Was lactose tolerance inevitable?
Back in the days before I’d ever read any probability or population genetics, I imagine I considered, as many laymen still do, evolution as a sort of deterministic march towards some optimum. I still remember being amazed at the simple equations that show how much stochasticity is involved; how random chance and historical accident can shape the fate of genetic variants. But are there cases where the layman’s instinct is correct, where we can say that evolution was deterministic? Obviously, in some sense this is impossible to prove; one can’t simply rewind the clock a thousand times and watch the outcomes. But there are natural experiments that I think shed some light on the subject.
The advent of dairy cultures in various human populations around the world provides one such natural experiment. I’m writing about this because of a recent study identifying yet another allele leading to lactose tolerance, this time in a Saudi Arabian population that drinks sheep’s milk. A previous study, regular readers may remember, identified three other polymorphisms leading to the phenotype in Sub-Saharan pastoralists. Along with the “European” allele, this brings the total of probable lactose-tolerance-causing mutations segregating in humans to five. Let’s make some assumptions: lactose tolerance is perfectly dominant, has a selection coefficient of around 0.1, and all these mutations will continue to fixation (this last one would be almost certainly true if the selection coefficient were constant–all the alleles have escaped the stochastic phases of their trajectories–but is an open question. What is the fitness advantage today of lactose tolerance? Surely this is testable). With these assumptions, one predicts that lactose tolerance has arisen around 25 times since it became advantageous. Given that we’re talking about less than ten thousand years since dairy farming, that’s quite remarkable.
The relevant parameter here is the mutational target size–if lactose tolerance could only be caused by a change at one particular base pair in humans, it would never have arisen independently so many times. But with a mutational target so large, and a selection coefficient so strong, it becomes inevitable that any culture that developed dairy farming would eventually develop lactose tolerance. But it still seems amazing to me that it happened so quickly!
Labels: Genetics, Human Evolution, Population genetics
the bizarro thing (to me) is that i don’t know of any other mammal where this occurs. i mean, why should it? we’re strange creatures….
Now two lactase-persistent haplotypes have been found which also happen to be the longest, unless I’m mistaken, of any human ones. Why do these escape recombination, if thousands of years have gone by since their founding? Does this mean that their presence in a population would formerly have eliminated any alternative shorter haplotypes, even those which include the relatively quite short, functional part, which yields lactase-persistence?
JSBolton: ” … the relatively quite short, functional part, which yields lactase-persistence … “
Correct me if I’m wrong, lactase-persistence is actually the loss of a function.
Maybe pet cats have developed some lactose tolerance? And then there’s that picture of rats drinking milk in India.
Correct me if I’m wrong, lactase-persistence is actually the loss of a function.
the paper is open access and makes the molecular genetic details pretty clear. i think it can be modeled as a gain of function (or persistence of function). people seem to assume it is dominant, which isn’t really typical if it is loss of function. if you enjoy mol gen, from the intro:
Functional evidence for the C/T?13910 variant in the regulation of lactase activity in intestinal cells has also emerged, lending additional support for this variant being the true causative one.8, 9, 10 Functional studies in vitro have further shown that the LP trait-related T?13910 allele binds Oct-1 transcription factor more strongly than does the C?13910 allele. It has been further demonstrated that a wider DNA region encompassing the C/T?13910 variant contains an enhancer element with binding sites for several transcription factors such as Oct-1 and GATA-6 (region from ?13909 to ?13934), HNF4? and Fox/HNF3? (region ?13857 to ?13817), and Cdx-2 (region ?14022 to ?14032). All these factors probably contribute to the regulation of the lactase gene in intestinal cells.10 Furthermore, the expression of Oct-1 has been shown to drive the reporter gene expression from both T?13910 and C?13910 variant/LCT promoter constructs only when it is coexpressed with HNF1?, suggesting that the ?13910 enhancer effect is mediated through HNF1? bound to the proximal promoter of the LCT gene.
Milking a cow and then drinking the milk (or drinking it straight from the cow) does seem like a pretty bizarre thing to do, when viewed completely objectively. But it need not have started that way.
If you kill a calf not long after it has fed from its mother, its intestines are still full of congealed milk. In fact, an Italian friend told me there are restaurants in Rome that specialise in this kind of delicacy. Bleh. But it’s not hard to imagine how a taste could have developed for this nutrient rich source by accident in those who didn’t get sick on it, and for it then to become deliberate. Any parent knows how you end up eating the kids’ leftovers. I had this discussion with Greg Laden once where I speculated (in a complete vacuum) that maybe the first use, after opportunistic consumption of calves’ intestines, was of treated milk products which are somethat lower in lactose and that people graduated to drinking fresh milk later.
It does seem to have been very quick, what Raz once rather poetically referred to as a hammer blow of selection, but then I suppose tolerance would have conferred a very big survival advantage, and maybe if it wasn’t quick it could’t have happened at all. Would not lactase persistence be delayed loss of function?
Two things that interest me about lactase persistence:
1. Humans have converged on the phenotype so many times. This implies that inferring phylogeny from phenotypes is perhaps worse than we had expected (which was not very good to start with!). What do we do with fossil morphologies when we see how convergent phenotypes can be?
