events how do we claim a purpose for ourselves?

While I understand this fear, I don't share it. Our lives, our actions, our interactions are exactly what we make of them, good or bad, helpful or hurtful, intelligent or ignorant, caring and giving or selfish and self-indulgent. I choose to help, to gain information and to share it. We can all make that choice or a similar one no matter what is happening inside our DNA. Evolution has given us that power of individual choice, a power no other animal or plant can wield. Evolution is not just the most powerful idea in science. It's the power inside all of us.

Lactose Tolerance Makes You Fat

The European Human Genetics Conference will be held later this month in Vienna. Excited yet? No? Here are some titles of papers to be delivered there:

• Phylogeography of human Y chromosome haplogroup R1b1b2 (R-M269) in Europe.

• The genetic position of Western Brittany (Finistère, France) in the Celtic Y chromosome landscape.

• Mitochondrial Genome Diversity in Tungusic-speaking Populations (Even and Evenki) and Resettlement of Arctic Siberia After the Last Glacial Maximum.

Still not psyched?

Then let me play my trump card.

European Lactase Persistence Allele is Associated With Increase in Body Mass Index

J. A. Kettunen et al.

The global prevalence of obesity, usually indexed by body mass index (BMI) cut-offs, has increased significantly in the recent decades, mainly due to positive energy balance. However, the impact of a selection for specific genes cannot be excluded. Here we have tested the association between BMI and one of the best known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We found that the variant responsible for lactase persistence among Europeans was also associated with higher BMI in a Nordic population sample (p = 1.3*10-5) of 15,209 individuals, the size of the effect being close to that of FTO*. We tested the effect of population stratification and concluded that the association was not due to population substructure.

* FTO is a gene that appears to be correlated with obesity.

Let me attempt to translate that.

Europeans tend to have the highest rates of lactase persistence, also known as lactose tolerance, in the world. (Since the majority of white Americans are descendants of European immigrants, most American adults can also drink milk without suffering symptoms.) We know that lactose tolerance is a simple mutation on chromosome 2. And it is a dominant mutation. So the ability to drink milk as an adult will show up unexpectedly but spread through a population because it conveys at least a small advantage in survival and in having more children survive. That helps account for the European dairy culture.

Why does the ability to drink milk convey an advantage? Milk is an excellent food, with high nutrition in a compact and good tasting source. This study goes beyond that to suggest that milk drinkers will be heavier than non-milk drinkers. In olden times, when starvation was a very real possibility, this was an advantage. Today it may lead instead to obesity, or at least greater weight.

You can find an interesting discussion of this abstract led by Razib at the Gene Expression blog.