A friend of mine once had an encounter with a fairly prominent geneticist* who thought that there was only one clear example of heterozygote advantage in humans – sickle-cell. Of course that is not the case: we know of a number of genetic malaria defenses that work in similar ways – alpha-thalassemia, beta-thalassemia, G6PD deficiency, Melanesian ovalocytosis, etc. Not all such are malaria defenses: cystic fibrosis has some advantage, nature unclear, but it’s not malaria resistance.
CF is mostly a European disease, particularly in northern Europeans and their diaspora. The gene frequency for CFTR mutations is around 2%, mostly one mutation, delta-508. It’s easy to show that CFTR mutations have some sort of heterozygote advantage, although that same fairly prominent geneticist didn’t think this had been established. Realize that the input of new mutations per generation is insignificant. Without any advantage in carriers , the frequency of mutated CFTR genes should slowly decline, since the mutation used to be lethal in homozygotes and is still very, very unpleasant. The rarer these mutant alleles get, the slower the decline, since a smaller fraction of them run into each other.
But if you run time backward, the frequency should increase more and more rapidly. If there was no advantage in carriers, a frequency of 2% today implies a frequency of 50% 1200 years ago. Takes a code of several lines to show this!
The scenario is ridiculous. This would require a super-tight bottleneck, in which Europe was first wiped out and then refounded by a population of 2 about 1200 years ago, but that never happened – although it might seem reasonable to some young geneticists. When John Hawks and I talked about the genetic impact of the big population expansion in the Neolithic, which greatly increased effective population size, I remember a person like that saying that we didn’t really know that there was a large ( >> 10,000) population in Pharaonic Egypt. I guess he thought that Paul Bunyan built the Pyramids. By the way, another very prominent geneticist, upon hearing our idea, asked “Why would there be more mutations with a larger population?” I got a million of ’em!
I think I don’t know what the advantage was. This puts me ahead of many people, including Wikipedia, because they think that it’s a cholera defense. It may well protect against cholera in carriers, but that’s not why it became common, because cholera was never seen in any part of Europe until 1817. Better to know nothing than to know what ain’t so. The people who proposed that in Nature weren’t stupid – they had evidence that it protected against cholera in vitro. They were merely deeply ignorant of history. Which is stupid.
* although I have never quite been able to figure out what he is famous for. I have another, much funnier anecdote about him, by the way.
West Hunter 
How about hereditary hemochromatosis? Do you think it conveys heterozygous advantage?
Obviously.
I have felt for several years that all or almost all ARD’s persist because of heterozygote advantage. Reasonable?
The ones that are especially common and widespread do. Less common ones, mutational pressure and founder effects.
In the case of Huntington’s Disease does it persist because symptoms usually appear in later life after the individual has already had children? So despite being a terrible disease it doesn’t reduce fitness that much?
That’s the general idea with autosomal dominant disorders like HD, but it’s complicated. First off, why would even a slight reduction in fitness persist? Some observant clinicians have long suspected that disorders in this group may be associated with enhanced fitness in youth that typically, only becomes a problem after the reproductive years. Myotonic dystrophy, the most common muscular dystrophy, may fit this pattern – a surprising number of patients are quite athletic in youth despite moderate to severe physical disability beginning in middle age.
Many of these autosomal dominant disorders, including HD and MD, are trinucleotide repeat disorders. Here, there is a threshold of repetition for a given trinucleotide, say 27 CAG sequences in a row in this case, within DNA coding for the relevant protein in HD, called huntingtin. 27 repeats would be normal. Adding more CAG sequences to this increases the likelihood of HD and, when HD does appear, also decreases the age at onset and increases the severity. MD and all the other trinucleotide repeat diseases work much the same way.
For some of these disorders, there is evidence that a limited addition of trinucleotide repeats can result in improved function of the affected protein. This may help explain the origin and persistence of the disorders and would represent an autosomal dominant type of heterozygous advantage. It could also correlate with the anecdotal clinical tradition of, say, an athletic youth for MD patients.
A very interesting aspect of these disorders is the phenomenon of genetic anticipation within affected families: the number of trinucleotide repeats tends to build up within a given kindred with each affected generation. So the affected founder of a given HD kindred, for example, might have 40 repeats and mild HD with late onset, an affected child might have 50 repeats and develop moderate HD starting at age 50, and an affected grandchild might have 60 repeats and develop severe HD starting at age 40.
This has micro-Darwinian implications within these kindreds, implications that also help explain the persistence of the diseases. The reason is that as anticipation progresses in a kindred, it will eventually reach the point where an affected individual is not suitable mating material at a reproductively more optimal age (take the above example even further and suppose it eventually leads to an affected individual, with say, 80 repeats, who is beginning to show quite odd behavior at age 20).
What may be going on in these disorders is that the primary effect is via DNA polymerase. Imagine for example that there is a mutation telling the polymerase to, in effect, ‘add 10 more CAG’ and this is actually the ‘command’ that’s inherited. At low repeat numbers, the altered protein product, huntingtin say, may be beneficial, but as each generation gets 10 more, the disease appears, then gets worse, until it disappears in that branch of an affected family in the way I have outlined, by which time it has probably started up again in another branch. In this way, autosomal dominant disease can persist.
