A Genetic Tale: Our Diversity, our Evolution, our Adaptation

Darwin and Mendel: the origins of population genetics

The Chair that I have the honour and pleasure of inaugurating brings together two disciplines, genetics and evolution. These disciplines were founded separately, in the mid-nineteenth century, by Gregor Mendel and Charles Darwin. It took many decades for biologists to establish a link between the principles of heredity and the processes underlying evolution. Yet thinkers since Antiquity appear to have defended the idea that an organism could change into another organism. Anaximander of Miletus claimed that the first animals lived in water and that land animals evolved from them, and Empedocles affirmed that living beings did not have a supernatural origin. However, the fact that philosophers as influential as Plato and Aristotle argued in favour of the divine origin of living beings, and the subsequent 2,000 years of Christianity, prevented the emergence of evolutionary thinking before the early nineteenth century, despite a few advances by Enlightenment thinkers.

It was the Frenchman Jean-Baptiste Lamarck who first formulated a theory of evolution in his book Philosophie zoologique, where he argued that organisms appear spontaneously and evolve towards a higher level of complexity under the pressure of their environment. However, after the Congress of Vienna and his death in 1829, there was no mention of evolution until Charles Darwin. In 1859, fearing that Alfred Russel Wallace would publish the same idea as his own, namely evolution by natural selection, Darwin published his masterpiece The Origin of Species. In this book, he developed the notion of “adaptation” to the environment and set out the extraordinary intuition that, if this adaptation is inherited, the proportion of individuals that survive in a specific environment will change over the generations. The book was a stunning success, selling over 1,000 copies on the first day. The violent reactions were no less exceptional, especially from the Anglican Church. Darwin recognized Wallace’s merits and, after the publication of his book, he led a solitary life in Kent, wounded by the reactions and controversy it had provoked. He died in 1882 at the age of 73.

It was with the Czech abbot Gregor Mendel, a contemporary of Charles Darwin and the founding father of genetics, that Darwin’s concept of “heritability” became a reality, with the publication in 1865 of his work on the transmission of hereditary traits. Ten years of experiments carried out on thousands of peas resulted in Mendel’s laws, which defined the way in which genes, which he called “factors”, are transmitted from generation to generation. In 1889, the Dutch naturalist Hugo de Vries proposed the term pangene to denote the physical unit of character transmission, and later, at the beginning of the twentieth century, the Danish botanist, physiologist and geneticist Wilhelm Johannsen introduced terms such as genetics and gene. Unfortunately, Mendel’s seminal paper was not at all successful, and Darwin never read it. The link between heredity and evolution had yet to be made.

The reconciliation of Darwinism and Mendelism was initiated by young researchers from Francis Galton’s British school of biometrics: Ronald Fisher, who laid the foundations of quantitative genetics; Sewal Wright, known for his concepts of “adaptive landscape” and “genetic drift”; and John B.S. Haldane, who was interested in the interactions between natural selection, mutation, and gene flow. All three founded population genetics, a discipline that combines evolution and genetics into a coherent mathematically-modelled framework.

Although Fisher, Wright and Haldane were the founders of theoretical population genetics, it was with Ernst Mayr, Theodosius Dobzhansky and Julian Huxley that an interdisciplinary consensus emerged, known as the “synthetic theory of evolution” – a neo-Darwinian theory based on the natural selection of random variations in the genome. This theory established the legitimacy of evolutionary biology, and natural selection became the only acceptable mechanism for explaining evolutionary changes.

It was with the advent of molecular biology in the mid-twentieth century that the understanding of the nature of hereditary inheritance, thus of DNA, emerged. The discovery of the structure of the double helix molecule by Francis Crick, Rosalind Franklin and James Watson was unquestionably a major breakthrough in biology, giving the scientific community one of the keys to understanding the secrets of life. Two pioneers of molecular biology, the Frenchmen Jacques Monod and François Jacob, both professors of the Collège de France and winners – together with André Lwoff – of the Nobel Prize in 1965, coined the concept of the “operon”. An operon is a unit made up of several genes whose expression is regulated by a single promoter – a notion also attributed to these two French scientists.

It was thanks to all these discoveries in molecular biology and, more generally, in genetics, that the Japanese scientist Motoo Kimura was able to combine theoretical approaches with empirical data, and proposed the neutralist theory of evolution (Kimura, 1968). According to this theory, most evolutionary changes are due to genetic drift, that is, a random process independent of natural selection and migration. However, the neutralist theory primarily refers to evolution at the molecular level, and Kimura himself recognized that phenotypic evolution cannot take place without the action of natural selection.

