The Pith: Natural selection is a quick & dirty operator. When subject to novel environments it can react rapidly, bringing both the good and the bad. The key toward successful adaptation is not perfection, but being better than the alternatives. This may mean that many contemporary diseases are side effects of past evolutionary genetic compromises.
The above is a figure from a recent paper which just came out in Molecular Biology and Evolution, Crohn’s disease and genetic hitchhiking at IBD5. You probably have heard about Crohn’s disease before, there are hundreds of thousands of Americans afflicted with it. It’s an inflammatory bowel ailment, and it can be debilitating even to very young people. The prevalence also varies quite a bit by population. Why? It could be something in the environment (e.g., different diet) or genetic predisposition, or some combination. What the figure above purports to illustrate is the correlation between Crohn’s disease and the expansion of the agricultural lifestyle.
But don’t get overexcited Paleos! There are many moving parts to this story, and I need to back up to the beginning. The tens of thousands of genes which you inherited from your parents are embedded within the genome and aligned in a set of sequences, one after the other. On the one hand for the purposes of conceptualizing evolutionary dynamics, such as natural selection or random genetic drift, focusing on a single gene is useful. It has power to illustrate some basic and elementary principles. But sometimes you need to take a more synoptic view, and look at genes in their broader context. In this post I’ll avoid molecular or statistical epistasis, gene-gene interaction. Rather, let’s just consider the static landscape of the genome, where genes are physical concrete entities which are embedded in a particular spatial relationship to other genes, upstream or downstream in the genetic code. These physical or statistical associations of genes can form a de facto supergene through linkage, and their variants combine to form haplotypes, sequences of markers across small stretches of the genome. But recall that these associations are counter-balanced by genetic recombination, which tears apart physical sequences and sows them to the opposite DNA strand.
The big picture that the above highlights is the fact that evolutionary dynamics operate not just on the gene, but also upon the local genetic neighborhood. Therefore, when we talk about selection upon a gene, we need to recall that this has consequences for that gene’s neighbors. Let’s use a concrete and real example. Northern Europeans tend to have very long haplotypes around the LCT gene, which encodes the production of lactase. Functionally this haplotype has embedded within it a variant which allows for continued production of lactase as an adult, and therefore the ability to extract all the calories from milk beyond childhood in the form of lactose sugar. The molecular genetic details of how this happens does not concern us. Instead, let’s consider why LCT is characterized by a very long haplotype.
This is what we think happened. Between 5 and 10 thousand years before the present there lived an individual who carried a dominant genetic mutation which allowed for the persistent production of lactase into adulthood. Only one copy of the lactase persistent allele is needed for lactose tolerance. That’s why populations such as in Denmark where the persistent allele is present in proportions of 80-90% have nearly universal tolerance. As per the Hardy-Weinberg equilibrium a recessive trait would express at frequencies of 1-4% (square the frequency of the minor allele). Going back to the individual with the mutant copy, if one considers a scenario where lactase persistence would be highly beneficial (this is not hard to imagine) then the frequency of that mutant would rapidly rise. It would “sweep” through the population. As it has a dominant mode of expression half of the children of the original mutant would express the trait and carry the allele, while half would not. Over the generations that one original copy could replicate rapidly within a population due to positive selection and intermarriage.
But it’s not just the functionally relevant genetic variant which would proliferate. The lactase persistent allele would be embedded within the context of a host of other genetic variants across the sequence of the DNA strand in which it was located. As the lactase persistent allele rose rapidly in frequency in a selective sweep its neighbors would hitchhike along. The extent of the hitchhiking would be conditional upon distance from the positively selected variant and the speed of the sweep, which itself would presumably depend upon the strength of selection. All of this together explains the very long haplotype around LCT in Northern Europeans: 5 to 10 thousand years ago a relatively large genomic segment of an individual who carried a lactase persistent allele was driven up in frequency very rapidly because of adaption to new conditions. Not only did that particular individual’s functionally relevant variant, the target of selection, sweep nearly to fixation in some Northern European populations, but many adjacent variants also rose in frequency, in direct proportion from distance from the focal variant. In other words, natural selection in this case was about one specific functional unit within LCT, but as a side effect it also reorganized a whole swath of the total population genome structure of Northern Europeans.
