World wide distribution of lactase persistence alleles

[Angela]

See: Anke Liebert et al
https://link.springer.com/content/pdf/10.1007/s00439-017-1847-y.pdf

"The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [−13910*T (rs4988235), −13907*G (rs41525747), −13915*G (rs41380347), −14009*G (rs869051967) and −14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the ‘Old World’ and their haplotype lineages. We examine and confrm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the fve LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection.

The supplementary materials can be found here:
http://www.umm.edu/news-and-events/...gest-pharaoh-akhenaten-had-two-rare-disorders

Basically, other than new frequency distribution, they seem to be saying that while there was selection and it was recent, there might be something structural going on in that area of the chromosome that drives the passing on and retention of these alleles, and not selection alone.

That makes sense to me given that, as they point out, it's not such a huge selective advantage given that you can make cheese products which spoil less quickly and can usually be digested by most people without real problems.

Anyway, they reiterate what has been proposed previously by Mathiesen that it was present in extremely low numbers perhaps in WHG given the earliest discovery of it was in the Spanish Neolithic, but Anatolian Neolithic people didn't carry it. Their explanation is that it probably served some other purpose but came in handy once domesticated milk producing cattle came on the scene.

Given that and the following graphic I find it odd and amusing but typical that some people insist on tying it to eastern Europe and the EHG. It seems to me much more likely that Indo-Europeans picked it up in central Europe and then carried it all the way to India.

 

[Expredel]

Basically, other than new frequency distribution, they seem to be saying that while there was selection and it was recent, there might be something structural going on in that area of the chromosome that drives the passing on and retention of these alleles, and not selection alone.

That makes sense to me given that, as they point out, it's not such a huge selective advantage given that you can make cheese products which spoil less quickly and can usually be digested by most people without real problems.

A cup of milk has 12 grams of milk sugars. If a cow was producing a gallon of milk a day in the neolithic that's 750 calories worth of sugar.

If you have twelve milk cows you can feed 6 extra people, assuming they are lactose tolerant. It's a gigantic selective advantage.

Anyway, they reiterate what has been proposed previously by Mathiesen that it was present in extremely low numbers perhaps in WHG given the earliest discovery of it was in the Spanish Neolithic, but Anatolian Neolithic people didn't carry it. Their explanation is that it probably served some other purpose but came in handy once domesticated milk producing cattle came on the scene.

People likely ate cheese prematurely, tolerating small amounts of lactose. Those with the mutation would have had an advantage, extra calories, and having sugars in your digestive tract isn't good for you.

Has it been established that the 13910-T mutation didn't develop independently in India? This has a fairly high probability, especially with this new data proving lactose tolerance mutations were strongly selected for.

 

[Angela]

A cup of milk has 12 grams of milk sugars. If a cow was producing a gallon of milk a day in the neolithic that's 750 calories worth of sugar.

If you have twelve milk cows you can feed 6 extra people, assuming they are lactose tolerant. It's a gigantic selective advantage.


People likely ate cheese prematurely, tolerating small amounts of lactose. Those with the mutation would have had an advantage, extra calories, and having sugars in your digestive tract isn't good for you.

Has it been established that the 13910-T mutation didn't develop independently in India? This has a fairly high probability, especially with this new data proving lactose tolerance mutations were strongly selected for.

I think it's probably possible it developed independently in India. If we ever get these ancient South Asian samples from before the arrival of the Indo-Europeans, it will be interesting to see if they carry it.

As for the selective advantage argument, the authors never say there wasn't an advantage. They're just saying it wasn't as extreme as people supposed. I find their statistical analysis persuasive.

Imo, a lot of claims were made about the advantage this conferred when it was part of the "Indo-European" narrative. I always had and expressed my doubts about that, and I think recent research supports my opinion.

First of all, I think it's a mistake to compare modern dairying to dairying in the Neolithic and Bronze Age. Originally, cows didn't lactate year round and the yields were far lower than they are today. Milk also spoils much quicker than cheese, and it can make you, and especially children, very sick indeed.