Human genome sequencing and the quest for diversity

Studies in genetics developed rapidly with the advent of DNA sequencing techniques and, above all, the sequencing of the human genome, which was completed in the early 2000s. This sequence provided key insights into the structure and content of the genome. We now know that it is made up of around 3.1 billion nucleotides and that each individual, with the exception of monozygotic twins, has their own, unique genome. We also know that our human genome contains around 20,000 protein-coding genes, proteins being the essential building blocks of a living being, and that the majority of the genome (98%) is noncoding and is largely involved in regulatory functions.

The sequencing of the human genome nevertheless provided very little information about the extent of genetic diversity between individuals or populations, since it mostly involved a single sequence. It was with the advent of new genomic technologies, such as DNA chips and next-generation sequencing, combined with the decrease of sequencing costs, that the study of human genome diversity entered its golden age. Several international consortia were set up to characterize human genetic diversity across multiple populations worldwide, thus facilitating studies in population genetics and medical genetics. Thanks to them, we now know that each of us carries 250 to 300 loss-of-function gene variants, raising questions about the levels of redundancy in the genome (Auton et al., 2015). We also know that we are all born with 50 to 100 mutations, fortunately in the heterozygous state, associated with genetic diseases.

These genomic studies have also increased our understanding of the demographic and adaptive history of human populations, how our ancestors admixed with other, now-extinct human forms such as Neanderthals or Denisovans, and the influence of natural selection on genome diversity (Fan et al., 2016; Leonardi et al., 2017; Nielsen et al., 2017; Quach and Quintana-Murci, 2017; Skoglund and Mathieson, 2018; Vitti et al., 2013). These studies have also provided invaluable knowledge for the clinical interpretation of genetic variants identified in patients and for dissecting the genetic architecture of morphological and physiological traits.

It is in this context that I would like to pay tribute to a pioneering initiative in the study of human genetic diversity: the Jean Dausset-CEPH Foundation. The CEPH is the Centre for the Study of Human Polymorphism, and Jean Dausset, a visionary, great scientist and physician, to whom I owe a great deal. I had the fortune and honour of knowing him personally and learning a great deal from him during our discussions, both in Majorca, my native island where he had settled, and in his Paris flat, just across from the cour d’honneur of the Collège de France. I will never forget him and I dedicate this inaugural lecture to him with my deepest affection.

With Jean Dausset’s support, Howard Cann, an American paediatrician and member of the Foundation, in collaboration with Luigi Luca Cavalli-Sforza of Stanford University, set up a panel comprising over a thousand immortalized cell lines from individuals from fifty-two populations around the world. Over the last twenty-five years, and despite being underestimated at national level, the CEPH has acquired a leading international reputation, since its multi-ethnic panel has made it possible to characterize the genetic diversity of our species at an unprecedented level of resolution.

Human migration and natural selection

Studies in human genomics have also uncovered important information about the origins and migrations of Homo sapiens. Paleoanthropological records indicate that our ancestors appeared in Africa around 200,000-300,000 years ago, then dispersed out of Africa around 60,000 years ago, rapidly colonizing Eurasia and Australia (Nielsen et al., 2017). Humans ultimately reached more distant locations, such as the Americas, around 15,000-35,000 years ago, and then the remote islands of Oceania, where they settled as recently as 1,000-4,000 years ago (Fig. 2).

Genetics has also revealed a great deal of substructure of populations within continents. In sub-Saharan Africa, population genetic structure is correlated with geography, the distribution of language families, and modes of subsistence, whereas in Europe genetic diversity is strongly driven by geography, with population structure being detectable within even small areas about 500 km apart (Novembre et al., 2008).

Alongside the analysis of so-called “neutral” genomic regions, which inform past demographic events, the detection of the signatures of natural selection in the genome makes it possible to reconstruct our adaptive history, that is, the ways in which humans have biologically adapted to their environment (Fan et al., 2016; Jeong and Di Rienzo, 2014; Novembre and Di Rienzo, 2009). Although the shaping of population genetic diversity is primarily driven by genetic drift, natural selection also influences genetic diversity and can take varied forms (Vitti et al., 2013).

The most widespread form of selection in our genomes, purifying selection, eliminates deleterious alleles from the population, while positive selection acts on mutations that are advantageous for our survival, according to different evolutionary models. In the classic selective sweep model, positive selection acts upon a newly arising advantageous mutation that will rapidly increase in frequency in the population. Polygenic selection, on the other hand, involves the simultaneous selection of numerous variants on numerous genes, each making its own small contribution to better adaptation. Genetic adaptation can also be achieved through balancing selection, which preserves functional diversity through heterozygote advantage, frequency-dependent selection or pleiotropy. Each form of selection leaves very specific molecular signatures around the selected region (Vitti et al., 2013).

