Maternal-fetal health and natural selection

By Razib Khan | May 4, 2013 4:11 pm

Credit: USDA

A few years back I was rather fixated on issues of maternal fetal health. In particular I was worried about gestational diabetes in relation to my wife because I come from an ethnic group with an elevated risk for these sorts of problems, and the effect when you are in mixed-race marriages seems to be additive (i.e., unlike some risk factors associated with pregnancies the mother’s ethnicity is not the only relevant variable). This is embedded in the broader suite of metabolic diseases which exhibit ethnic variation. Early work on genome-wide selection in humans yielded the result that there was a strong enrichment for signals of adaption within regions of the genome associated with metabolism, so this should not be that surprising. Humans are a geographically dispersed species that inhabits a wide range of environments, so natural selection would shape the distribution of phenotypes within populations if evolution is a significant historical process (it is).

A paper in last month’s Trends in Genetics highlights more precisely how natural selection would operate in a life history context in specific cases. Many ways to die, one way to arrive: how selection acts through pregnancy:

When considering selective forces shaping human evolution, the importance of pregnancy to fitness should not be underestimated. Although specific mortality factors may only impact upon a fraction of the population, birth is a funnel through which all individuals must pass. Human pregnancy places exceptional energetic, physical, and immunological demands on the mother to accommodate the needs of the fetus, making the woman more vulnerable during this time-period. Here, we examine how metabolic imbalances, infectious diseases, oxygen deficiency, and nutrient levels in pregnancy can exert selective pressures on women and their unborn offspring. Numerous candidate genes under selection are being revealed by next-generation sequencing, providing the opportunity to study further the relationship between selection and pregnancy. This relationship is important to consider to gain insight into recent human adaptations to unique diets and environments worldwide.


The logic is eminently simple if the abstract didn’t make it clear. Adaptations which increase fitness early in life are much more beneficial in an evolutionary sense than adaptations which increase fitness late in life. What might seem like a late life adaptation, menopause, is actually generally interpreted as a means by which females can increase the fitness of their daughter’s offspring. In other words, though the mechanism manifests late in life, the evolutionary target remains younger individuals.

Credit: Hamilton 1966

The figure to the left, from a 1966 paper by W. D. Hamilton, illustrates the change in reproductive value over a lifetime (the curves are based on Taiwanese data, and in this case assume a constant population). The peak is at ~20, and declines down to about zero around age 50. It is therefore no surprise that for women this latter period of life history is when the physiological changes which we label menopause occur, as females trade off their low direct reproductive value for increasing their own descendant’s fitness indirectly through supplementing the resources of their daughters.

In the Trends in Genetics paper the authors focus on gestational diabetes mellitus (GDM), preeclampsia (hypertension in pregnancy), neural tube defects, hypoxia, and various infectious diseases. When it comes to neural tube defects due to folate deficiency (and the inverse, vitamin D deficiency), the work seems an extension of Nina Jablonksi’s model for the origin of variation in skin color. The altitude adaptation issue is probably the most straightforward case, as hypoxia would no doubt lead to higher fetal and maternal mortality. As for infectious diseases, as the authors note there is surprisingly little deep exploration of the effects of endemic illnesses such as influenza. This is an area where populations which have been subject to “mass society” and agriculture for thousands have years are likely very different in substantive ways from those which have been hunter gatherers.

Gestational diabetes and preeclampsia are the diseases of particular interest to me. The broad outlines of the situation are evident in the table below:

The authors note that “insensitivity to salt in the diet is common in Japanese: women consuming the most salt (20.6 g/day) have no more hypertension than those consuming the least (8 g/day)…By comparison, the WHO recommends less than 5 g/day of salt consumption for adult.” To me this seems like an important datum indeed considering how much debate there is in our society about the consumption levels of salt. If you are from a genetic background where risk for hypertension is reduced then you might be leaving a lot of utility on the table if you cut back on salt due to coarse guidelines that are blind to your own individual priors.