Second of all, we know from milk residue in food containers that Neolithic people, whether in Anatolia, or central Europe, or the British Neolithic consumed a lot of dairy, and yet they didn't have the derived European version of a LP gene.

That's most likely because they were consuming cheese. Mature cheeses contain very little lactase.

It's even possible to create cheese with no lactase, as the results from the testing of the Bronze Age mummies in China proved.

See:
https://www.usatoday.com/story/tech/2014/02/25/worlds-oldest-cheese/5776373/

"The Chinese cheese dates back as early as 1615 BC, making it by far the most ancient ever discovered. Thanks to the quick decay of most dairy products, there isn't even a runner-up. The world's best-aged cheese seems to be a lactose-free variety that was quick and convenient to make and may have played a role in the spread of herding and dairying across Asia."

"If the people of the cemetery did indeed rely on a kefir starter to make cheese, they were contradicting the conventional wisdom. Most cheese today is made not with a kefir starter but with rennet, a substance from the guts of a calf, lamb or kid that curdles milk. Cheese was supposedly invented by accident when humans began carrying milk in bags made of animal gut.Making cheese with rennet requires the killing of a young animal, Shevchenko points out, and the kefir method does not. He argues that the ease and low cost of the kefir method would have helped drive the spread of herding throughout Asia from its origins in the Middle East. Even better, both kefir and kefir cheese are low in lactose, making them edible for the lactose-intolerant inhabitants of Asia. The new results are reported in an upcoming issue of the Journal of Archaeological Science."


Just anecdotally, I grew up in eastern Liguria/N.W.Tuscany where levels of LP are much lower than in, say, Ireland or Denmark(although I have two copies of the derived version), and perhaps as a result I never saw either adults or children drink milk. I still don't drink it: I just have never become accustomed to it, and I actually really don't like it. However, we eat a lot of cheese, maybe more than half of it sheep's cheese, which also has a lot of lactase, and the rest from cow's milk, and I never heard about people not being able to tolerate it, and believe me Italians are constantly concerned with the state of their digestion. We also have very long lived people, the Sardinians even more so, and they have even less lactase persistence. Italy has also always been over-populated for the amount of good agricultural land. The olive and cheese took up the slack.

I'd also point out that the Chinese have managed to grow a vast population while being severely lactose intolerant.

 

[Expredel]

I think it's probably possible it developed independently in India. If we ever get these ancient South Asian samples from before the arrival of the Indo-Europeans, it will be interesting to see if they carry it.

I doubt ancient samples are lactose tolerant. The vast majority of beneficial mutations arose in the past 5000 years, almost entirely due to massive population growth.

First of all, I think it's a mistake to compare modern dairying to dairying in the Neolithic and Bronze Age. Originally, cows didn't lactate year round and the yields were far lower than they are today. Milk also spoils much quicker than cheese, and it can make you, and especially children, very sick indeed.

Drinking milk doesn't mean you can't make cheese. Once cheese became important selection started that would lead to the milk cow, so year round lactation is likely in the Neolithic.

Second of all, we know from milk residue in food containers that Neolithic people, whether in Anatolia, or central Europe, or the British Neolithic consumed a lot of dairy, and yet they didn't have the derived European version of a LP gene.

I think they'll end up finding half a dozen European mutations that aid in lactose digestion. They probably stopped looking after finding the most effective one.

"The Chinese cheese dates back as early as 1615 BC, making it by far the most ancient ever discovered. Thanks to the quick decay of most dairy products, there isn't even a runner-up. The world's best-aged cheese seems to be a lactose-free variety that was quick and convenient to make and may have played a role in the spread of herding and dairying across Asia."

That would explain the lack of lactose tolerance in Asia. Very interesting find!

I'd also point out that the Chinese have managed to grow a vast population while being severely lactose intolerant.

Mostly due to rice.

 

[davef]

Angela,

you at least like chocolate milk right? I used to love milk, especially chocolate! You should go to the gas station and buy a few bottles of nesquick, you'll thank me later
Back in kindergarten, a kid who sat next to me at lunch was drinking strawberry milk and told me it was "pig milk" (I believed him).
If i had the means, I'd try milk from sources that aren't commonly used for dairy such as elephants, rodents, deer, pigs, horses, antelopes, etc .