What does that have to do with Crohn’s disease and agriculture? Crohn’s disease may be a modification of the LCT story in a genomic sense, and the trigger of that modification may have been agriculture. Before I go any further, let me post the paper’s abstract:
IBD5 (inflammatory bowel disease 5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn’s disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn’s disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency, and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European…populations…To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high-density microarray data in a sample of 1868 Crohn’s disease cases and 5550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease…In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three gene…as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn’s disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn’s disease patients (p=0.0006) and no significant difference in expression of OCTN1….
It’s all a mouthful. But let’s review here. IBD5 is a 250 kilobase haplotype implicated in Crohn’s disease. A long segment of associated markers which also seem to correlate with individuals with the illness. This does not imply that the whole segment is causally connected with Crohn’s disease. But, there are two genes which have been pegged as likely candidates, IRF1 and IL5. Finally, there’s another gene, OCTN1, which is statistically associated with Crohn’s disease, but lacks a biologically plausible connection. Rather, it seems to have a role in absorption of the amino acid ergothioneine, with the 503F allele of OCTN1 resulting in gain of function in regards to this process. Interestingly the authors observe that OCTN1 is positioned exactly in the middle of the haplotype. In other words, you can think of the genome upstream and downstream of OCTN1 extending out across the haplotype as two wings or fringes of this gene.
The IBD5 haplotype is the broader landscape. IRF1, IL5, and OCTN1 are general features embedded within this landscape. 503F is a specific feature, in that it is a flavor of OCTN1. Crohn’s disease is another phenomenon which has an association with this genomic landscape, but is of a different class or category. It is correlated in particular with IBD5 haplotypes with 503F allele. The main aim of this paper is to tease apart all these multitudinous associations. What the authors found is that in terms of biochemistry the symptoms of Crohn’s disease are not correlated with the 503F allele if that allele is not associated with known risk variants of IRF1 and IL5. These are instances where genetic recombination has broken apart the association which couples 503F with the risk alleles of those two genes. The architecture of the genomic landscape then in this case has obscured the more specific causal chain which leads to an increased risk for Crohn’s disease.
So what happened? The authors posit that the 503F allele was selectively favored at some point in the past, and flanking it were the Crohn’s disease risk elevating variants of IRF1 and IL5. All things equal it is best not to have a risk for this disease, but all things are not equal. If there was a strong enough selective pressure on the target, 503F, then the downsides of the fact that it came as a “total package” with some deleterious alleles would be irrelevant. Over a long enough evolutionary time the deleterious alleles would be purified through negative selection because recombination does break apart associations, but there’s a lot of reality which consists of being between beginnings and ends.
