Natural selection at the molecular level Understand article

We know that particular genetic sequences can help us to survive in our environment – this is the basis of evolution. But demonstrating which genetic sequences are beneficial and how they help us to survive is not easy – especially in wild populations. Jarek Bryk describes some relevant recent…

When humans first left Africa some 150 000 years ago, settling in the valleys of the Tigris and Euphrates, sailing between the islands of Indonesia and trekking over the Bering Strait to America, they encountered many challenges. Coming from hot, dry African savannahs, the populations had to adapt to the local conditions, and over generations their physiology and appearance changed accordingly (Harris & Meyer, 2008). People’s skin became paler after they had lived in less sunny regions (Lamason et al., 2005). Populations whose members drank milk from domesticated animals retained the ability to digest lactose into adulthood, a feature lost soon after infancy among non-milk-drinking groups (Tishkoff et al., 2007). Populations that ate starch-rich food produced more salivary amylase, the enzyme that helps to break down starch (Perry et al., 2007).

At least some of these changes are thought to have been a consequence of positive selection (see glossary for all italicised terms). This implies that in a particular environment (the selection pressure) in the past, individuals that happened to have an advantageous DNA sequence survived and left more offspring than individuals with a different, less beneficial, sequence. Today, using the genomic sequences of many species, including humans and their closest evolutionary relatives, scientists can compare traits and DNA sequences from populations or species with different lifestyles and from different environments to identify which sequences may have played a role in the adaptations. This, in turn, allows researchers to investigate the function of a DNA sequence and its potential adaptive value for an organism.

Some of the genes known to affect skin colour in humans show a specific geographic pattern of sequence variation; in particular, sequence comparisons between European and African populations suggest that variation in skin colour is due to positive selection. Lightness of skin positively correlates with increasing latitude, and several hypotheses have been proposed to explain its potentially advantageous effects.

One hypothesis, which states that light skin favours the production of vitamin D, is supported by observations that dark-skinned people living at high latitudes suffer from vitamin D deficiency. Furthermore, light skin is more sensitive to the harmful effects of sunlight: greater exposure to sunlight correlates with increased incidence of skin cancer in pale-skinned people. Therefore, pale skin in human populations living at higher latitudes may be an evolutionary compromise between protection from the carcinogenic effects of sunlight and allowing sufficient production of an essential vitamin.

Although this is a solid hypothesis, the evidence behind it is indirect. A direct demonstration of the adaptive value of this trait would require measuring whether, at higher latitudes, individuals with paler skin show improved survival and reproduction. Such demonstrations in our species, however, are difficult: survival experiments (in which individuals with different traits are exposed to an environment to see which survive) cannot be performed on humans, and our long generation time makes it difficult to investigate differences in reproductive rates. The circumstances in which it is possible to observe the adaptive value of any trait in humans are therefore very limited — but they do exist.

One example involves two diseases: sickle-cell anaemia and malaria. The gene involved in sickle-cell anaemia has two variants, or alleles: a ‘normal’ allele and a sickle-cell allele. Individuals with two sickle-cell alleles suffer from serious sickle-cell anaemia, whereas those with one sickle-cell and one normal allele do not exhibit such severe symptoms. Mortality data suggest that the sickle-cell allele can, however, be advantageous: in populations exposed to the malaria parasite, individuals carrying one sickle-cell allele and one normal allele are more likely to survive than people carrying two normal alleles, because the parasite (Plasmodium falciparum) requires healthy blood cells to invade and multiply. Therefore, the frequency of the allele that causes sickle-cell anaemia increases in malaria-exposed groups – the allele is adaptive in this environment.

Another example demonstrating the adaptive value of a human trait concerns a fragment of chromosome 17, known to have been inverted in our ancestors more than three million years ago (Stefansson et al., 2005). The fact that this variant spread across European populations suggests that it has been positively selected for – it has conferred an advantage on individuals that carry it. By genotyping almost 30 000 Icelanders, scientists investigating the hypothesis were able to determine that over the last 80 years, individuals who carried the sequence variant had on average 3.2% more offspring per generation than individuals with the normal sequence, a plausible explanation of how the variant came to spread so rapidly.
Although the two examples clearly demonstrate the recent action of positive selection in humans, the molecular mechanisms of how the sequence variations confer their advantages are not well understood and must be investigated on a case-by-case basis. To elucidate the causal relationships between putatively adaptive DNA sequences and an individual’s fitness, scientists turn to organisms that are easier to experiment on than humans.

For instance, coat colour in the Oldfield mouse, Peromyscus polionotus, matches the soil of the habitat, providing camouflage. Mice living on the pale sands of Florida beaches are much lighter than inland-living mice of the same species. The adaptive value of this trait was demonstrated experimentally more than 30 years ago: mice with a coat that matched the soil colour were eaten less frequently by owls than the other, less camouflaged mice. However, scientists have only recently identified the genetic loci behind this adaptive trait (Hoekstra et al., 2006): variation in coat colour largely depends on different alleles of the McR1 gene. The protein encoded by this gene acts as a biochemical switch driving the production of either eumelanin, a dark pigment in the skin, or pheomelanin, a light pigment. The different alleles of the McR1 gene activate the pigment-producing pathway to a different extent, favouring the production of one pigment or the other.

Another example of a demonstrated causal relationship involves Staphylococcus aureus, a bacterium that can cause various diseases including pneumonia or heart valve inflammation. In a rare natural experiment, a patient with recurrent S. aureus infections was treated for three months with vancomycin, one of the few antibiotics that are still effective against S. aureus. Before and at intervals throughout the treatment, scientists collected samples (isolates) of the pathogen and sequenced the entire genome of the first and last isolates. When they compared the three million base pairs (the ‘letters’ of the genetic code) that constitute this bacterium’s DNA, they found only 35 differences between the first and last isolates.

By partially sequencing the intermediate isolates, the scientists then worked out the order in which these changes must have occurred. By testing the bacterial resistance to vancomycin in vitroin the different isolates, they were able to correlate particular genetic changes with effects on the bacteria’s growth and response to the drug. For instance, the first and second isolates of bacteria differed by six nucleotide substitutions (changes to the ‘letters’) in two genes. These six mutations alone were clearly advantageous: they increased the bacterium’s tolerance to vancomycin four-fold, allowing bacteria carrying these mutations to survive and reproduce better, becoming more common in the patient’s body. Twenty-six subsequent mutations over the following weeks of treatment doubled the tolerance, effectively producing a vancomycin-tolerant strain of S. aureus (Mwangi et al., 2007).

In short, investigating the molecular basis of adaptive evolution in wild populations is not easy. The challenges include defining the selective pressures, identifying the DNA sequences behind the associated traits, measuring individuals’ fitness, and finding mechanistic explanations for how the sequence changes influence the adaptive traits. However, with the use of model organisms and recent technological developments, these investigations are now becoming feasible, increasing our understanding of how specific changes at the genetic level allow organisms to adapt to their environment.

Acknowledgements

The author is grateful to David Hughes, Mehmet Somel and Ania Lorenc for helpful comments on the article.

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