Are Humans Still Evolving in Response to Epidemics?
Continuous interaction between hosts and parasites is a force that drives evolution. It forces its enemies to adapt. For mankind, this competition has shaped our immune system, modifying our key genes according to the parasites encountered. Today, scientists are studying the impact of two major infectious diseases: malaria and HIV.
Photo © Vidéothèque CNRS
Infectious diseases offer an original angle from which to study human evolution. All our parasites, be they microparasites such as viruses, bacteria and protozoa, or macroparasites like worms, have shaped our evolution; they applied what we call “evolutionary pressure”. Indeed, when a parasite infected a distant ancestor, either he could resist and endure the infection, or he died without descendants. Only those who had adapted a means of defence survived.
Thus, modern man’s immune system has been shaped by every kind of parasite our ancestors encountered. Even more fascinating, parasites such as viruses helped to build our genome. Some viruses, retroviruses, can insert DNA sequences into the host’s DNA. These have sometimes been passed down through generations and can now be found in our genome. They are called endogenous retroviruses (ERVs). The most recent endogenous retrovirus in our genome – ERVs of the K-family – was integrated around 150,000 years ago. Today, it is estimated that 8% of our genome originates from retroviruses. And we know that in some cases, these viral sequences have been used to produce novel developments. A protein called syncytin, which was coded by a viral sequence, led to the development of the placenta. Unfortunately, if we look more recently back in time, side-by-side evolution of humans and microbes looks more like an arms race than mutual development.
POPULATION DENSITY
Thus, key genes in our immune system, such as the complex Human Leucocyte Antigens (HLA), seem to change according to the parasites encountered, . On a global scale, we have noticed that the more human populations were exposed to parasitic pressure, the wider the diversity of genes in the HLA complex. Another example suggests the importance of parasites: we know that some of the transfers of genetic material (introgressions) from Neanderthal or Denisovan man shaped modern humans’ immunity to infectious diseases.
As a general rule, the main evolutionary pressures detected in the human genome, and dating from 10,000 to 2,000 years ago, are linked to the presence of infectious diseases. But what about recent history? Are contemporary humans finally free of evolutionary pressure?
One might imagine that, since settlement and then urbanization, our genomes would be under huge evolutionary pressure. Let us look at it from the viewpoint of a parasite infecting small groups of hunter-gatherers. The most suitable strain of parasite (that will cause the most long-term infections while avoiding extinction), will be the one that will be able to survive long enough inside their hosts. On the contrary, a parasite moving through a dense human population will always be in contact with new hosts, making the duration of infection secondary to the infectivity. This is confirmed biologically; in general, isolated tribes of hunter-gatherers are infected by parasites that cause chronic but mild infections. Conversely, high density populations are conducive to acute or virulent infections.
IMPACT OF GLOBALISATION
Most human evolution occurred in a context of low population density. Our immune system has evolved less with microparasites than with macro parasites like worms. They create infections that we have been able to cure for over a century, at a relatively low cost - widespread worming campaigns are currently underway in many countries. Could this be proof of both coevolution and our maladaptation? It is suspected that underexposure to these infections could lead to allergies or autoimmune diseases. But studies also show that infection by intestinal worms can relieve patients suffering from Crohn's disease, an inflammation of the digestive tract.
With urbanisation and, more recently, globalisation, parasites that could not have spread thousands of years ago could now threaten the entire world.
One disease that has possibly changed human evolution, is the human immunodeficiency virus (HIV). It already existed in the 1920s in Kinshasa, in the current Democratic Republic of Congo, and became a pandemic in the 1960s and 1970s. Today, in some regions of Africa, prevalence (the proportion of carriers), may exceed 30%, with dramatic consequences as the absence of treatment makes this disease 100% fatal.
Given the burden imposed by this virus, it seems plausible that, in the most exposed populations, individuals who are biologically more resistant than other to HIV, have more descendants. Evaluating this hypothesis is less ridiculous since we know that the virulence of the HIV infection is partially linked to variations in human genetics, especially in the HLA genes.
Up until now, although we have been able to demonstrate, that in the African regions most affected by the epidemic, the HLA complex of the host population changes the evolution of the virus, we haven’t detected the reverse. In other words, there is no proof of variation in the genes in the HLA complex providing sufficient resistance to the HIV to generate an advantage, as the genetic effects outweigh the medication, treatment and prevention.
The same applies to the CCR5 gene. Behind this acronym lies a membrane protein involved in getting the HIV virus into the host cell. One of the gene’s alleles (the CCR5-32 deletion) codes a truncated version of the protein. This deletion was discovered because some people, although highly exposed to HIV, remain seronegative. Having the CCR5-32 allele on each of the two chromosomes (i.e. being homozygous for the allele), brings almost full resistance against HIV. Unfortunately, the deletion was not very present at the outbreak of the epidemic in Africa, which partly explains the absent detection of natural selection. It should be noted that this deletion is mainly present in Europe and seems to have been selected during plague epidemics in the Middle Ages.
