Want a Maritime Culture? Live on an Inland Sea - It Doesn't Matter if It's Warm

It's been asked: (roughly) the same nutrition can be extracted from the ocean in Japan or in England. Why did the British Isles not develop a maritime diet and culture to the same degree that Japan did? Two answers come immediately to mind: the cultural center of Japan (southern Honshu and Kyushu) is warmer than Britain; and there is nothing like the sheltered inland sea in the UK. Even the Irish Sea or narrowest part of the Channel are often quite a rough go.

A new paper shows that fishing disappeared quickly after the development of dairy farming in the British Isles - but contrasts this against the cultures around the Baltic, where fishing and farming coexisted quite a bit more. The Baltic is colder than Britain but the water is more sheltered. So: cultures around a sheltered sea are more likely to develop a maritime culture, even if the water is colder.

The Physical Diversity of Uralic Speakers

The Uralic language family has always intrigued me. Partly it's because some people think that there is a Uralic substrate to proto-Germanic (see Kalevi Wiik); partly it's because Uralic speakers live in the center of a continent that is at once the center of the Old World, and in many ways not thoroughly explored with its interior still largely wild and uninhabited. But it's really intriguing to see how different Uralic speakers look from one another. They range from blonde, Scandinavian-looking, about-as-white-as-you-can-get Finns and Saami, to very Asiatic-appearing Nenets people in north central Siberia. Is this because there really aren't many genes for face shape, eye shape and hair type - that is, if you looked at, say, Germans and Spaniards genetically, are they genetically as distant on average as Finns and Nenets (just a few genes) but the differing German and Spanish genes don't happen to all be represented in easy-to-spot features? Or is there really a greater genetic distance? In which case, are these people whose ancestors adopted the language, or were they such a small group of hunter-gatherers running into big Turkic and Indo-European populations that their genes were swamped by whoever they met?

The interesting thing is that here the Urals form a fairly clear boundary for these genes. The Udmurts to the west (one of the groups above) are famous for being the most red-haired people on the planet, while on the other hand it's not hard to imagine that the Nenets family above is related to Native Americans and Inuit. (The Udmurts are the first one and the Nenets second, but I probably didn't have to tell you which are which!) But of course there is still cross-over between the two, and it's interesting precisely because most of us in the U.S. don't see these traits represented in the same people very often.

Evolution and Rh Negativity in Historical Populations

A Kleihauer-Betke stain showing fetal blood cells circulating in maternal blood. Even 0.5 mL of fetal red
blood cells can be detected with this method. It can also be detected by the mother's immune system.

The Rh antigens on human blood cells always bothered me; what a terrible system. If a mother who does not have the Rh protein on her blood cells reproduces with a male that does, she may have a baby who also has the Rh protein. The first such baby is fine; but the mother stands a chance of getting enough of the baby's blood cells in her own circulation during the birthing process that her immune system sees it. Now, if she has another baby that is Rh+, her immune system will attack the baby's blood cells and destroy them. 5% of babies who are the second Rh+ baby of an Rh- woman will get hemolytic disease of the newborn (HDN), and be very anemic and sick; possibly die.


Structure of Rh factor. That's a channel-looking protein if ever there was one. From Mike Merrick at the John Innes Centre.

So what happened, I always wondered, before Rhogam? (The injection that stops an Rh- woman from making antibodies to Rh+ baby's blood cells.) Did we go through a hundred thousand years until 1960 with stillbirths and sick, anemic babies affected for their whole lives being born left and right, and life was just so scary and incomprehensible and miserable that we just accepted this?

I looked into this during my OB-GYN rotation and ended up giving a short talk about it. It turns out that Rh negativity is most a European thing; especially, it turns out, a Basque thing. Europeans are 15% Rh negative, Basques about 36%. The interesting connection is that the function of the Rh protein is an ammonia channel that, among other things, confers resistance to toxoplasma - which is spread through the feces of cats - which did not exist in pre-Holocene Europe. There's our answer! There was no pressure for the Rh factor be maintained once Europeans were in Europe, and the longer they were there, the more they lost it. So if the Rh factor is lost, no big deal, right?