 

[Expredel]

If i had the means, I'd try milk from sources that aren't commonly used for dairy such as elephants, rodents, deer, pigs, horses, antelopes, etc .

Might wanna be careful with the bestiality laws these days.

 

[bicicleur 2]

I'd also point out that the Chinese have managed to grow a vast population while being severely lactose intolerant.

milk was part of the early neolithic in SW Asia
in China it wasn't, the population was already vast before milk arrived

 

[SoloWarrior]

This is interesting but Chinese do drink milk. You'll find them drinking such as exchange students & even in Chinese-specific shops.

 

[Angela]

@SoloWarrior
Perhaps it depends on which East and Southeast Asians one has encountered. The ones I know never voluntarily drink milk, in fact we joke about it, and many even have a problem with cheese, even its smell, although as I explained mature cheeses have very little lactose, so it may be cultural or just not having developed a taste for it.

Anyway, the point is that despite not drinking milk or consuming cheese to any significant degree, the East and Southeast Asians have grown very large populations. Lactose intolerance obviously had no detrimental effect. The populations which have survived and thrived have used food products which can be produced in their areas and which they can assimilate without discomfort.

The mantra used to be that the Yamnaya probably had lots of LP because they were "nomads" or "pastoralists", and so being able to drink milk while "on the move" gave them a big advantage. Problem is they didn't carry LP genes, so they wouldn't have been drinking milk. It seems the gene may have been present in WHG, serving some different purpose, was incorporated by farmers in Europe, and then spread.

@Expredel,
The point is that one cannot compare modern dairy yields, which are the result not only of thousands of years of experimentation, but of selective breeding and practices like artificial insemination, to what would have been possible in the ancient periods we're discussing.

In periods like Victorian England milk consumption in cities, where it didn't come straight from the cow, was extremely hazardous, especially for children. That's why pasteurization was such a monumental discovery. I first remember reading about it in an English literature class when we were discussing the work of Charles Dickens.

See:
https://aof.revues.org/310

"Bread was not the only food being altered - tests on 20,000 milk samples in 1882 showed that a fifth had been adulterated - but much of this was done not by manufacturers but by householders themselves. Boracic acid was believed to "purify" milk, removing the sour taste and smell from milk that had gone off. Mrs Beeton told consumers that this was "quite a harmless addition", but she was wrong. Small amounts of boracic acid can cause nausea, vomiting, abdominal pain and diarrhoea, but worse, it was what boracic acid concealed that was particularly dangerous. Before pasteurisation, milk very often contained bovine TB, which would flourish in the bacteria-friendly environment created by the substance. Bovine TB damages the internal organs and the bones of the spine, leading to severe spinal deformities. It is estimated that up to half a million children died from bovine TB from milk in the Victorian period."
http://www.bbc.com/news/uk-25259505

https://theconversation.com/explainer-what-is-raw-milk-and-why-is-it-harmful-35428

This is why I think it's a mistake to extrapolate modern circumstances into the past.

@Davef,

It's not as if it would make me gag or anything, I just would never reach for a glass of milk if I were thirsty. In fact, now that I think of it, I did consume milk at times as a child. My mother would occasionally make me a hot, rice "soup": rice in milk with sugar, butter, vanilla extract, and sometimes even an egg or two for added nutrition. I guess you could say it was like a loose version of rice pudding. My mother worried about me a lot because I was really, really, skinny as a child, and had bronchitis and even pneumonia when I was little, and absolutely would not eat eggs in any form. Now those made me gag, even just the smell of them.

No, I didn't used to mind chocolate milk, even occasionally drank it, but it's sweet. Other than for breakfast I can't imagine drinking it with a meal. I only drink water, flat or carbonated, or wine with dinner.

 

[davef]

Im the opposite, I'm an egg freak. I'll take em any style (scrambles is best) and throw some PEPPER JACK cheese on top with hash browns and ketchup and I'm on cloud 9.

And if the egg smell makes you gag, imagine smelling an egg and provolone omelette as it sizzles in the pan. Trust me, I used to make those and if you crank up the provolone and egg smell by a factor of 10, you'll get an idea of the smell .