In relation to the statistics on gestational diabetes the numbers are rather stark. From studies in British samples one can see that Bangladeshis in particular seem to have a greater likelihood of metabolic diseases than other South Asians. The question here is whether the cause is genetic in a direct and classic sense, or is the risk elevation a complex mix of epigenetics, environment, and conventional genetics. Let me give the authors the floor here:

By comparison, South Central Asians had a much higher incidence of GDM in the NYC cohort (14.3%), with Bangladeshis the highest at 21.2% [19]. Traditionally, Bangladeshis have had high consumption of fish, a low glycemic food; rice, of moderate glycemic index due to little processing; and no dairy 36 and 37. Finally, among African-Americans, the incidence of GDM was intermediate at 4.3%…This is consistent with their admixed ancestry and the mixed consumption of dairy across populations in West Africa, the origin of most US African-Americans.

First, I don’t see much evidence in the data that African Americans have much ancestry derivable from those populations (e.g., Fulani) which consume milk. So I have no idea why this was introduced in the text (there are large data sets of African Americans out there). It seems straightforward that African American non-European ancestry derives from coastal agriculturalists across the broad swath of territory from Senegal down to the Yoruba land in Nigeria. Second, as suggested by Henry Harpending there needs to be more input from anthropologists who study food production before we infer that because South Asians have metabolic disease they must not have been as exposed to as much refined starch as Northern Europeans over evolutionary time scales. Agriculture did not arrive in Scandinavia until ~5,000 years ago, so it isn’t as if one can presume that the whole ~10,000 years of Middle Eastern derived agriculture shaped the Northern European genome (unless Northern Europeans are mostly derived from those original Middle Easterners, which seems unlikely). Second, the widespread cultivation of much of Bengal was relatively recent (last ~3,000 years), but the genetics makes it clear that most of change was not due to adoption of agriculture by hunter-gatherers, but the migration of farmers from the west (some of the genetics though implies a non-trivial admixture from eastern populations; but these were the ones who brought rice). Obligate hunter-gatherers in any case were likely not present in South Asia by this time, as opposed to slash and burn populations which also practiced horticulture.

It is the fact that South Asians tend to have higher rates of diabetes than African Americans, which suggests to me that it isn’t a simple story of agricultural adoption and extent of grain processing (West African agriculture tends to be lower in intensity, and likely more diversified in diet and nutrient content, than South Asian grain societies). If one wants to adhere to a standard genetic narrative then perhaps metabolic disease is a more confounding side effect, with no straightforward relation to food production. Or, it may be time to look at environmental co-variates. Unlike East Asian cuisine the South Asian culinary tradition does allow for rather rich sweets. In pre-modern times these would be rare treats, but today consumption levels are much higher. Because of my awareness of metabolic disease in South Asians I’m rather scolding when I see co-ethnic loading up on treats with refined sugars (South Asians tend toward more obesity than East Asians in any survey I’ve seen in the West or developed non-Western societies such as Singapore). Ultimately I am profoundly skeptical of the idea that South Asians cluster with hunter-gatherers (e.g., Australian Aboriginals have similar problems) because of late adoption of agriculture or diversified diet with lack of processing (milling).

Related: Carl Zimmer has also talked about this paper. Excellent as usual.

  • Dmitry Pruss

    Salt consumption and genetic modifiers of hypertension risk – you may be amused to find out that we marketed a genetic test for angiotensin regulatory mutation which makes Europeans salt-insensitive (the ancestral allele, common in Africa, predisposes to high blood pressure in response to salt). The test was pretty much a flop, and is no longer offered. We were told that limiting salt is a common-sense good dietary advice, and physicians won’t test their patients just to find out that this advice doesn’t apply to some of them. And that in cases of clinical hypertension, it just takes several months of drug regimen to figure out if the regimen works … thus no need in genetic testing to foretell it :) So 10 years later, ancestry still remains the best proxy!

  • http://www.facebook.com/profile.php?id=771138266 Annie Kopecký

    I am genuinely befuddled that this article refers to the only gene flow to African-Americans as West African with the possible exception of Fulani. All the DNA/genomic studies I have ever seen show between 15-20 percent average DNA from Western Europe. This article should be edited to reflect this.

    • razibkhan

      reading is good for you. try it! it clears up befuddlement:

      It seems straightforward that African American non-European ancestry derives from coastal agriculturalists across the broad swath of territory from Senegal down to the Yoruba land in Nigeria.

