GeneBites

We know how important it is to get our protein, but what about our magnesium or selenium? This new study explores how living in areas lacking specific micronutrients could influence human genetics.

Photo by: Wendy Wei

If you’re someone who likes to check nutrition labels when you go to the grocery store, you’ve likely noticed that aside from the amounts of fat, carbs, and protein you can also find things like iron, calcium, or vitamin D. These are micronutrients, and they are just as important for your health as macronutrients like protein are. In a modern society where it’s often easier to get highly processed, low-nutrient foods than nutrient-rich things like fresh produce, it’s critical to understand how the lack of access to various micronutrients has affected humans throughout history. The legacy of human micro-malnutrition will allow us to address its effects on our health both now and in the future.

Micronutrients are a class of vitamins and minerals crucial for human health and development in tightly controlled amounts. They cannot be synthesized by the body, so must be absorbed through dietary sources like fresh fruits and vegetables. The micronutrient content of those dietary sources is highly dependent on the soil they are grown in, as soil composition varies widely both by geography and local agricultural practices. For example, modern agricultural practices, such as overfarming, have potentially played a role in depleting the nutrients that are present in a given location.

Such depletion can lead to micronutrient deficiencies in the population, causing a number of health problems to arise. Pregnant people and young children are at especially high risk as deficiencies are associated with birth defects and impaired cognitive and physical development in early life.The general population may feel the effects as well, since micronutrients are critical for proper metabolism and immune system function. If someone develops anemia due to an iron deficiency, for example, they’ll develop extreme fatigue, headaches and/or dizziness, and feel much weaker than usual. This can significantly impair that person’s ability to function in their normal life. If enough people in a local population start developing deficiency symptoms like this, it’s easy to imagine it having a major effect on that population’s genetics; the people who survive long enough and are healthy enough to reproduce will be those with genes conferring some resistance to nutrient deficiencies.

That’s the idea that Rees, Castellano, and Andrés sought to test with a computational approach. Previous studies have found evidence of positive selection, or an increase in how common a particular version of a gene  is because of the environmental advantage it offers, in genes associated with the micronutrients selenium, iodine, and zinc when they are deficient in the local soil. These studies paint a picture of how deficiencies can impact a relatively narrow population, but the authors of this paper want to understand how deficiencies have impacted human evolution across the world and over time. In this way, they hope to explain not only a piece of human evolutionary history, but also how any genetic adaptations have led to health disparities in the modern day.

The authors used a large dataset with 913 geographically and culturally diverse individuals from seven major continental regions (Africa, Middle East, Europe, Central-South Asia, East Asia, the Americas, and Oceania). They also curated a list of 269 micronutrient-associated genes related to the uptake, metabolism, and regulation of 13 micronutrients chosen for their known roles in human health. Their analysis then looked for evidence of positive selection in 477,029 single nucleotide variants (SNPs), or specific sites in the DNA where individuals could have different letters, like an A instead of a T, across those 269 genes.

First, the authors found that in most populations, most micronutrient-associated genes show no evidence of positive selection. This means that micronutrients likely did not drive adaptation on a global scale. However, they did find that each micronutrient is associated with adaptation in at least one population, indicating that adaptation may have occurred on a more local scale and at specific time points. Their analyses point to the idea of oligogenic adaptation, where a few genes in each micronutrient-associated gene set show the most evidence of positive selection and thus drive a population’s adaptation. Some genes in specific populations, such as the magnesium-associated genes MECOM and MLN in Central-South Asian populations, are instead indicators of monogenic adaptation, which means that changes in those genes alone are enough to drive adaptation without changes in other magnesium-associated genes. Broadly, positive selection seems to be driven by local availability. The authors re-discover the selenium-associated adaptation in East Asians, zinc-associated adaptation in non-Africans, and iron-associated adaptation in Europeans, plus a novel association of iodine adaptation in the American Maya, indicating that micronutrient-associated adaptation is prevalent the world over.

Micronutrient deficiencies are alarmingly common across the world. The authors cite that  an estimated 2 billion people worldwide are affected, primarily in sub-Saharan Africa and South-Central Asia, with an estimated 178 million of those being children who have stunted growth due to deficiencies. However, an analysis from 2022 reports that these may be substantial underestimates, with their estimates on affected preschool-aged children and non-pregnant women of reproductive age alone being 372 million and 1.2 billion, respectively. The micronutrient levels of soils worldwide are changing due to climate change and farming practices, so understanding how populations have adapted in the face of deficiencies previously is a timely issue that may help us manage future deficiency issues. Rees, Castellano, and Andrés’ analyses provide a glimpse into how populations have adapted to a local lack of micronutrients throughout evolutionary history. Linking these findings to existing biobank or public health datasets may identify additional associations between the variation in micronutrient-associated genes and susceptibility to other micronutrient-associated diseases. Looking forward, this research could help inform better farming practices that preserve or improve the nutrient profile of the soil, or motivate public health initiatives to increase access to fresh produce. Maybe one day we’ll even have micronutrient fact labels on our fruits and vegetables!

Edited by John Laver and Jameson Blount