To infer that 503F was the target of natural selection the authors used a haplotype based test for detecting such this phenomeon, iHS. This test tends to detect selective sweeps in midstream, or those which do not shift to fixation because of balancing dynamics. One implication of this is that the allele which was the target of selection will tend to have modest frequencies at best, and that is so. From the supplements here are a list of populations with the percentage of the selected allele (some duplicates because they sampled different data sets):
| Population | N = 503f alleles | N = 503L alleles | % of 503f |
| Sardinian | 40 | 16 | 71% |
| Tuscan | 9 | 7 | 56% |
| Turku | 11 | 9 | 55% |
| Basque | 23 | 23 | 50% |
| Adygei | 15 | 17 | 47% |
| Orcadian | 15 | 17 | 47% |
| Italian | 12 | 16 | 43% |
| Utah | 40 | 56 | 42% |
| French | 24 | 34 | 41% |
| Kuopio | 8 | 12 | 40% |
| Tuscan | 23 | 35 | 40% |
| Pole | 7 | 13 | 35% |
| Druze | 27 | 67 | 29% |
| Russian | 13 | 35 | 27% |
| Uygur | 5 | 15 | 25% |
| Terekli-Mektab (Daghestani) | 13 | 43 | 23% |
| Makrani | 11 | 39 | 22% |
| Balochi | 10 | 40 | 20% |
| Mozabite | 12 | 48 | 20% |
| Palestinian | 19 | 83 | 19% |
| Kalash | 8 | 42 | 16% |
| Pathan | 8 | 42 | 16% |
| Kubachi (Daghestani) | 7 | 39 | 15% |
| Brahmin Niyogi | 4 | 26 | 13% |
| Brahmin | 5 | 33 | 13% |
| Hazara | 6 | 42 | 13% |
| Burusho | 6 | 44 | 12% |
| Brahmin Vydika | 5 | 41 | 11% |
| Sindhi | 5 | 43 | 10% |
| Bedouin | 10 | 88 | 10% |
| Brahui | 5 | 45 | 10% |
| BantuSouthAfrica | 1 | 15 | 6% |
| Yakut | 3 | 47 | 6% |
| Xibo | 1 | 17 | 6% |
| Daur | 1 | 19 | 5% |
| Lahu | 1 | 19 | 5% |
| Tu | 1 | 19 | 5% |
| Yi | 1 | 19 | 5% |
| Cambodian | 1 | 21 | 5% |
| Mbuti Pygmy | 2 | 74 | 3% |
| Mbuti Pygmy | 2 | 74 | 3% |
| Mbuti Pygmy | 2 | 74 | 3% |
| Mbuti Pygmy | 2 | 74 | 3% |
| Mandenka | 1 | 47 | 2% |
| Khonda Dora | 1 | 51 | 2% |
| Irula | 1 | 59 | 2% |
| BiakaPygmy | 1 | 69 | 1% |
| !Kung (San) | 0 | 22 | 0% |
| Alur | 0 | 16 | 0% |
| BantuKenya | 0 | 22 | 0% |
| Biaka Pygmy | 0 | 10 | 0% |
| Cambodian | 0 | 10 | 0% |
| Chinese | 0 | 16 | 0% |
| Dai | 0 | 20 | 0% |
| Han | 0 | 70 | 0% |
| Han-NChina | 0 | 18 | 0% |
| Hema | 0 | 42 | 0% |
| Hezhen | 0 | 20 | 0% |
| Japanese | 0 | 62 | 0% |
| Japanese | 0 | 38 | 0% |
| Khmer Cambodian | 0 | 8 | 0% |
| Malasian | 0 | 12 | 0% |
| MbutiPygmy | 0 | 30 | 0% |
| Melanesian | 0 | 44 | 0% |
| Miao | 0 | 18 | 0% |
| Mongola | 0 | 20 | 0% |
| Nande | 0 | 36 | 0% |
| Naxi | 0 | 20 | 0% |
| Oroqen | 0 | 20 | 0% |
| Papuan | 0 | 34 | 0% |
| Pedi (northern Sotho) | 0 | 22 | 0% |
| San | 0 | 14 | 0% |
| She | 0 | 20 | 0% |
| Sotho | 0 | 10 | 0% |
| Southern Chinese | 0 | 8 | 0% |
| Taiwan | 0 | 6 | 0% |
| Tsonga | 0 | 12 | 0% |
| Tswana | 0 | 14 | 0% |
| Tujia | 0 | 20 | 0% |
| Vietnamese | 0 | 18 | 0% |
| Xhosa | 0 | 4 | 0% |
| Yoruba | 0 | 50 | 0% |
| Zulu (Nguni) | 0 | 18 | 0% |
From these data the authors make the inference that the 503F allele was selected for its enhanced transport of ergothioneine, which is lacking in many plant foodstuffs which became prominent with the Neolithic Revolution. In other words, Crohn’s disease is a byproduct of an adaptation to nutrient deficiencies brought on by agricultural monocultures. The main problem this thesis seems to have is that many Middle Eastern populations which have long been agricultural don’t have a high frequency of the 503F allele. This doesn’t mean that the selective model proposed here is impossible, but, it does indicate that if this was a plausible adaptation then Middle Eastern populations must have their own distinctive variants.