PS: Any ‘autosomal dominant heterozygous advantage’ would just be the usual benefit of an advantageous expressed allele, except in this case it comes at the cost of disease later in life, or in subsequent generations (the latter being equivalent to later in the allele’s life).
John Hostetler – Thanks for your very informative replies. I have an in-law who has Hintington’s Disease. I believe he has about 50 repeats. When younger he was extremally successful in the software industry. He is now beginning to exhibit evidence of delusional beliefs.
The HD mutation is the excessive repetition of a trinucleotide in the gene. There is an idea that DNA replication may be particularly prone to this sort of error, due to the difficulty of accurately aligning two DNA strands in a region where they both have a long series of repetitions. So it’s conceivable that the problem is that the mutation rate for this particular mutation is quite high.
@Jim: Interesting but unfortunate for your in-law. Since HD is a disease of cognition, behavior and motor patterning, the equivalent to ‘myotonic dystrophy patients who were particularly athletic when young’ might be ‘HD patients who were particularly creative when young.’
In that regard, history’s most famous HD patient, Woody Guthrie, is interesting, though clearly one can’t make science from an n of 1.
For the whole trinucleotide advantage hypothesis to make sense, it would be good to look at the asymptomatic carrier relatives of index patients, those with a borderline number of repeats: they should have higher than expected motor capacity in MD lineages, say.
@Dale: The rate of new mutation for HD is very low.
Last I checked, it also seemed that HD incidence is much higher in Europeans than in Africans or East Asians. Possibly because of predisposing haplotypes. True?
@Dale: Thanks for providing the spark to dig a little deeper: it looks like the classic teaching on HD, that new mutations are rare, and which I repeated above, must be reconsidered. It goes back to the time before the trinucleotide repeat mechanism was known: the observation in medical genetics clinics was that one could nearly always find an affected relative of the index patient in HD kindreds, and where one couldn’t, dyspaternity was usually admitted or suspected.
However, now that the trinucleotide mechanism of genetic anticipation is understood, we can see that the great majority of HD kindreds had multiple affected relatives (thus ‘no new mutations’) because that mechanism makes for a pool of potential HD candidates in every family, as some progress from normal-length CAG’s, to at-risk length, to affected length.
Then when you consider those population studies, you realize that what’s really going on is that the whole idea of new mutation, as it would apply to many non-repeat genetic disorders, does not apply here. Europeans for example, have the highest mean CAG length in their huntingtin genes, and thus constitute, as a whole, an at-risk pool. When these get a little longer still in selected families, some members of whom eventually develop HD, is that really a new mutation? One could arbitrarily select some CAG length and call that a new mutation, but there is no fixed relationship between CAG length and phenotype anyway, just a very significant trend.
The population studies really bring to mind a certain phrase well known here – ‘a race is a large extended family that is slightly inbred.’ I find it unlikely that the differences in CAG length around the world are due to chance, and I wonder more than ever whether the trinucleotide repeat disorders could provide the same sort of ‘this is the genetic cost of that’ clues seen in ARD’s like Tay-Sachs.
That’s my understanding too.
http://hmg.oxfordjournals.org/content/3/12/2103.abstract
The association with increased CAG size in normal N. European chromosomes is interesting. I wonder if huntingtin plays a role in Western dynamism versus East Asian conformity. (And I was surprised at how Wade basically got away with taking this trait difference as given in ATI.)
“The CFTR gene normally creates a protein that regulates levels of sodium and chloride in cells. If the CFTR gene is defective, it results in a build-up of thick, sticky mucus in the body’s tubes and passageways. ”
Typically, people with (comparatively small levels of) excess mucous are put on a dairy-free diet. Is there any possibility that CF could be linked with lactase persistence?
Alternatively, or additionally, it should be associated with something affecting renal physiology https://www.inkling.com/read/renal-physiology-koeppen-stanton-5th/chapter-6/regulation-of-extracellular
Maybe the way the kidney functioned had to adapt to milk-drinking?
I notice Professor Hawks never posts on these blogs despite his research interests, and has no comments on his own. If I pointed out this is a snub, it would sound like an accusation of snobbery. But I can’t blame him, and not just because of the politically motivated gobshites who know nothing, hanging out in the comments (the creepy people have already been asking wether hes racist.) Theres also unprofessionalism in the HBD-o-sphere with a speculation becoming accepted and repeated as fact among anonymous bloggers and commentors.
Though I don’t have anything against for example the gay germ idea, people are talking about it as though it were a proven truth. Then worse still, anyone who objects is accused outright of a presumed political motivation. This is what the sinister radical anthros do of course, but at least theyre a bit more slick and organised. HBD is its own worst enemy in my view and I see it more as an online subculture than anything serious in scientific (or political) intent. That subculture is based on anything the shitlibs dislike, because HBD dwells upon pissing them off, ergo the overlap between HBD and everything between PUAs and anarcho-capitalism. It is kneejerk and silly, and people who use the word HBD seem interested in spamming other peoples Twitter and blog comments like kooks, making the research into an easy straw man to knock down.
1UP. I totally agree that kneejerk contrarianism and HBD orthodoxy are serious problems. Don’t expect me to believe global warming is a hoax just because this or that blogger does. Don’t expect me to believe in fat acceptance just because of some outlier study. Even the heavy emphasis on IQ science makes people seem small or maladjusted like teenagers who say “YES!” whenever they get a right answer on a test question gone over in class.