Well, this still bothers me, for the simple problem that where we find Rh negativity, we don't find only Rh negativity. The Rh factor didn't disappear completely, so there's still a price to pay in terms of HDN and sick babies. In an all Rh- population, things would be fine; there would be no Rh-caused HDN, and no disadvantage to being an Rh- homozygote. But in the absence of an advantage to being Rh- (or even heterozygous) - which we're not aware of - it's a disadvantage, balanced against no advantage. I used to tell myself that maybe the mortality numbers were low so it didn't matter, but nature keeps close score. Even if Rh negativity is a little bit deleterious in terms of HDN, it should be selected out - eventually.



Using the Hardy-Weinberg equation, we can construct a simple model that tells us how rates of Rh negativity should change over time.

- Assume mated pairs have the same number of births on average, regardless of Rh status.

- Assume that for the second and further Rh+ babies born to an Rh- mother, 5% have HDN, and all these babies die. (They wouldn't have all died, even in the paleolithic, so the gene will disappear more slowly than this model predicts.) Future Rh+ babies get HDN at a higher rate than 5% but again, as long as I assume 100% death for them the gene will disappear more slowly than the model predicts.

- Assume there's no advantage to Rh negativity; its effect is entirely negative through HDN as above.

- Plug in current gene frequencies in Europe.

Since the gene will disappear more slowly than this model predicts due to the assumptions outlined above, we can project back based on current gene frequencies, and get dates that are probably slightly more recent than reality.

This model tells us that for the gene frequency to drop to 1% will take 565 generations - between 8,475 to 11,300 years, using a short generation time of 15 to 20 years. For the current Basque frequency of 36% Rh- (assuming it has remained static) to come down to the wider European frequency of 15% would have taken 208 generations, or between 3,120 and 4,160 years.

Assuming that Rh- was at fixation in proto-Basque populations in Iberia and Gascony, the introduction of just 1% Rh+ homozygotes would have taken 22,110 to 29,480 years to get the Basques to 36%. It doesn't escape notice here that these date ranges are all post African exodus, and some of them are within the scope of antiquity of the Near East.

Finally and most interestingly: assuming about an 8.6% injection in a 0 Rh- population of Rh+ 2,025 to 2,700 years ago, this would give us 36% today. That period coincides with the establishment of Phoenician and later Roman colonies in Iberia, and quickly established colonies and armies could easily introduce 1/12th the human DNA in the sparsely-populated Iberian peninsula. This assumes that during this time, Semitic and Indo-European people were Rh+.

It seems impossible without further research, particularly on ancient DNA, to distinguish between these three possibilities:

1) Rh negativity confers no advantage, and there was a founder effect that gradually eroded. Rh positivity was lost completely in a small ancestral Basque population, and very gradually Rh+ through HDN has been decreasing the proportion in the population; in turn Rh negativity has spread throughout the western half of the Old World.

2) Rh negativity confers no advantage, and a dramatic amount of Rh positivity was introduced in antiquity by migrants from around the Mediterranean. The high Rh negativity also seen in some parts of Africa could support a Phoenician mechanism of gene flow (Rh+ into Iberia, Rh- out).

3) Rh negativity does confer an advantage that partially or totally counterbalances the HDN problem that we are so far unaware of. Not exclusive of #1 or 2.


Rh factor isn't nearly the only immune incompatibility between maternal and fetal blood that can cause HDN, and we certainly have a lot to learn about the function of these markers.

Intracytoplasmic Sperm Injection and Autism Risk: an Epigenetic Connection?

A JAMA paper by Sandin et al looked at neurodevelopmental differences in IVF and non-IVF children, and considered differences between IVF methods. There were slight trends, but no significant differences, associating autism and retardation in all IVF-produced children (RRs 1.14 and 1.18). The big news was the RR increase in intracytoplasmic sperm injection (ICSI, where sperm DNA is injected into eggs): for autism and retardation the RR was 4.6 and 2.35, both statistically significant. The obvious confounder here would be age but they controlled for it.

