What genes can't tell us about lactase persistence

Lactase persistence results in the ability to break down the lactose sugar in milk as an adult, lactase being the enzyme which breaks down lactose. If one can not digest that sugar, and still consumes milk, then one exhibits the symptoms of lactose intolerance. Originally diagnosed as a disease it has come to light that 2/3 of the world's population is lactose intolerant, and, that this is probably the ancestral "wild type" (I would be interested if readers could name a mammal which exhibited lactase persistence aside from humans). Lactase persistence is a relatively new trait which emerged in the wake of cultural changes which were triggered by the Neolithic Revolution, primarily the domestication of cattle, goat, etc., and their utilization as a source of milk. The latter does not always entail from the former; the Gond tribe of India apparently has utilized cattle & goat for meat, but avoids drinking milk as adults (presumably they're lactose intolerant).

The ability to digest milk as an adult is a phenotype has been elucidated in terms of its genetics rather well in the past ten years, at least in relation to a host of other traits of interest such as height & weight. A few genes of large effect generate a dominant phenotype whereby lactase continues to be produced into adulthood, and, there are alternative genetic architectures which can lead to this persistence. In other words, there are different instances when mutations arose which conferred lactase persistence.

So as far as human genetics questions being illuminated in the "post-genomic era," lactase persistence is probably one of the successes. And yet there is much we don't know. A new paper addresses the issue by attempting to connect the dots in the holes of our knowledge, A worldwide correlation of lactase persistence phenotype and genotypes:

We used surface interpolation of Old World lactase persistence genotype and phenotype frequency estimates obtained from all available literature and perform a comparison between predicted and observed trait frequencies in continuous space. By accommodating additional data on sample numbers and known false negative and false positive rates for the various lactase persistence phenotype tests (blood glucose and breath hydrogen), we also apply a Monte Carlo method to estimate the probability that known lactase persistence-associated allele frequencies can explain observed trait frequencies in different regions.

Lactase persistence genotype data is currently insufficient to explain lactase persistence phenotype frequency in much of western and southern Africa, southeastern Europe, the Middle East and parts of central and southern Asia. We suggest that further studies of genetic variation in these regions should reveal additional nucleotide variants that are associated with lactase persistence.

I've tried to look at the lactase persistence data myself, and one problem is how you measure the phenotype. This isn't like height or weight, where precision is pretty good. Their method attempted to taken into account the error rates in detecting lactose intolerance, both false positives and negatives. They also had to account for the fact that they had lactase persistence data on some populations, but no genotype data. But using geographical extrapolation methods they constructed a series of maps which show the clines of both the allele and trait frequencies. Here's one which illustrates the differences between the two sets of maps, with blue being the genotype over-predicting lactase persistence, and red under-predicting:


It is clear that there is a trend toward under-prediction to a much greater magnitude than over-prediction. This makes sense when you consider the possibility that there are likely other lactase persistence alleles out there which haven't been picked up in association studies because the samples aren't representative of the world's genetic variation.

Citation: BMC Evolutionary Biology 2010, 10:36doi:10.1186/1471-2148-10-36

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Look, I love sucking on hind teat as much as the next guy but when are we gonna get your analysis of your readers? We need to know how many socially far-left, fiscally far-right fertile virgin Muslim PUAs lurk among us.

Or are you just too depressed to get to it as you note that (despite exhortations each annum) we're still not breeding.

Also relevant: How about another secular right poll. The goal would be to catch all of the Paulites and ban their IPs from ever accessing the page again.

Do you know if there is any evidence that people figured out the use of milk for cheese and yogurt, prior to drinking it as a beverage? Those both have less lactose per calorie. And for most of human history, those calories were something eagerly sought rather than avoided.

Evidently, many cats have lactase persistence.

Now, do you know of any nonmammalian animals with lactase?

By Anonymous (not verified) on 17 Feb 2010 #permalink


In the GWAS studies of height, did the genes for lactose persistence show up as having a large effect on adult height? (I suppose not since my recollection is that there were no genes of really large effect.)

It seems to me that lactose persistence gives people an easy way to continue to ingest large amounts of protein and calcium during their childhood and adolescence. I know a lot of, e.g., east Asian kids who never really like (cow's) milk, even when quite young, whereas other young kids seem to derive a huge fraction of their calories/protein/calcium from that one food item alone.

Do you know if there is any evidence that people figured out the use of milk for cheese and yogurt, prior to drinking it as a beverage?

i think so. people who have lower frequencies of LP have traditions of cheese and milk.

steve, interesting point. from what i recall the height studies are done on northern european population sets. including on finns, who have an non-trivial proportion of non-LP individuals, so i would assume it would show up. but perhaps the frequency in the sample was too low.

also, note that i think you can digest the fat and protein. it's just the carbs in the milk that go through. but as you indicate, the major issue might be the unpleasantness that the undigested carbs cause might dissuade kids from drinking a lot of milk.