 

[LeBrok]

Like with the concept of them being "atheist" - atheist, however, only in western mind for they aren't legitimately atheist - claims about certain Asian countries are to be taken with a pinch or two of salt. Chinese are capable of drinking dairy milk. You will see them drinking dairy milk in western countries, after all, while as exchange students. You'll find milk in Chinese food stores.

Chinese are lactose intolerant to varying degrees. More it is likely due to the fact milk isn't a stable of their diet, period. It is a modern addition. But as they don't "glug" it down like westerners many assume they have to be 'severely' intolerant.

Are you sure it wasn't soya "milk"? Or maybe stuff light on lactose like butter or sour milk? We have to keep in mind that kids of all races are able to digest milk, the problem is with adults ability to do so.

Here, China is not even on the list of milk drinking per capita:
https://en.wikipedia.org/wiki/List_of_countries_by_milk_consumption_per_capita

 

[Expredel]

The point is that one cannot compare modern dairy yields, which are the result not only of thousands of years of experimentation, but of selective breeding and practices like artificial insemination, to what would have been possible in the ancient periods we're discussing.

Modern cows produce up to 8 gallons a day, I used 1 gallon a day in my example. A calf needs about 1 gallon a day. Selective breeding had probably raised this quite a bit by the time lactose tolerance was developed. Milk production likely has an environmental trigger as well, calves do come in twins, so we can easily assume 2 gallons a day.

This is why I think it's a mistake to extrapolate modern circumstances into the past.

You're comparing the 18th century environment to the 5000 BC environment. You do make a good argument that farm life didn't readily translate to city life. In fact, some argue that cities had a negative birthrate for much of human history, requiring a constant influx of peasants to maintain their populations.

As for the selective advantage argument, the authors never say there wasn't an advantage. They're just saying it wasn't as extreme as people supposed. I find their statistical analysis persuasive.

It appears the lactose tolerance gene is in a region that is persistent to recombination. I'm not sure if you read the article correctly in this regard. Because of the lack of recombination it's hard to estimate the age, because the age of the haplotype predates the actual mutation. I hope that makes sense. Whoever wrote the article had great difficulty using clear and concise English so it's open to interpretation.

 

[Angela]

Expredel;523318]Modern cows produce up to 8 gallons a day, I used 1 gallon a day in my example. A calf needs about 1 gallon a day. Selective breeding had probably raised this quite a bit by the time lactose tolerance was developed. Milk production likely has an environmental trigger as well, calves do come in twins, so we can easily assume 2 gallons a day.

I'd be very interested in seeing some papers where the authors have found evidence that selective breeding, modern or even 18th century C.E. dairy management methods, and a production of one or two gallons a day of milk per cow was common in the Bronze Age. I'm not saying it's impossible, but so far all I have is your belief that this was the case.

Just generally, I've seen a lot of speculation that LP was really advantageous in times of famine. I don't know that I believe that anymore. If there's famine it's usually because the crops have failed, often for weather related reasons. In that case, pastures fail too. That's in fact been proposed as one of the reasons that Corded Ware moved into Central Europe.

Now, if it's a pastoralist society, then it's different. If you're a pastoralist who depends almost solely on animals, you would think being LP would be essential. (Yet, Yamnaya people weren't LP, and even today Central Asian herders are less LP than European farmers.) If we're talking about farmers, I've never totally bought the argument. If there's famine, it's probably because the crops failed. If the crops failed because of climate or whether related factors the pastures would fail too.

You're comparing the 18th century environment to the 5000 BC environment. You do make a good argument that farm life didn't readily translate to city life. In fact, some argue that cities had a negative birthrate for much of human history, requiring a constant influx of peasants to maintain their populations.

No, I'm trying to get some actual data on what dairying was like in 3000 B.C. compared to, say, the 18th or 19th century. I also remember reading something to the effect that LP was still not widespread quite a long time after the Bronze Age. The question is why.

It appears the lactose tolerance gene is in a region that is persistent to recombination. I'm not sure if you read the article correctly in this regard. Because of the lack of recombination it's hard to estimate the age, because the age of the haplotype predates the actual mutation. I hope that makes sense. Whoever wrote the article had great difficulty using clear and concise English so it's open to interpretation.