I think this is a great paper, though I’m not confident about the conclusion. Agriculture was obviously one of the major selective pressures on the human genome. Even if some of the preliminary tests of natural selection from the mid-2000s don’t hold up because they tend to confuse genuine natural selective targets from spurious positives I’m rather confident that genes which are associated in some way with agriculture are going to be enriched in terms of functional constraint and adaptive sculpting.
Citation: Chad D. Huff, David Witherspoon, Yuhua Zhang, Chandler Gatenbee, Lee A. Denson, Subra Kugathasan, Hakon Hakonarson, April Whiting, Chad Davis, Wilfred Wu, Jinchuan Xing, W. Scott Watkins, Mike Bamshad, Jonathan P. Bradfield, Kazima Bulayeva, Tatum S. Simonson, Lynn B. Jorde, and Stephen L. Guthery Crohn’s disease and genetic hitchhiking at IBD5, Mol Biol Evol, doi:10.1093/molbev/msr151.
Razib Khan’s degrees are in biochemistry and biology. He has blogged about genetics since 2002, previously worked in software development, is an Unz Foundation Junior Fellow and lives in the western US. He loves habaneros.
August 10th, 2011 at 4:14 am
I worked with a guy with Chrones -quite a mysterious disease. Every time I’d ask him “can you eat this?” he usually reply with a “ummm….maybe.” It seemed like he didn’t even understand it himself.
August 10th, 2011 at 4:29 am
I have crohn’s, and when the disease is acting up, eating is like playing russian roulette. You never really know how something you eat is going to effect you. You can eat something one day and be fine and eat the same exact thing a few days later and be double over in pain.
August 10th, 2011 at 4:54 am
That’s some great data, and confirms a suspicion I’ve long held that we overemphasize the power of recombination to separate the good from the bad. I wonder though if humans represent a somewhat unusual case for observing this sort of extensive linkage of positive and negative selected traits? You have a large recent population expansion into a fairly wide variety of environments.
August 10th, 2011 at 5:56 am
Anecodtally, every person I’ve met who had Crohn’s disease was an Ashkenazi Jew. That was four people who I knew in NYC. Maybe coincidental, but Wikipedia reports that studies have confirmed a higher prevalence of the disease in that population. However, the citation is gives is paywalled and there’s nothing in the abstract about this.
Do you happen to know whether this is true? If so, do you have any hypotheses as to why?
August 10th, 2011 at 8:21 am
#4, i believe it is more common in that group. no idea why. i have known non-ashkenazi jews with crohn’s though.
August 10th, 2011 at 8:33 am
My sister had Crohn’s, but all the women on my mom’s side of the family have some sort of autoimmune disease (usually rheumatoid arthritis). I’ve often wondered if there’s some genetic flaw that predisposes us to overactive immune systems.
August 10th, 2011 at 8:37 am
That’s fascinating!
If the 503F allele (ergothioneine production) selection is for its antioxidant properties, then probably we could expect populations who are highly selected for this, to also be longer lived.
I’ve mostly heard of Crohn’s among Ashkenazi Jews, but the above would suggest that Sardinians have the highest concentration, and lo and behold, both of these populations are among the longest lived?!
I have a sister with Irritable Bowel Disease – and a grand-aunt who died at 103 yo, and some other very long lived relatives…
August 10th, 2011 at 8:55 am
#7, http://www.slate.com/id/2300578/
#6, everyone has ‘flaws’
in any case, i’d like to think that those of us prone to autoimmune responses have some upside.
August 10th, 2011 at 9:09 am
Emily and Paul – I know someone who has both rheumatoid arthritis and Crohn’s. She ended up needing to have her whole bowel removed, and now craps in a bag, if you will please excuse the expression.
She’s 87 years old and still going strong. Lives alone in her own house, no problem. Her doctor predicts that she’ll top 100 easy. There are some very long-lived people in her family.