  • Melissa

    It’s interesting to compare this in Nordic countries. We have Finland, where prevalence of GDM is between 10.3% and 11.2% and Sweden where it’s ~2% and Denmark where it’s ~3.6%. Despite living in the same region of the world, Finns are quite genetically distinct possibly the remnants of an ice-age hunter-gatherer population, but whatever the case with their origins, the other Scandinavians seem to be descended from Southern farmers that settled there relatively late.

    • http://twitter.com/SarahAnn_Madden Sarah Madden

      Although that may be due to differences in screening. For example Ireland had a prevalence rate of ~4% due to selective screening. Rates rise to 12% when universal screening is implemented. I couldn’t find any literature as to whether Sweden and Finland implement universal screening. In any case, GDM is more prevalent in southern European countries, and on world-wide basis most prevalent in people of Indian or middle-eastern descent.

      • Melissa

        I know Finland’s screening program is known to be rigorous so that might be the case. And if GDM is most prevalent through the places where Western ag originated and where their populations settled, that would seriously threaten the hypothesis that it is a maladaptation to carbohydrates.

        • http://twitter.com/SarahAnn_Madden Sarah Madden

          If I was a betting woman, then I would say magnesium deficiency has a huge role to play. We know that birth-spacing could be a risk factor, so that would support the depleted nutrient aspect. That and the usual suspects of obesity, older age, lack of physical activity etc.

  • Melissa

    ” Or, it may be time to look at environmental co-variates. Unlike East Asian cuisine the South Asian culinary tradition does allow for rather rich sweets. In pre-modern times these would be rare treats, but today consumption levels are much higher.”

    As an aside I always laugh when Americans are self-deprecating about our tastes and say we have an unusual proclivity towards sweets compared to the rest of the world. Clearly these people have not had Indian sweets. SE Asian sweets like those in Indonesia can be pretty cloying as well. I had the Indonesian cendol recently which is like sugar flavored sugary sugar, and it was sweeter to me then the also excessively sweet tea served in the South US where I’m from.

  • http://twitter.com/omarali50 omar ali

    The authors of the trends in genetics piece seem to be offering a version of the “carnivore-connection” hypothesis (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253466/) and give the example of Bangladeshis as a population that may have shifted relatively recently to a high glycemic index diet, thus making them very susceptible to the ill-effects of insulin resistance. But it seems that almost all of the populations of South Asia tend to be insulin resistant and it is hard to argue that people from Gujarat or Punjab transitioned to a high-cereal, high-dairy diet relatively recently compared to Europeans. Why would they be so prone to insulin resistance compared to Europeans?
    What am i missing here?

  • Stephan Guyenet

    I think your skepticism is justified. This “evolutionary” explanation for the high gestational diabetes prevalence in Bangladeshis (in this paper and in Zimmer’s discussion of it) is nothing more than a just-so story. Rice and wheat have a similar glycemic index, both cultures traditionally consumed it in minimally refined form, and there’s no evidence I’m aware of that the ancestors of modern Europeans consumed more starch than the ancestors of modern Bangladeshis. Furthermore, there’s no compelling evidence that starch consumption per se increases the risk of gestational diabetes in the first place!

    Gestational diabetes probably results from similar factors as regular type 2 diabetes, which are primarily excess (abdominal) fat mass, physical inactivity, and refined foods. Recently industrialized populations are disproportionately susceptible to diabetes, but this has nothing to do with increased carbohydrate intake because most cultures actually decrease % carb intake with industrialization (e.g. China and S Asia), in parallel with major increases in diabetes prevalence. SE Asians are particularly susceptible to visceral fat accumulation even if they don’t have a high total fat mass.

  • ohwilleke

    The big issue, of which this is only the tip of the iceberg, is whether the ideal “heathy diet” varies by ethnicity. There are a variety of hints that this may be true (many East Asians have trouble with milk, this study, possible Native American issues with processing alcohol, etc.), but public health officials and the media coverage of diets have been very resistant to the possibility that, for example, a Mediterrean diet may be ideal for people who are ancestrally Mediterrean but less than ideal for others.

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Gene Expression

This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!

About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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