It's certainly possible I misread it. Where, however, do you find anything in the discussion or conclusion that would negate these conclusions?

"The LCT/MCM6 chromosomal region of Europeans had been reported to show one of the strongest ‘signatures’ of selection genome wide (Bersaglieri et al. 2004; Sabeti et al. 2002), namely marked EHH of the derived allele relative to the ancestral allele at rs4988235. While strong selection for LP has been supported by various studies (Aoki 1986; Coelho et al. 2005; Gerbault et al. 2009; Holden and Mace 1997; Itan et al. 2009; Mathieson et al. 2015; Schlebusch et al. 2013; Sverrisdottir et al. 2014), the features of the chromosomal region highlighted here show that other processes, such as recombination, may have influenced the patterns observed."

"This might contribute to a more rapid increase in frequency and help to explain why the effect of selection seems so high for a phenotype whose selective advantage(s) are still somewhat elusive and environmentally variable (reviewed in Segurel and Bon 2017)."

The Segurel and Bon study to which they refer can be found here:
http://www.annualreviews.org/doi/abs/10.1146/annurev-genom-091416-035340

"Lactase persistence—the ability of adults to digest the lactose in milk—varies widely in frequency across human populations. This trait represents an adaptation to the domestication of dairying animals and the subsequent consumption of their milk. Five variants are currently known to underlie this phenotype, which is monogenic in Eurasia but mostly polygenic in Africa. Despite being a textbook example of regulatory convergent evolution and gene-culture coevolution, the story of lactase persistence is far from clear: Why are lactase persistence frequencies low in Central Asian herders but high in some African hunter-gatherers? Why was lactase persistence strongly selected for even though milk processing can reduce the amount of lactose? Are there other factors, outside of an advantage of caloric intake, that contributed to the selective pressure for lactase persistence? It is time to revisit what we know and still do not know about lactase persistence in humans."

Unfortunately, it's behind a pay wall.

 

[Expredel]

I'd be very interested in seeing some papers which proffer evidence that selective breeding, modern or even 18th century C.E. dairy management methods, and a production of two gallons a day of milk per cow was common in the Bronze Age. I'm not saying it's impossible, but so far all I have is your belief that this was the case.

It's common sense Angela. A calf drinks about a gallon a day. If a wild cow has twins I doubt one of the calves will starve, so milk production of wild cows likely increases to 2 gallons in the case of twin calves. When milking a wild cow its biology likely assumes it gave birth to a twin causing it to produce more milk. Even if the maximum milk production was 1.5 gallons artificial selection should have quickly raised this to 2 gallons a day.

This then means you can feed an extra person for each cow you have if they are lactose tolerant. It's a massive advantage and explains why lactose tolerance evolved independently at least 5 times.

No, I'm trying to get some actual data on what dairying was like in 3000 B.C. compared to, say, the 18th or 19th century. I also remember reading something to the effect that LP was still not widespread quite a long time after the Bronze Age. The question is why.

It would have spread with the Germanic expansion which started around 750 BC. Obviously a milk drinking culture requires high LP, otherwise it becomes a disadvantage.

https://commons.wikimedia.org/wiki/File:Germanic_tribes_(750BC-1AD).png

"The LCT/MCM6 chromosomal region of Europeans had been reported to show one of the strongest ‘signatures’ of selection genome wide (Bersaglieri et al. 2004; Sabeti et al. 2002), namely marked EHH of the derived allele relative to the ancestral allele at rs4988235. While strong selection for LP has been supported by various studies (Aoki 1986; Coelho et al. 2005; Gerbault et al. 2009; Holden and Mace 1997; Itan et al. 2009; Mathieson et al. 2015; Schlebusch et al. 2013; Sverrisdottir et al. 2014), the features of the chromosomal region highlighted here show that other processes, such as recombination, may have influenced the patterns observed."

"This might contribute to a more rapid increase in frequency and help to explain why the effect of selection seems so high for a phenotype whose selective advantage(s) are still somewhat elusive and environmentally variable (reviewed in Segurel and Bon 2017)."