A few speculative ideas about what could explain these findings:

- epigenetic changes resulting from ICSI relative to normal sperm penetration and genome delivery. This could be due to changes introduced by the handling of the sperm and genetic material or because of lack of a physiologic egg penetration event resulting in aberrant methylation
- co-occurring diseases influencing both sperm mobility/penetrance and neuronal migration. There are known syndromes where defects cause loss-of-function in both sperm and lung cilia. Bypassing defective DNA delivery by sperm in individuals who are heterozygous recessive, have a de novo mutation or are mosaic would allow these to appear in the offspring.
- mechanical damage caused to chromosomes by the injection process
- damage to the membrane from the injection process influencing neurodevelopment in ways we don't yet understand


If the first bullet at least partly explains the problem, we now have an unfortunate set of natural experiments to investigate the speculated relationship between epigenetics and neuropsychiatric illness. GWAS studies on these diseases have produced frustrating few replicable results. We now know that non-coding regions of the genome do produce RNAs that are more likely to come from disease-associated SNPs outside open reading frames, and specifically in some cases are associated with neuropsychiatric disease, possibly we can start to connect the dots.


References:

Sven Sandin, Karl-Gösta Nygren, Anastasia Iliadou, Christina M. Hultman, Abraham Reichenberg. Autism and Mental Retardation Among Offspring Born After In Vitro Fertilization. JAMA. 2013;310(1):75-84.

Matthew J. Hangauer, Ian W. Vaughn, Michael T. McManus. Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs. PLoS Genetics, 2013; 9 (6).

Alexander D. Ramos, Aaron Diaz, Abhinav Nellore, Ryan N. Delgado, Ki-Youb Park, Gabriel Gonzales-Roybal1, Michael C. Oldham, Jun S. Song, Daniel A. Lim. Integration of Genome-wide Approaches Identifies lncRNAs of Adult Neural Stem Cells and Their Progeny In Vivo. Cell Stem Cell, Volume 12, Issue 5, 2 May 2013, Pages 616–628.

MAO Polymorphisms Predict Free Rider Behavior

Not surprising, but at least proof of concept, or actually instantiation of concept.

Mertins, Vanessa; Schote, Andrea B.; Meyer, Jobst. Variants of the Monoamine Oxidase A gene (MAOA) predict free-riding behavior in women in a strategic public goods experiment. Journal of Neuroscience, Psychology, and Economics, Vol 6(2), Jun 2013, 97-114.

Cross posted to the Late Enlightenment. For more information about ealth distribution among players with different hardware, go here.

HDAC Inhibitors and Neuropsychiatric Illness

The mechanism of valproic acid (Depakote) is inhibition of histone de-acetylases. For a mood-stabilizer and anti-epileptic, this has struck many people as unexpected. A paper by Tang at Scripps in Translational Psychiatry now strengthens the link, showing the acetylation levels at some promoter regions of genes implicated in schizophrenia and bipolar disorder (samples were taken from PFC). In non-psychiatric patients the levels drop consistently with age, but in the psychiatric patients they didn't. Treatment with a novel HDAC inhibitor altered expression of the homologous genes in treated mice.

Maybe a heavy epigenetic bias to the pathophysiology of schizophrenia is the reason we've had such trouble making schizophrenia markers stick.

Rapid Evolution in Tibetans - and Who Else?

Science paper isn't up yet but probably will be by the time you read it. Tibetans only split from Han less than 3,000 years ago and already they've built up a whole repertoire of genetic low-oxygen adaptations.

While that may not be a surprise, the speed with which it occurred probably is. More and more, it's becoming clear that cultural choices we make (what we eat, where we live) over time affect our genes. So this leads us back to the elephant in the room of human evolution studies. There are genes which affect cognition. Why do we think these haven't been selected differentially as well?