Even the term “human biodiversity” has neo-Nazi overtones, like we’re comparing racial purity to ecosystem sustainability. If we need to maintain human diversity by banning racial mixing, what should we do with people from Spain and Italy?
Neo-Nazi overtones? Come now. We’ve got to call human variation by groups something, what on earth do you want to call it? I agree, some HBDers go overboard, but this is just silly.
If the words “Chicago” and “you people” are racist, then “human biodiversity” is certainly racist. Biodiversity is a prescriptive cause. We could call it “human biological diversity.” We could say that there is meaningful diversity within our species, which would really F with their heads. We could not label ourselves and spend our energies actually pointing out specific biological differences between populations. Since they are so obsessed with telling us not to say “race,” we could pepper our language with “place of origin.” I used to like “race realist” because it doesn’t mince words or suggest an agenda, but I think Jared Taylor came up with it.
nooffensebut,
Must everything be about you? You continually hoot on about MAO-A like a boy humping on a single piano key to the irritation of the entire room. We get it. You’re famous. Nicholas Wade mentioned you in a footnote. Or came close to mentioning you. In any case, your centrality to the story is apparent to you. Move on.
What’s more, you’re now making the strangest inferences, jumping from neo-Nazis to IQ mongers, from global warming skeptics to fat acceptance, and laying it all to blame on the HBD community … or contrarians … or something. You hop around so much it’s hard to follow your argument.
Plainly, you’re unhappy and want people here to know about it. Consider us informed. Now can you aim your splenetic effusions in a more worthwhile direction? It’s not that I don’t consider your campaign against neo-Nazis to be an important crusade, but perhaps a foe that actually has some power and influence in the twenty-first century might be more worthy of your attention.
Now, there is an effective strategy. Vague incoherence is an impervious target. Loser neo-Nazi strategies are really small, so I should stop picking on them. I actually think they are kind of cute, dividing up American territory on maps, but they should do it wearing special hats, like maybe ancient Roman helmets or something. Portlandia should do an episode about when white nationalists decide they are taking command. I also like how you call me vainglorious for writing about a specific gene, the lesson being that I should only write about IQ like everybody else. That must be why your writing is so memorable. Or is the lesson that I should be writing about many specific genes? That will go over well with GWAS Jihadists. You criticize me for being “unhappy.” Others criticize me for making offensive jokes. They say it makes me a neo-Nazi. I think you are all conspiring to make me dizzy with your stupid stupidity.
I’m not the kind of person who uses the word ‘racism’ but on the subject of racial biases in HBD, the racialists over at MPC agree with the anti-racist interpretation of HBD as nunge wink racism.
Most of HBD seems obsessed with demonstrating Anglo supremacy and African inferiority – most HBD people are English speaking whites topped up with high IQ market dominant minorities. (From an ethnocentric and working class white perspective, such people are potentially as dangerous for whites as are blacks, just in a different way – why would they push white intetrests?) There are exceptions like Robert Lindsay and JayMan, but this is true as a rule so everyone notices it.
Actually the traits they favour in the English (and English-like cultures) are of dubious worth. At present the values of Anglo society are working as a death sentence for themselves and for others who have attempted to adopt them.
Likewise the eugenics kick many are on as regards intelligence. It never seems to dawn upon IQ people, that the present idiocracy is nothing compared to the damaging idiocy of smart people with abstract ideas. Yet we ‘need’ more smart people, getting educated (indoctrinated) in hostile universities, coming up with new and toxic ideas. It seems to me that their eugenics is based around a self-image as superior, and a disdain for less fortunate whites.
There isnt really a reasoned perspective on eugenics or on race. But shared narratives about the subjects are common enough in the HBD subculture.
Could you explain how it is different from nudge wink racism?
nooffensebut,
Not at all. Keep up your fine work of fighting Colonel Klink. Should we pitch in to buy you a uniform for your service?
I don’t hand out lessons, and your work doesn’t bother me. Your continual self-promotion at everyone else’s expense is a little annoying, however.
I noticed you over at your site latching on to IQ as an explanatory mediating factor when MAO-A doesn’t have a straightforward relationship with race and violence. So apparently you buy into the importance of psychometrics when it has something critically important to say about your favorite subject. I guess those psychologists have something useful for you, after all.
It is indeed a conspiracy. We’re trying to wind you up because we’ve invented a drinking game where everyone at the table has to drain their mugs whenever you interrupt a discussion to talk about the warrior gene. Like all good drinking games, it’s designed for maximum effectiveness.
I think everyone should remember that Cochran’s post is about cystic fibrosis. I did like B&B’s comment, and I wanted to add to it, but it is only Pincher Martin and LeadingLady who wanted to turn this forum into an indictment on me and MAOA. Too bad they have nothing intellectual to say about either.
I never said that IQ research was bad, I just said that the details within that field aren’t worked out and adequately connected to hard science, yet. I forgot to mention that, before he died, Arthur Jensen personally handed me three free passes that allow me to say wrong things about IQ without you all getting on my case. So there!
nooffensebut,
Here’s a wonderful quote from Francis Galton about the limited apprehension that most people – even most educated people who profess to be interested in scientific topics – have after listening to a learned public lecture:
With this in mind, how is it that you expected the commentators at these various so-called HBD sites were going to perform any better?
