It’s easy to understand our preoccupation with infectious disease. For millennia, viruses have been a leading cause of premature death and even in the modern world are still significant contributors to human mortality. Moreover, these diseases have shaped the fabric of human culture. Lingering impressions have been made by a deadly, unknowable foe; viruses have decimated whole populations in sudden outbreaks, can be harnessed as tools for war, and are seemingly forever a step ahead of modern medicine. Of course, such threats are no longer quite so mysterious and scientific research has greatly illuminated viral biology. We now possess tools capable of mitigating many of the dangers posed by infectious disease. An oft neglected realization, however, is that these same pathogens have been one of the strongest selective pressures on the human species. Beyond causing disease, they contribute to the continued evolution of Homo sapiens, defining, in a sense, our very nature as a distinctive species.

To appreciate the influence that viruses have had on human evolution, it is helpful to review the historical context of interactions between infectious agents and human society. Humans arose from within the family Hominidae and diverged 7 million years ago from our closest surviving relative (chimpanzees/bonobos). Anatomically modern humans appeared around 200,000 years ago on the African continent and global migration began 140,000-160,000 years later. Another important milestone in human evolution is the advent of agriculture 12,000 years ago. While all these events are in of themselves directly important to our evolution, they also had a major role in dictating the type and abundance of viruses capable of infecting humans. This, in turn, hints at the mechanisms by which a particular virus may influence our evolution. For example, some highly mutative RNA viruses (such as influenza) are easily transmitted between species and likely gained significance to humans after animal domestication, increased population densities, and emergence of commensal rodents. The intersection of these large pools of viral hosts in close proximity increased infection rates and selective pressure on human populations through direct mortality. Conversely, retroviruses that integrate into the host genome represent a stable, and more ancient form of infection. Such genome insertion events are shared with our common ancestors and largely conserved across the various species of apes. These genetic elements have been estimated to constitute 8% of the human genome and can directly regulate host gene expression.

[pullquote]“Viruses influence genetic diversity within the immune system, dictate the degree of genetic mixing between populations, contributed to our expansion out of Africa, and ancient infections shared across our lineage may live on as co-opted elements regulating modern biological function.”[/pullquote]

Clearly, the high morbidity associated with viral disease imparts a strong selective pressure on human populations. Quantifying the contribution to our evolution is a little more complicated. Besides pathogens, our ancestors’ evolutionary development was shaped by myriad other environmental conditions including climate and diet. Recently, published work examined the relative importance of each of these variables by correlating allele frequency distributions from more than 50 different human populations to their local surroundings. Intriguingly, pathogen load emerged as the dominant predictor of population divergence while climate and diet were only minor contributors. For example, the authors identified 103 genes significantly correlated between mutation frequency to pathogen load, but far fewer correlating to climate (11 genes) or diet (0 genes). Unsurprisingly, many of these 103 genes were directly involved in immune function; in particular, those that encode signaling molecules and pattern recognition receptors. These genes were also enriched for SNPs that had been previously associated with autoimmune disease. This supports a prominent hypothesis that autoimmune susceptibility alleles have been maintained because they bestow resistance to infection.

Previous studies have identified another notable trend: the immune system has been the predominant target of recent (<30,000 years ago) selective events. One interpretation of this is that immunological processes have been more challenged in recent history in line with the argument that burden from infectious diseases rose dramatically following adoption of agriculture. As mentioned previously, an outcome of this event is a changed relative contribution of various pathogens to the overall selective pressure acting on humans. Viral diseases such as measles, rubella, and smallpox may have only gained prominence after human population density reached a sufficient threshold for them to persist as endemic infections, or transfer from the close proximity of zoonotic reservoirs. This is supported by evidence that illustrates the differential specificity of selective pressures imparted by various classes of pathogens on our immunological genes. As an example, viruses seem to have exerted the strongest selective pressure on the highly polymorphic HLA class I and TLR genes, while helminths have mostly acted on more stable interleukins. The respective function and polymorphism of these immune genes fits with the persistent and ancient threat of helminths compared with a more episodic danger imposed from recently acquired viral infections.

Relative impact of viral families on humans over time. Illustrated by Michael Le and Joy Qu.
Relative impact of viral families on humans over time. Illustrated by Michael Le and Joy Qu.

Thus far, our discussion has highlighted how viruses impose a strong selective pressure that increases immune diversity. This notion assumes that we are the descendants of people who survived viral infections: theirs were the winning genes. While this is the dominant hypothesis, this is not the only possibility. One of the scariest attributes of many viral diseases is their long history of being used as biological weapons. A striking example is the depopulation of North and South America during European conquest in the 16th-18th centuries. Several diseases, especially smallpox, spread both intentionally and unintentionally, contributed to outbreaks in native populations. By the year 1600, these had killed over 90% of the indigenous population in the Caribbean, Central America, and Peru. Such rapid and extensive mortality is an atypical selective pressure and a consequence of virulent diseases being suddenly introduced en masse to an immunologically ignorant population. Rather than selecting genes that conveyed increased resistance, the dominant evolutionary force in this event was the huge loss of genetic diversity held by the inhabitants of the Americas. This phenomenon is termed virus-mediated competition: in essence pitting viral associated morbidity in a host reservoir species (or population) against the morbidity of another competing species (or population). Besides New World colonization by Europeans, this has happened several times in human history. Humans carried along several viruses as they migrated out of Africa and introduced these pathogens to other hominids thereby increasing speciation. Neanderthals may have been particularly unfortunate targets of these diseases as differences in their nasal structure – which was less efficient at filtering incoming air – likely increased their susceptibility to inoculation by human rhinoviruses and enteroviruses. Even if this alone did not cause a precipitous population decline it may have been a contributor to their eventual extinction, and, as a result, our success. Models show that if Neanderthals had a mortality rate only 2% above that of humans it would have been sufficient to cause their extinction after only 1,000 years of competition.

If describing what makes a human, one’s first ideas might relate to our physical characteristics, our cultural tendencies, or maybe our biological profile. We stand up on two legs, we listen to music, and our genome has 3.2 billion base pairs. This is static; it describes how we are now, but not where we’ve been or where we are going. The contextual background that shaped our evolutionary path as a species is a requisite component for understanding our identity and future. Here we have seen that our viral companions were key players that helped mold the recent fate of humanity. Viruses influence genetic diversity within the immune system, dictate the degree of genetic mixing between populations, contributed to our expansion out of Africa, and ancient infections shared across our lineage may live on as co-opted elements regulating modern biological function. Until the unlikely day when viral infections have no impact on our evolutionary fitness, we will continue to be shaped by their presence.


2. Van Blerkom, L. M. Role of viruses in human evolution. American Journal of Physical Anthropology Suppl 37, 14–46 (2003).

3. Fumagalli, M. et al. Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution. PLoS Genetics 7, e1002355 (2011).

4. t, L. B. & Quintana-Murci, L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nature Reviews Genetics 11, 17–30 (2010)

5. Lovell, W. G. “ Heavy Shadows and Black Night ”: Disease and Depopulation in Colonial Spanish America. 82, 426–443 (2013).

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Joshua Moreau

Josh is in his 3rd year as a PhD student in the Department of Immunology studying B cell development during inflammatory conditions. Originally from British Columbia, Josh likes outdoors activities and is an ardent runner and cyclist.

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