2. Lactase non-persistence seems to be a case where mothers win the parent-offspring conflict. Individual offspring would probably like to go on enjoying mother’s milk longer, however, mom would likely prefer the energy to go into a sibling. How has the advent of lactase persistence altered parent offspring conflict in pastoralist societies? Do mothers of lactase persistent offspring experience greater difficulty with weaning?
Weaning occurs much earlier than the loss of lactose tolerance. In my personal experience at approximately age 23. That would make a strange sight – unweaned fully-adult lactase-persistent humans.
Weaning occurs much earlier than the loss of lactose tolerance in who? What population are you speaking of? This is important.
From Lomer et al. (2008)…
“For effective utilization of lactose without symptoms of intolerance, only 50% of lactase activity is necessary and it is present only at the level that it is required, as is the case for other intestinal disaccharides….”
“The decline in lactase expression is usually complete during childhood but the decline has also been reported to occur later in adolescence. The rate of loss of lactase activity also varies according to ethnicity but the physiological explanation for this difference in timing is currently unknown. Chinese and Japanese lose 80?90% of lactase activity within 3?4 years after weaning, Jews and Asians lose 60?70% over several years postweaning and in white Northern Europeans it may take up to 18?20 years for lactase activity to reach its lowest expression.”
As I understand the question you posed, the effects of lactose intolerance/hypolactosia would serve as positive inducement for the child to stop nursing. In populations with lactase persistence, the lack of such effects might make weaning more difficult or it may occur at a later age. My point was that the effects of lactose intolerance/hypolactasia don’t coincide chronologically with the roughly 2-4 year time frame in which weaning occurs. These effects manifest later in life.
Roger,
I think you are correct in pointing out the age of weaning and the age of loss of lactase tolerance, however I don’t think your populations are the most relevant.
I would be curious to know what age weaning occurs in a hunter gather population. The demographic transition may have altered weaning practices significantly. I am interested in, say, the comparison between the Hadza and the Massai. Anecdotally, I think we see parent offspring conflict in the early weaning populations you mention, which is what, I think, Trivers would predict. …if I remember correctly (and I probably don’t but don’t have time to check…), Nick Blurton Jones has shown that !Kung have a particularly long interbirth interval and weaning occurs much later too. Does loss of lactose tolerance aid in weaning amongst the !Kung? Is weaning a much gentler experience for !Kung than it is for lactase persistent populations?
I think this would be an interesting way to test thy hypothesis that loss of lactase production is a result of parent offspring conflict. Alternatively, the loss could just be from the savings from not producing a useless enzyme.
James: Maybe pet cats have developed some lactose tolerance? And then there’s that picture of rats drinking milk in India.
Hedgehogs. People have been luring them with milk for who knows how long (they eat pests and vipers and they’re immune to cats, so they can survive near human settlement). Hedgehods mature in, what?, a tenth of the time it takes humans, so even if the benefit is lesser, they have had more generations to get there.
Still, hedgehogs are apparently not tolerant, but they’d have to be the most likely wild population to develop it. (I feel great sympathy for hedgehogs, being myself of the oppressed intolerant minority. As a kid I had endless encounters with people who just refused to believe than milk is not good for everyone. Trying to convince people not to give milk to hedgehogs was just as futile.)
there’s other stuff in milk that’s of nutritive value besides lactose. just sayin’….
Talk about parent-offspring conflict – I picked up my baby daughter one day while not wearing a shirt, and she fastened onto my nipple like a vacuum cleaner. It was a struggle to get her off while avoiding hurling her across the room.
I’m her father. OK, I have decent pecs from weight training, but I thought she was being ridiculous.
Naked HGs? If the mother picked up the kid, the kid was on her like a suction cup.
I knew a woman who was still breast feeding her daughter on demand at 7 years old – it looked pretty weird. Welsh.
jaak – is there a big problem with hedgehog diarrhoea around your way?
Talk about parent-offspring conflict – I picked up my baby daughter one day while not wearing a shirt, and she fastened onto my nipple like a vacuum cleaner. It was a struggle to get her off while avoiding hurling her across the room.
dude. too much information….
What’s more interesting is thinking about how this could apply to other cultural innovations, e.g. writing.
Where I grew up – Ireland – lactose intolerance is very rare, so although I developed it at about 8 yo, I didn’t have a name for it till my 20′s at least.
When I was home last summer and was talking to my maternal uncle about his possible Alano-Sarmatian heritage, and mentioned lactose intolerance – he surprisingly had never heard of it, but said that milk always given him “stomach cramps”, and he hadn’t drank it since he was a child either.
pconroy: “… maternal uncle …”
Supposedly it’s a recessive trait, so you’d have to have gotten it from your mom and your dad.
The only reason I say that is pretty much all of my Mother’s family are lactose intolerant – and they also seem to have some Central Asian blood… but yes, I would have had to inherit one recessive allele for it from my Dad too, even though he and family do not suffer from this at all.
Just saw this article on Lactose persistence / Cystic fibrosis tradeoff – very interesting!!!