August 10th, 2011 at 10:58 am
To Kelly: I have it too and you hit it right on the head. Not only do I have a list of what I can and cannot eat, that list can change to *everything* when I’m in the middle of a bad time.. She got it perfect: “Russian roulette” with eating. Although I did just get my 2nd surgery a few weeks ago so I can finally get my state fair corn tihs weekend that I haven’t had in over 8 years
To Emily: One of the weird things they have yet to figure out is a lot of the drugs that work for RA work for Crohns and vice versa. Also a lot of people who get crohn’s develop RA later in life. Just an odd correlation in my opinion..
To everyone else: One of the things the study forgot to mention (chose not too, not sure didn’t read the original study jsut this article) is that Canada (namely quebec area) has an insanely high ratio of people with Crohn’s. The other problem is slide B almost entirely misses the “Fertile Crescent”.. If it were more related to the ‘rise of agriculture’ it has some ‘splainin to do with canada and the fertile crescent.. I am much more in agreement with those that think it is a combination of genes and recombination of allele function..
Either way, and however it turns out, being 18 years into the disease, it is still a thought provoking read..
August 10th, 2011 at 11:33 am
So much more information is tumbling out of science- I have Gilbert’s Syndrome, and the genetic basis of it is interesting, and I imagine is another mutation that is running in the European population. http://en.wikipedia.org/wiki/Gilbert%27s_syndrome
Tracing it would be interesting. Further, it has some very odd side effects, including a significantly decreased risk of heart disease.
For that benefit, you get to occasionally suffer from mild jaundice, especially on a diet.
August 10th, 2011 at 12:41 pm
I wanted to draw the attention of this posting to someone with Crohn’s, but the title put me off :-S
August 10th, 2011 at 1:15 pm
hmm, I may have this. It seems like it may be related to gluten intolerance.
August 10th, 2011 at 1:58 pm
I wonder if Kosher Jews (no meat and milk mixed type of rules) have less trouble with IBS and Crohn’s
August 10th, 2011 at 2:28 pm
Razib, what do you make of the studies in which certain kinds of parasites such as hook worm, appear to significantly impact the symptoms of Crohn’s disease? One thing I’ve been curious about are odd evolutionary effects between human evolution and the evolution of other creatures. Obviously this is a big issue with some creatures (i.e. certain kinds of bioluminescence coming from cultures of bacteria in some fish) While it seems like the medicine is just getting going the evolution seems quite interesting to me.
Obviously if there is a tie to the expansion of agriculture then an interplay between humans and certain parasites makes perfect sense. The problem with genetic studies is that you’d have to study not only human DNA but also the production of these other creatures.
As an aside I’ve heard some are now promoting the hypothesis that the appendix has as its function a storage system for helpful bacteria. If so then that would suggest some interesting interplay between human and bacterial evolution.
August 10th, 2011 at 3:45 pm
Razib, what do you make of the studies in which certain kinds of parasites such as hook worm, appear to significantly impact the symptoms of Crohn’s disease
i don’t know about this specific case, but i think there are many of these interaction effects all around us. that’s why having gene X increases your risk, but is no guarantee.
August 10th, 2011 at 5:50 pm
Razib, do you have a personal interest in Crohn’s disease and research for it, if you don’t me asking?
Admittedly, this research is much too advanced for me. I know very little about genetics, yet believe many autoimmune conditions are the result of epigenetics, the interplay of genes between the environment, intestinal permeability and our microbiome.
August 10th, 2011 at 7:29 pm
#17, no (not that i know of).