Some folks were bound to misinterpret what they heard, like those who think IQ explains everything under the sun; a few, like malicious racists, were bound to abuse the knowledge (although I suspect they didn’t need any new knowledge to go that direction); and some were inclined to learn a little from it.
But how is this really different from any other intellectual movement? As an area of knowledge grows more popular with the public, it’s inevitable that many people – including many smart and educated people – won’t understand what they hear or will abuse and twist it for their own purposes.
That will happen no matter what safeguards a public intellectual takes, and no matter how carefully and frequently he explains the subject matter.
So why worry about it? Out with the truth, I say. People can abuse lies just as easily as they can abuse the truth.
To me, the far more interesting and important topic than misinformed HBDers and neo-Nazis – and it’s covered here in Greg’s post about cystic fibrosis – is why scientists frequently don’t seem to know their fields as well as we think they should and why they often abuse their knowledge for political reasons.
If the neo-Nazis ever seem on the verge of moving out of their mothers’ basements and taking power, I’ll change my mind about the relative importance of these two topics. But until then I think your attention is misplaced.
That quote justifies my tolerance of this off-topic and acrimonious subthread. But no more, please.
I never comment but this needed to be said. I was just thinking about this because it’s getting embarrassing. Gay germ theory (no offense to Greg but there are people who won’t shut up about it despite there be no evidence for it.), MAO-A aggression correlations, hajnal line, inbreeding – outbreeding, citing Kanazawa, speculation about Idiocracy, a lot of the stuff Wade said (even though I love that he said it and loved the book.), basically everything Mangan types, etc. are all pretty much just guessing and will probably be wrong or way off. Greg Clark’s book shouldn’t be Gospel yet. Science is science so let’s stop pull back from turning it into D&D make-believe science. I say this with love even though it sounds mean.
“MAO-A aggression correlations …are all pretty much just guessing and will probably be wrong or way off.”
YeahhhhhhhhNO. You know that I love to debate this. What do you need to be convinced? Apparently not meta-analyses. You want to trash decades of research, explain away Brunner syndrome, CSF 5-HIAA correlations, imaging, etc. Okay, give it your best shot.
@nooffense I put that in there ESPECIALLY for you:) There’s a reason why you get ignored/banned around the web. Believe me when I say I *want* it to be true but pretty much the only credible evidence supporting it simply shows that people with that variant have a harder time *recovering from trauma.* And that’s pretty much all there is to it. A study with a sample of 100 like you enjoy citing is pretty much completely worthless.
“Science is science”: them wuz the days.
“ESPECIALLY for you:)”
Well… isn’t that special.
“ignored/banned around the web”
Ignored? I don’t write a blog post for six months, but my blog keeps gaining popularity. I would say that my influence is growing via my influence on Ron Unz, Kevin Beaver, and Nicholas Wade.
I only know of one place that I was temporarily banned. YouTube deleted my account when I posted The Genetics of Black Violence, which consisted almost entirely of study verbiage. It wasn’t that great of a presentation, but it still received multiple tens of thousands of views. I am proud that Razib Khan threatened to ban me when I criticized John Horgan on the subject of the genetics of violence. I have pointed out that Horgan spread the anti-Chinese copy-and-paste error claiming that 77% of Chinese men have MAOA-3R, which Khan failed to notice in his review. Later, the “HBD community” took notice of Horgan when he called for researchers who study race and IQ to “be detained indefinitely in Guantanamo.”
“the only credible evidence supporting it simply shows that people with that variant have a harder time *recovering from trauma.* And that’s pretty much all there is to it.”
I would understand people feeling annoyed and accusing me of monomania about MAOA or SAT data, but I think specialization makes sense. Most people in HBD Land worship people like Gregory Cochran, Arthur Jensen, Charles Murray, Steve Sailer, etc., become IQ generalists, and try to pile on whenever IQ is in the news. I think it would be more effective to find a smaller niche, gain expert knowledge, and serve as a go-to person on that subject. From what you just wrote, I do not speak nearly enough about MAOA because you haven’t the slightest idea what the research actually says. I calculate an MAOA sample size of 15,232 for the Ficks and Waldman 31-study meta-analysis that just determined that MAOA-3R has a slight main effect (meaning no child abuse considered), just as I would have predicted.
“A study with a sample of 100 like you enjoy citing is pretty much completely worthless.”
I enjoy citing Fergusson et al, which had a sample of 1,265, because it proves that the obsession with only considering MAOA in the context of child abuse is just a social-science ideological bias. The MAOA-IQ interaction is more important than the interaction with child abuse. The unwillingness of scientists to study MAOA-IQ interaction more is not an argument against it.
Moreover, I do have an MD, and I do consider it highly offensive that GWAS Jihadists are convincing credulous people like you that small-sample research, like imaging studies and studies on rare diseases, is worthless. I guess you could put observations about this phenomenon in the category of, how do you say, “speculation about Idiocracy.”
I sincerely hope you’re right but I doubt you’ll ever be vindicated. There’s just not much there and you know it, deep down.