There may be post-transcriptional or post-translational factors involved in lactase persistence vs. non-persistence. In an earlier study in which I was involved (Sebastio G, Villa M, Sartorio R, Guzzetta V, Poggi V, Auricchio S, Boll W, Mantei N, Semenza G. Control of lactase in human adult-type hypolactasia and in weaning rabbits and rats. Am J Hum Genet. 1989 Oct;45(4):489-97), lactase non-persistent subjects had 20 to 80% as much lactase mRNA as persistent subjects. Later studies, mainly by others, seemed to show a better correlation between enzyme and mRNA, so I had assumed something was maybe not quite right with our samples. But maybe we were in fact on the right track.
Also, if one takes tissue samples along the small intestine of rabbit or rat, the amount of lactase per amount of mRNA varies strongly (Keller P, Zwicker E, Mantei N, Semenza G. The levels of lactase and of sucrase-isomaltase along the rabbit small intestine are regulated both at the mRNA level and post-translationally. FEBS Lett. 1992 Nov 30;313(3):265-9). Partly this might just reflect amounts of intestinal proteases along the length of the intestine.
As an anecdote, the first chromosomal gene sequence for lactase was determined on clones of my own personal DNA. Sequencing a kilobase upstream of the mRNA start using my DNA (lactose tolerant) and then from a clone derived from a lactase non-persistent subject showed no differences that could explain the phenotype (Lloyd M, Mevissen G, Fischer M, Olsen W, Goodspeed D, Genini M, Boll W, Semenza G, Mantei N. Regulation of intestinal lactase in adult hypolactasia. J Clin Invest. 1992 Feb;89(2):524-9). In those days it would have been difficult to extend the sequence up to the SNP's discovered later (at about -13 kb).
Two comments on previous comments: I am not sure that cats are really all that lactose tolerant. In response to razib, drinking milk when lactose intolerant is more than just unpleasant. If you don't digest the lactose, bacteria in your large intestine will be happy to take care of it for you. The result is violent diarrhea and bloating.

By Ned Mantei (not verified) on 17 Feb 2010 #permalink

In the case of my kids my son drinks tons of milk and is (roughly) > 99th percentile for height, whereas my daughter seems to like milk much less and is around 60th percentile. If I roughly estimate calcium and protein intake I can see huge differences, largely driven by milk consumption!

Maybe this has to do with acquired microbial fauna? I could imagine an interaction between genotypes that make it easier or harder for microbial gut communities to establish that affect lactase persistence.

I believe there are studies which show that Africans in particular, the ones who drink a lot of raw milk, have different SNPs for lactase retention than those found, and commonly tested for, in Europeans.

I am lactose intolerant, I don't have the right SNP version, I drink milk with no qualms or ill effects. Of course there are other lactase persistence SNPs out among Africans, some Europeans and SW Asians.

As for steve and his son and daughter. You can't extrapolate from two children and of different sex. How about switching to Soy Milk, non GM soy if you like, with added calcium. East Asians have been using it for millenia and look how many of them there are, and the Northern Asians are quite tall.

Cats drink cow's milk placed in their bowls. That does not make them lactose tolerant. Cat's cannot digest lactose, and too much milk makes them sick. Obviously someone does not take their cat to the vet and the cat is probably not neutered, and eating every small mammal and bird the cat can find depleting the environment of biodiversity.

Maybe having a little lactose over time stimulates the body to create lactase? I propose this hypothesis based on the alcohol model -- you stop drinking and your liver figures it doesn't need to produce the form of alcohol dehydrogenase that it used to when you were putting them back regularly (meaning a daily glass of wine with your daily dinner). The next drink you take after a very long dry spell certainly has a terrible effect; basically, if you want to keep drinking, you have to keep drinking, or your liver won't keep producing.

Re cats: Mine enjoyed lactose-free milk occasionally, when they decided water was not sufficiently interesting. It's silly to expect any adult mammals to be able to digest lactose; we humans are weird that some of us can. I can't, and my cats benefited from that.

By zephyr haversack (not verified) on 17 Feb 2010 #permalink

Cats have shorter digestive tracts. Are they digesting the lactose in milk? Or just not much bothered by the failure to do so?

I guess the question about lactose-free-milk-drinking cats is are they digesting the galactose and glucose in that sort of milk? I have no idea. Maybe someone knows whether cat guts can absorb "*any* kind of sugars?

By zephyr haversack (not verified) on 18 Feb 2010 #permalink