August 10th, 2011 at 8:26 pm
Dustin, that’s really interesting. I didn’t know that about Quebec. I wonder if that’s just a random artifact of who ended up colonizing Quebec or something about Quebec as an environment. This paper looked into it, adjusting for native and Jewish ancestry. They suggest that there’s something in the environment acting as a trigger. What on earth that could be I can’t imagine. Perhaps if there is a parasite connection someone should look at the types of parasites in the area and check medical records for things like hook worm. i.e. I’m not sure the Quebec example falsifies the agriculture connection unless we know what it is about agriculture that might lead to Crohn’s. (Assuming there is a connection, of course – that thesis is still somewhat in doubt)
August 10th, 2011 at 8:27 pm
Hookworms are fairly easy to explain; in order to make a proper “home” for themselves, they tweak TH1/Th2 autoimmunity in their favor. In this case, it happens to favor the host by decreasing inflammation. However, it’s by no means an explanation in terms of the origin of the disease; not everyone in countries where colitis is rare has a nest of hookworms in them. You would expect to see a smaller number of Crohnies, but not a zero number- as was the case for the entire Ivory Coast until 2004 (Med Trop (Mars). 2004;64(4):384-6. [Crohn's disease: first report in Côte-d'Ivoire]). Trowell and Burkitt (British-trained physicians) noted the near-absence of Crohn’s in Africa in their 1977 book on fiber (insisting that fiber was the preventative factor).
In fact, an entire chain of events has led to the identification of the “hygiene hypothesis,” suggesting not enough dirt and grit is responsible for Crohn’s. However, it seems more likely that the reason IBD is nearly absent in these developing countries is 1) lots of UV light resulting in 2) large amounts of vitamin D. Populations in urban areas tend to move indoors, and northern populations tend to get less sunlight; we know already the incidence of multiple sclerosis (another cryptic disorder) increases with distance from the equator, and studies have suggested more vitamin D (through UV or diet) decreases the severity of disease for both these disorders.
Ebringer in the UK has suggested ankylosing spondylitis (AS) is caused by molecular mimicry with proteins from Klebsiella pneumoniae; although generally well-accepted, his corollary (that Crohn’s is caused in a similar fashion- different target organ) is not. I would humbly submit that those who suffer with Crohn’s pursue a starch-free, low-carb diet- WITH NO GRAINS. Put me in remission for >3-1/2 years now; blood values are normal, and my life is back to normal, no meds.
August 10th, 2011 at 10:18 pm
OT
I haven’t seen you blog about this paper. (I wrote what follows for some other blogs so the language is simpler than I’d use to you, but what hey, just cutting and pasting.)
I know you’ll be very interested in a study that was published on Tuesday in a peer reviewed journal. It finds that at least 51% of fluid (problem solving) IQ is due to the additive effects of a lot of different genes. It’s a very large study with a sample size of more than 3500. Although there have been many suggestive hints about genetic variance effects on intelligence this is the first comprehensive direct proof, or something close to it, I believe.
http://www.guardian.co.uk/science/2011/aug/09/genetic-differences-intelligence
The article links the research paper.
August 10th, 2011 at 10:35 pm
#22, you’re the second person to OT this. i recommend twitter/fb/emailing me this stuff. or perhaps an open thread would be more convenient? anyway, i’m blogging the paper now. i’m going to start deleting OT comments.
August 11th, 2011 at 9:09 am
What’s the relationship between ergot (fungus wheat rust) and ergothioneine besides naming? Would there be some relationship between 503F and the capacity to tolerate eating large amounts of rotting grains?
August 11th, 2011 at 1:58 pm
#7, its a bit of a stretch to connect anti-oxidant absorption (and I am not sure how this SNP affects the absorption of other anti-oxidants at all) to longevity because feeding people anti-oxidants does not seem to make them live longer…http://www.slate.com/id/2300578/
August 15th, 2011 at 10:32 am
I’m an Ashkenazi Jew with Crohn’s. I manage my disease quite successfully with a paleolithic/traditional diet that includes fruits, vegetables, nuts and seeds, meat and fish, and cultured dairy. I also eat a lot of cultured foods such as sauerkraut, yoghurt, cheese and kombucha. I’ve been healthy and symptom-free for more than six years. This is an interesting article about the genetic link, but to understand the disease, one must look at the recent research that’s been done on the connection with intestinal bacteria, which is also related to the consumption of refined carbohydrates and starches.