John Hawks is incredibly busy and has to manage his time. I have no idea where he finds the time that he does to devote to his wonderful blog. Perhaps slave grad assistants, check it out http://johnhawks.net/article/. I linked you to the stories section.
John Hawks probably blogs too much as it is. He is one of those guys who has the ability to make a contribution to mankind and blogging is just a distraction. I read his blog religiously but it makes me feel a little guilty. I want him back in the field not amusing me over my coffee.
What does “PUA” mean?
http://lmgtfy.com/?q=pua
Seriously, Google exists for a reason.
Now, there is an effective strategy. Vague incoherence is an impervious target. Loser neo-Nazi strategies are really small, so I should stop picking on them. I actually think they are kind of cute, dividing up American territory on maps, but they should do it wearing special hats, like maybe ancient Roman helmets or something. Portlandia should do an episode about when white nationalists decide they are taking command. I also like how you call me vainglorious for writing about a specific gene, the lesson being that I should only write about IQ like everybody else. That must be why your writing is so memorable. Or is the lesson that I should be writing about many specific genes? That will go over well with GWAS Jihadists. You criticize me for being “unhappy.” Others criticize me for making offensive jokes. They say it makes me a neo-Nazi. I think you are all conspiring to make me dizzy with your stupid stupidity.
@B&B:
You paint too broad a brush. “HBD,” in my view, is limited only to me, hbd chick, Peter Frost, misdreavus (though he doesn’t blog), Audacious Epigone, Steve Sailer, Razib Khan (though he doesn’t identify as such) and maybe a handful of others. The rest, the echo chamber, is largely people with various axes to grind that find HBD-inspired ideas expedient for their own purposes.
‘very prominent geneticist, upon hearing our idea, asked “Why would there be more mutations with a larger population?”’ Is he a fool more generally, or only a focussed fool?
He doesn’t seem to know or believe in theory generally, in genetics. But that’s not so unusual, really: true of lots of people in the field.
I think it depends on how the trace is configured with the phenotype. Perhaps, cystic fibrosis was not so bad when it was supposed to inherited 50% of the population or at least his version heterozygous.
When a trait is relegated to the status of recessive, it can lose its advantage. Recessive disadvantageous and may be for a few times.
Maybe the Europeans of the past inherited condition but without expressing it and change the selection to become directly disadvantageous.
Maybe you don’t have the faintest idea what you’re talking about,
Maybe I have.
No, you don’t. The most common CF allele completely wrecks the protein – it never gets exported from the cell. With two copies of delta 508, no CFTR gets anywhere, your lung are screwed up and you die young. There is no way to ‘not express’ that. With antibiotics and other more advanced medical treatments, life expectancy is about 30. It’s a nasty disease.
How do you make sure that ?? Have you ever investigated the entire population to have made sure that there is no such possibility ??
There is not only the homozygous and heterozygous condition of a demographically minority. A minority phenotype can spread into smaller by much of the population leads.
For example, genes for schizophrenia (ok, next time, if there is a next time, I will change the example). Only 1% of the population is homozygous and we think it could be up to 4% heterozygous, ok, may be less, but this is not the most important. The most important is that everyone has at least some fraction of these genes.
The increased genetic load can cause schizophrenia or genius while the majority of the population has a limited number of these genes or lower.
Why not think the same thing for cystic fibrosis ??
Suggestions only, calm down man, his fame is not the best.
I know that cystic fibrosis is a serious genetic disease, such as that neurological disease affecting Ashkenazi Jews, I forgot the name.
We are dealing with a case of coevolutionary pathogenesis, when the pathogen adapts to the body of a minority of people, but rather to cooperate with the carrier, it attacks.
The same thing happens with schizophrenia.
I left the idea that half of Europeans in the past could have been carriers of the disease. As you said yourself, this is technically impossible. So I thought of a way to make this possible, happens could be true.
Some people are vulnerable to certain viruses while others have ‘adjustments to it’ as cases of AIDS patients who not manifest the disease.
I think it’s fun when I see a group of scientists denying absurd ideas, when their works are based on reviews of previous absurd ideas that were vilified in the beginning. Will learn when?
I do the idea that genetic traits are malleable in the long term as your inheritance and that when they are demographically recessive, they can not manifest predominantly sustainable way. Most traits with low heritability are not being selected, but remains because they are a universal heritage, prior to any specific founder effect of any human variety.
I’m just suggesting what may have happened, but it seems that good manners are not a behavioral priority at prestigious universities.
And if I did not know what you were talking about, I would not be here.
Genetics, mathematics, music, survival, politics, conspiracy theories … everything can be understood through standards. Science just follows them.
Genetics, mathematics, music, survival, politics, conspiracy theories … everything can be shredded and stirred into logic hash with word salad on top.