Today, the malaria haematozoa is the only documented example of a parasite exercising evolutionary pressure on our species. Like HIV, this is a major disease which, according to the World Health Organisation (WHO) infected over 200 million people in 2015 and caused over 400,000 deaths, mostly children. Its origins go very far back as they coincide with those of our species.
The millennial side-by-side evolution of humans and malaria has led to the persistence of thalassemias, genetic diseases that affect the red blood cells. It is found in various forms, that have evolved separately in several regions of the globe. The best known of them is drepanocytosis or sickle cell anaemia, in which a random mutation on chromosome 11 leads to the formation of S-shaped red blood cells. These molecules tend to polymerise and form long chains. These chains deform the red blood cells, shaping them like a sickle (hence the name).
From a clinical viewpoint, the severity of the disease changes of the deleterious allele Hbs is carried on both chromosomes (homozygous) or on only one (heterozygous). Half of all heterozygous carriers have normal haemoglobin, thanks to their HbA allele, and have very few or no symptoms, except in cases of hypoxic stress. However, homozygous carriers suffer from episodes of anaemia and very painful crises, which appear from the age of 5 to 6 months. They are also vulnerable to infections and may suffer from many other symptoms of this chronic disease.
As for all genetic illnesses with early harmful consequences, it could be expected that natural selection would lead to its disappearance. The fact that the HbS allele persists and even reaches prevalence close to 20% in some regions of Africa suggests that it is not only deleterious. The biological explanation, shown in the 1950s, is that drepanocytosis reduces the risks of episodes of severe infection-linked anaemia by almost half. In regions where malaria is rife, individuals with greater chance of having descendants are HbA/HbS heterozygous, which leads to persistence of the HbS allele. This also explains the very strong geographical correlation between drepanocytosis and malaria.
PUBLIC POLICIES
Unlike other species, we have a unique ability for non-genetic evolution, also known as cultural evolution. If we adopt this reading, it becomes evident that epidemics still shape our evolution. For example, the ravages caused by bacterial diseases have led to a growth in antibiotics. This has mechanically selected antibacterial-resistant strains, as the microbes evolve very rapidly. In return, this leads to changes in public health policies, with the WHO recognising antibacterial resistance as a serious issue in 1998 and in 2006, with the European Union banning antibiotics in animal feed.
Evidently, these issues are mainly sociological and anthropological, but evolutionary biologists can contribute to the debate by providing knowledge about microbial evolution. Our culture remains our best defence against infectious diseases; it alone gives us a head start on evolution.
IN MADAGASCAR, A MALARIA-RESISTANT ALLELE
About ten years ago, an international programme was launched to reveal the mystery of the origin of the inhabitants of Madagascar. Geneticists, linguists and anthropologists visited the island to document its diversity. The inhabitants who accepted to participate gave their saliva for genetic studies. After analysing data from 700 individuals sampled in 257 villages across the country, the scientists discovered that Malagasy populations are on average 38% of Asian descent and 62% of African descent. Surprisingly, in all individuals studied, a wide region on chromosome 1 (corresponding to 1,300 genes) conserves significantly more African ascendance that the average for the genome, up to a maximum of 92% (1). Demographic history alone cannot explain this huge deviation.
Why such selection? In this region of the chromosome 1 of African ascendancy is a mutation that provides resistance to one of the agents of malaria, the parasite Plasmodium vivax. People carrying this African allele were probably advantaged (longer life and more descendants), as they were immune to Vivax malaria. Thanks to this advantage, the African allele resisting malaria gradually spread throughout the Malagasy population.
Photo : Woman with hat near Toliara, Madagascar © Bernard Gagnon
NEANDERTHAL CONTRIBUTION TO IMMUNITY
When Homo sapiens arrived in Europe, they met Neanderthal man, who had been living there for at least 250,000 years and had hence adapted to that environment. With this merger, “modern humans” acquired genetic diversity that helped them to survive, particularly from infections. This is what the team of Lluis Quintana-Murci at the Pasteur Institute showed by studying the 1,500 genes of our innate immune system. According to this research, these genes are indeed richer in Neanderthal DNA than the rest of our genome. Some of them contain 30 to 60% Neanderthal DNA. This is the case for genes from the OAS family, involved in antiviral response, and for TLR1/6/10 genes, involved in the inflammatory response.
> AUTHOR
Samuel Alizon
Evolutionary Biologist
CNRS director of research at the Mivegec laboratory in Montpellier, the evolutionary biologist Samuel Alizon uses mathematical modelling to study ecology and the evolution of infectious diseases, especially human parasites such as HIV or the papillomaviruses.