The selective advantages are massive. I doubt these researchers are stupid, so they're probably lacking in objectivity or open-mindedness.

The researchers don't provide any hard evidence at all. It's even likely that the gene has multiple mutations that increase LP, just that a mutation that makes LP 100% masks the mutations that are far less effective. Keep in mind that mutations close to (but outside of) a gene can impact gene expression, so what we are seeing here is that mutations outside of the gene were selected for at one point. This makes sense as cheese making may have started as early as 10,000 BC.

We also have to keep in mind that humans take longer to mature, so prolonged LP would have seen selected for regardless.

Edit: Link on human vs neanderthal breastfeeding. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725337/

 

[Angela]

Perhaps you should contact the authors and show them how their analysis is faulty. I'm sure they'd be interested to hear from an expert who knows more about the issue than they do.

By all means also point out to them that they have an agenda. Please report back; I'm fascinated to learn what agenda a researcher working at Cambridge from a country with massively high LP percentages could have...

Refusing to see the complexities of this trait and its spread seems more "agenda like" to me than the very measured and cautious analysis in this paper.

One of those complexities is that one agricultural area, Europe, has such high levels of it, and another agricultural area, China, doesn't have it at all.

Of course, you can believe whatever you want.

 

[Expredel]

Perhaps you should contact the authors and show them how their analysis is faulty. I'm sure they'd be interested to hear from an expert who knows more about the issue than they do.

Unfortunately modern education doesn't select for intelligence and objectivity but for the ability to mindlessly repeat information and use predefined formulas. This then explains the liberal bias among university graduates, despite a high IQ they are unable to change preconceived notions or draw any independent conclusion. Keep in mind that IQ is the ability to solve problems, and liberals excel at finding plausible explanations why their worldview is correct despite overwhelming evidence to the contrary.

If I wrote the authors they'd probably show me the same hostility and inability to grasp very simple logical arguments that you do.

 

[Angela]

The only one exhibiting an agenda and mindlessly repeating dogma is you.

I had a feeling it came from the typical white supremacist "Indo-European" obsessives, and that you would tip your hand eventually.

Honestly, some people are so predictable.

 

[Expredel]

You tip your hand as to your liberal bias by falsely accusing me of being a white supremacists. Let me guess, you call Trump supporters white supremacists as well?

Most conservatives have the same problem as liberals, they are unable to change pre-conceived notions and draw independent conclusions.

I made a very simple and well reasoned argument that Neolithic cows produced 2 gallons of milk a day. This would feed 3 adults with LP, 2 adults without. Even less if we take into account the total calorie expenditure of making cheese. Your insistence that this isn't a large evolutionary advantage can only be attributed to low intelligence or low objectivity, because any objective observer capable of performing simple math will agree with me.

 

[davef]

You tip your hand as to your liberal bias by falsely accusing me of being a white supremacists. Let me guess, you call Trump supporters white supremacists as well?

Most conservatives have the same problem as liberals, they are unable to change pre-conceived notions and draw independent conclusions.

I made a very simple and well reasoned argument that Neolithic cows produced 2 gallons of milk a day. This would feed 3 adults with LP, 2 adults without. Even less if we take into account the total calorie expenditure of making cheese. Your insistence that this isn't a large evolutionary advantage can only be attributed to low intelligence or low objectivity, because any objective observer capable of performing simple math will agree with me.

Calm down, she's not a liberal extremist, in fact she did call out the idiotic Halloween policies set forth by ultra liberal school boards in another thread. And if your theory is proven true by scientific research and published in a journal, I don't see her writing a nasty email to the researchers accusing them of racism.

 

[Expredel]

Calm down, she's not a liberal extremist, in fact she did call out the idiotic Halloween policies set forth by ultra liberal school boards in another thread.

I'm not the least bit upset to be honest, I'm just a very confident Lactose Supremacist.

I do very much appreciate the effort Angela puts into Eupedia. There was a study recently where they found a gene regulation mutation outside the actual gene for some rare genetic disease, so I think it's a matter of time until someone else connects the dots.