The history of once-thought-absurd ideas actually is interesting and actually gives rise to interesting philosophical problems. Up to about Popper philosophers of science thought seriously and somewhat productively about it. Post-Popper, the statistics and machine learning people successfully took up the thread about the time that pompous political goofs finished their takeover of academic philosophy. Historically, it is not so easy to find historical cases where it was smart to bet on the thought-absurd idea except when (1) the evidence for it was quite strong or (2) when there was good reason to think that the claims of absurdity followed from a political agenda rather than technical. Logically it is neither incredibly easy nor incredibly hard (given prerequisites like calculus and information theory) to understand and apply the modern analyses (like http://en.wikipedia.org/wiki/Minimum_description_length and http://en.wikipedia.org/wiki/Vc_dimension) of how reasonable it is to infer something from a given dataset. And just as actual QM and actual relativity don’t mean that it’s useful to trot out woo paraphrases like “everything is uncertain” and “everything is relative”, actual learning theory doesn’t make the point leading up to “Will learn when?” useful or sensible: it’s just thought blue cheese dressing on a bed of scrambled thought Ho Hos.
santoculto – I’m really having difficulty understanding your last comment. I take it from your somewhat bizarre syntax that you are not a native speaker of English.
Looking at his webpage it seems like he’s a brazilian.
My working hypothesis has been that it is Gottlieb with improved English.
Me. When I talked about absurd ideas I was ironic, to ”aspie” who responded to my first comment, Mr. Newman. I would suppose that their political agenda embedded within the science Mr. Newman would be the normativity of the most ancient and primitive social agenda of the human species.
The vast majority of scientists of Darwin’s time, gave laughter of his theory. Always is and always has been so, until when?
I will briefly repeat what I wrote in the last comment.
The degree of heritability is temporally recessive or dominant. What today is demographically dominant, can become recessive. Recessive traits when they are not being selected, tend to deteriorate or to regress to its previous state, metamorphic pathogens.
I only suggested that cystic fibrosis could be present in 50% of the population, at least if this population had another phenotype where the ‘genes’ of this disease are in harmony with the body and therefore presenting an asymptomatic. One theory, a suggestion.
Incoherent I can put with to an extent, crazy also, but the combination isn’t all that interesting. Banned.
R-A-T-Z.
The most likely candidate for advantage is Typhoid.
http://www.ncbi.nlm.nih.gov/pubmed/16078047
Hum Genet. 2005 Oct;118(1):138-40. Epub 2005 Oct 28.
Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR).
van de Vosse E1, Ali S, de Visser AW, Surjadi C, Widjaja S, Vollaard AM, van Dissel JT.
Author information
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is the affected protein in cystic fibrosis (CF). The high rate of CF carriers has led to speculation that there must be, similar to the sickle cell haemoglobin advantage in malaria, a selective advantage for heterozygotes. Such a selective advantage may be conferred through reduced attachment of Salmonella typhi to intestinal mucosa, thus providing resistance to typhoid fever. We tested this hypothesis by genotyping patients and controls in a typhoid endemic area in Indonesia for two highly polymorphic markers in CFTR and the most common CF mutation. We found an association between genotypes in CFTR and susceptibility to typhoid fever (OR=2.6). These analyses suggest that the role CFTR plays in vitro in S. typhi infection is also important for infection in the human population.
Makes sense. I have thought that typhoid was a good candidate for some time, in part because it has a carrier state and thus could have been a problem far back in the past, at low population density.
I ran into http://www.jstor.org/discover/10.2307/41465408?uid=3739696&uid=2129&uid=2&uid=70&uid=4&uid=3739256&sid=21104577973743 which says that a lot of CF mutations seem to have spread from a founding location, and identifies them. So it looks like there was a general disease problem across Europe, causing a lot of resistance mutations to start spreading from wherever they showed up first.
Hmmm, looking at the linkage statistics of those mutations might allow us to date the appearance of the disease that heterozygous CF protects us against.
Here is a set of thoughts
Hypothesis: Cystic fibrosis carrier geography reflects interactions of tuberculosis and hypertension with vitamin D deficiency, altitude and temperature. Vitamin D deficiency effects and CF carrier advantage. – Lubinsky M – J Cyst Fibros – 01-JAN-2012; 11(1): 68-70 (MEDLINE® is the source for the citation and abstract of this record )
Abstract:
Interactions between selective factors (hypertension and tuberculosis) and environmental effects (vitamin D deficiency [VDD], temperature, and altitude) largely explain cystic fibrosis (CF) carrier geography. For VDD sequelae such as hypertension and tuberculosis vulnerability, clinical evidence of carrier protection is supported by indications that decreased CF arylsulfatase B activity suppresses tuberculosis, and that excess CF salt loss decreases blood pressure. A need for salt retention in the tropics selected against CF carriers despite possible advantages against cholera, typhoid, and other factors, but salt retention was less important elsewhere. Increased hypertension with cold selected for carriers with increasing latitude, and with altitude, where hypertensive complications of pregnancy also rise. ΔF508 rates especially seem to follow these parameters, and may be particularly protective against hypertension, while lower rates in Ashkenazi Jews are consistent with a greater role for tuberculosis in this group. This scenario suggests geographical correlations of CF with other genes affecting blood pressure, and significant carrier levels, especially of ΔF508, in mountainous areas of Asia with VDD.
Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Here’s a later paper from the same author that reports typhoid enabling allele as well as protective variants.
Distribution of CFTR variations in an Indonesian enteric fever cohort. – van de Vosse E – Clin Infect Dis – 1-MAY-2010; 50(9): 1231-7 (MEDLINE® is the source for the citation and abstract of this record )
Abstract:
BACKGROUND: Enteric fever is defined by circulating Salmonella serotype Typhi or Paratyphi in the blood. The first step in developing enteric fever is internalization of salmonellae in the gut epithelium. In in vitro experiments, attachment of S. Typhi to the cystic fibrosis transmembrane conductance regulator (CFTR) on the intestinal mucosa is crucial for bacterial uptake. We recently found a microsatellite polymorphism in the CFTR gene, IVS8CA, to be associated with susceptibility to enteric fever in a case-control study in Indonesia. METHODS: To determine which functional variation in CFTR is associated with susceptibility to enteric fever, we sequenced all 27 exons of the CFTR gene in 25 individuals from Indonesia. Polymorphisms that occurred more than once were genotyped in the full enteric fever cohort of 116 case patients and 322 control subjects. RESULTS: We identified 12 variants in, or adjacent to, the exons: 1 novel variant (L435V), 3 known mutations (N287K, I556V, Q1352H), and 8 known polymorphisms. Variations that occurred more than once were genotyped in the full cohort. The IVS8 TG(11)TG(12) genotype appears to provide some protection from acquiring enteric fever: having this protective genotype or a variation that is known to affect CFTR protein expression provides modest protection from enteric fever (odds ratio, 0.57; 95% confidence interval, 0.37-0.87; P<.01). CONCLUSIONS: The findings demonstrate that a correlation exists between variations in the CFTR gene and protection from enteric fever. The IVS8CA polymorphism that was identified previously may, however, be the principal functional variation causing the difference in susceptibility.
Here is a paper suggesting TB as the major culprit (available as PDF)
Evaluating candidate agents of selective pressure for cystic fibrosis
Eric M Poolman* and
Alison P Galvani
Department of Epidemiology and Public Health, Yale University School of Medicine
60 College Street, Room 147, New Haven, CT 06520, USA
Author for correspondence (eric.poolman@yale.edu)
Next Section
Abstract
Cystic fibrosis is the most common lethal single-gene mutation in people of European descent, with a carrier frequency upwards of 2%. Based upon molecular research, resistances in the heterozygote to cholera and typhoid fever have been proposed to explain the persistence of the mutation. Using a population genetic model parameterized with historical demographic and epidemiological data, we show that neither cholera nor typhoid fever provided enough historical selective pressure to produce the modern incidence of cystic fibrosis. However, we demonstrate that the European tuberculosis pandemic beginning in the seventeenth century would have provided sufficient historical, geographically appropriate selective pressure under conservative assumptions. Tuberculosis has been underappreciated as a possible selective agent in producing cystic fibrosis but has clinical, molecular and now historical, geographical and epidemiological support. Implications for the future trajectory of cystic fibrosis are discussed. Our result supports the importance of novel investigations into the role of arylsulphatase B deficiency in cystic fibrosis and tuberculosis.
Now I’m really curious. I’m a carrier of cystic fibrosis — it was the only thing that popped up in the suite of scary conditions 23andMe (used to) test for. I assumed it was another of the many Ashkenazi diseases floating around our gene pool, but apparently not.
So where/when did it originate? Greg mentions it’s most common in Northern Europe and skimming wikipedia it looks like Finland has the lowest rates… given all this — common across Europe, pretty equal between Jews and other Europeans, less common in Finnic territories, uncommon in Middle East — could it be another EEF adaptation that only developed once they were already in Europe? Perhaps something to do with grain digestion, since I’ve heard cystic fibrosis mentioned in conjunction with celiac disease?
Here is something you might be interested in:
The Phenotypic Consequences of CFTR Mutations
Rebecca K. Rowntree and Ann Harris
Annals of Human Genetics
Volume 67, Issue 5, pages 471–485, September 2003
Geographical and Ethnic Variations
The incidence of CF varies markedly among different populations. In Northern European populations, such as Northern Ireland and Sweden, the incidence of disease varies from 1 in 1700 live births to 1 in 7700 respectively (Tsui, 1992). This equates to carrier frequencies of 1 in 20 in Northern Ireland to 1 in 44 in Sweden. The geographical distribution of CFTR mutations also varies worldwide. Across Europe there is a northwest to southeast gradient in the frequency of ΔF508, with the highest frequency in Denmark (90%), and the lowest frequencies in Turkey, where analysis of 122 unrelated chromosomes from 73 families revealed the prevalence of ΔF508 to be 18.8% (Onay et al. 1998), and Romania, where the proportion of CF patients carrying ΔF508 was determined to be 25% (Popa et al. 1997). Ashkenazi Jews have a low incidence of ΔF508 but have an increased frequency (60%) of the nonsense mutation W1282X (Shoshani et al. 1992). These variations are likely to be due to founder effects as the various groups migrated and settled in different areas. Such information is important in order to be able to design suitable screening programmes for different populations.
Ashkenazi Jews have about the same frequency of CF mutations as northern Europeans, but they’re mostly different mutations, with a different origin. In northern European, delta 508 accounts for the majority of CF mutations, in the Ashkenazim, W1282X does. W1282X is shared with Arabs and likely originated in the Middle East.
I think these fun Anglophile lovers of their language, that throughout history, except the modern nonsense, it was more a linguistic periphery, than anything else.
Philosophers are boring people who arrived earlier to answers that most people would not want to know. Everything is relative indeed. The science itself is an illusion.
The abstract philosophy is not wrong, it is only a kind of ”END GAME” theory.
Everything that the human being, however logical it may seem, will not be 100% correct.
I’ll just repeat that just worked out a possible answer to the paradox developed by Cochran in this post. May not have understood my last comment, but they understood each other.
Yes, I’ve had less luck than you guys and I was born in this damn country.
The problem of scientific reductionism is that for a theory to be accepted, other theories must die, when in fact, there is nothing in the universe that can justify this. I’m terrible at physics, but I know that an object can be observed by multiple perspectives.
Santoculto. If I ask you to consider the following question “What’s contained in this statement is false” do your circuits overload? The only reason I ask is that you sound like a chatbot rather than a human being. Anyone got a Turing test handy?
Even when CFTR mutations don’t kill they can have negative effects on fitness. Compound heterozygosity of the IVS8 5T allele in trans with a strong loss of function allele is associated with male infertility (CAVD). The frequency of IVS8 5T is something like 5% in Europeans.
How does multiple sclerosis fit into this picture?
Analogous to diabetes type 1. Genetic predisposition and environmental trigger with similar 30% of identical twins affected and HLA system involvement
Yeah, but is it associated with any advantage?
MS is thought to be an autoimmune disease. Most of these are considerably more common in women than men. They are rare in Amerindians.
An attractive evolutionary speculation is that they are the price to be paid for relative immunity to the large number of antigens introduced into the Old World through farming and its concomitant epidemics over the last 10,000 years. Ideally, the immune system would have 1:1 antigen specificity, and would only ever mount a response to a definitely foreign antigen that was part of one of these infectious organisms. Unfortunately, microbes have more proteins to invade us with than our immune systems have specific ways to respond, which results in overlap: the response recognizes foreign proteins, but under the wrong conditions can get turned against a self protein too.
So the idea is that the advantage of MS was that we weren’t as susceptible to Tb, or something else from the Old World, as the Indians were when we brought the microbes here.
It’s interesting that no one has yet figured out why autoimmune disease as a whole is so much more common in women. My guess is that it’s because women benefit from even lower immune specificity than men, since all women who have ever passed on their genes have spent one or more nine-month intervals with an antigenically foreign body growing inside their wombs, with an imperfect placental barrier. They have a much better chance of reproducing if they don’t reject these bodies, as in fetal Rh disease, for immunologically trivial reasons.
If I’m right, another benefit of MS, and autoimmune disease as a whole, is a lower rate of spontaneous abortion in societies exposed to recurrent epidemics.
One nice thing about speculating is 180 degree turns are allowed if you own up. I just realized, and not for the first time I’m embarrassed to write, that lower immune specificity in women should increase maternal attack on fetal components, not decrease it. Perhaps mothers are protecting themselves, not their fetuses, on this one.
I wrote the above before I saw the discussion of the ‘war in the womb’ and spontaneous abortion close by in this thread. If autoimmune disease is part of the price for relative resistance to the epidemics that result from living at close quarters, then higher rates of spontaneous abortion may be associated too.
We have made this argument to explain the so-called “hispanic health paradox” in which US Hispanics, comparable to US Blacks in poverty, have years’ higher expectation of life. There is blog post in our blog about it that can be searched for. (Also see Pennington, Renee, et al. “Group differences in proneness to inflammation.” Infection, Genetics and Evolution 9.6 (2009): 1371-1380.) The New World was apparently relatively free of micro parasitic infectious disease: for example the HLA system everywhere else shows signatures of natural selection but not in the New World.
We make the same argument about poor outcomes for the US Black population: an immune system with the thermostat cranked up higher than it ought to be.
The old post is at https://westhunt.wordpress.com/2012/09/09/the-black-white-mortality-crossover/
I recall seeing many years ago in an actuarial publication a comparison of death rates by cause in the US between Asian-Americans, Amerindians, Hispanics, whites and blacks. Their aggregate death rates were in the above order from lowest to highest. It was somewhat surprising to me that Amerindians did so well. The main drivers for the aggreagate death rates were cardiovascular conditions. Amerindians had much higher death rates for cirrhosis and alcoholism but in general had death rates for cardiovascular conditions lower than the other groups except for Asian-Americans. One disease for which whites had relatively good numbers was diabetes
I don’t recall if this article had much information on differences in age distribution between these groups.
John Hostetler – I was puzzled about your logic on maternal-fetal interactions.
A while back at GNXP you wrote about the anomalously high rate of miscarriage in humans. I was reminded of that when I came across this overview of genetic conflict in the womb, and wondered what you thought of it:
http://aeon.co/magazine/nature-and-cosmos/pregnancy-is-a-battleground-between-mother-father-and-baby/
One thing that surprised me is that it traced the source of conflict between siblings as being the result of possibly different paternity, my understanding is that even fraternal twins will be in competition as they inherited different genes from their shared parents (although they will have more shared genetic interests than half-siblings).
Can anyone link me to anything about the anomalously high rate of miscarriage in humans? Stresses of bipedalism?
Here is a GNXP thread from 2009 wherein that was discussed: http://www.gnxp.com/new/2009/07/09/a-live-birth-is-hard-to-do/
Apparently you don’t need all this difficult genetic thinking after all. I see on cable news this morning that curing ALS (Lou Gehrig’s Disease) is now treated with dumping ice water on your head.
It really makes you feel good when you stop.