Recent studies have led to a better understanding of the ways in which population history influences the efficacy of purifying selection (Henn et al., 2015; Lohmueller, 2014). European populations, for example, have a higher proportion of deleterious variants than African populations – a pattern that is consistent with less purging of deleterious alleles in smaller populations, where the effects of genetic drift are more pronounced. Similarly, populations resulting from strong founder effects, such as the French Canadians, or having experienced bottlenecks, such as the Finns, have an even higher proportion of deleterious variants, including some associated that lead to the complete inactivation of certain genes.

Conversely, the occurrence of positive selection informs the adaptive potential of our species (Fan et al., 2016). During their long journey across the globe, humans have had to adapt to a wide variety of climatic, nutritional and pathogenic conditions. In recent years, the study of positive selection on the genome has proved crucial in identifying some key genes involved in the morphological and physiological diversity of human populations. Iconic cases of positive selection are variants in the lactase gene (LCT), responsible for the persistence of lactose tolerance in adults (Tishkoff et al., 2007). Other examples include genes involved in the variation of skin pigmentation and adaptation to cold, to rainforests environments or to life at high altitudes in hypoxic conditions (that is, the lack of oxygen supply to the body’s tissues) (Fan et al., 2016). As we will see later, positive selection has also targeted genes involved in immune response and resistance to infectious diseases (Quach and Quintana-Murci, 2017; Quintana-Murci, 2019).

A long history of archaic and modern admixture

The possibility of sequencing DNA from fossil remains has been a scientific revolution over the last decade (Leonardi et al., 2017; Skoglund and Mathieson, 2018; Stoneking and Krause, 2011). The study of the DNA of hominins such as Neanderthals and Denisovans, present in Eurasia until around 40,000 years ago, has shown that our species, Homo sapiens, did admix with these ancient humans (Racimo et al., 2015) (Fig. 2). This phenomenon, known as archaic introgression, can be observed in the genome of modern human populations; at a rate of 2% for Neanderthal ancestry in the genome of Eurasians, and up to 5% for Denisovan ancestry in certain Pacific populations (Sankararaman et al., 2014). In most cases, there has been strong selection against archaic introgression, particularly among protein-coding genes, probably due to its deleterious effects in modern humans. Identifying regions of the human genome strongly depleted of archaic ancestry makes it possible to identify functions that may have contributed to the uniqueness of certain Homo sapiens traits.

Modern humans have however also acquired advantageous alleles through this ancient admixture, via a process known as adaptive introgression. For example, certain variants of the HLA (human leukocyte antigen) immune system, discovered by Jean Dausset and for which he was awarded the Nobel Prize in Physiology or Medicine in 1980, were acquired through admixture of early Eurasians with Neanderthals (Abi-Rached et al., 2011). Another significant example: the EPAS1 gene, associated with the response to hypoxia, displays a high degree of Denisovan ancestry in Tibetans, suggesting that this population acquired advantageous alleles for life at high altitude through admixture with Denisovans (Huerta-Sanchez et al., 2014). Our most recent work shows that admixture with both Neanderthals and Denisovans may also have enabled our ancestors to better survive life-threatening infectious diseases (Quintana-Murci, 2019).

Unlike archaic introgression, the role of admixture between modern populations in their adaptation to the environment remained largely unknown. The study of the genome diversity in over ninety human populations has shown that admixture has been a pervasive feature in our species (Hellenthal et al., 2014). Classic examples of admixture between populations are those associated with the expansion of the Mongol Empire in Eurasia and the Bantu languages in Africa. More recently, and for unfortunate reasons relating to slave-trade, we can mention the admixture between European settlers and slaves of African ancestry, leading to contemporary African-Americans. Cutting-edge statistical methods now make it possible to decompose the genomes of admixed populations into segments of different ancestry, which in turn makes it easier to identify the genetic variants associated with the risk of developing certain diseases.

We have only recently begun to study how modern admixture might also have facilitated human adaptation (Patin et al., 2017). This phenomenon, which we have termed adaptive admixture, had not until now been systematically tested in humans, even though it could represent a major asset in our evolution. The aim is to identify regions of the genome that, as a result of admixture, show an excess of inheritance from a parental population, compared with genomic expectations.

The history of Homo sapiens through the lens of evolutionary genetics

Over the past twenty-five years, the federating element of my research has been the study of the genetic diversity of human populations, which can be broken down into three main areas: understanding the demographic history of our species; understanding the history of human adaptation to their environment, in particular to the microbial environment; and finally, understanding the nature of the factors responsible for the variability of our immune system (Quach and Quintana-Murci, 2017; Quintana-Murci, 2016; Quintana-Murci, 2019). To this end, our laboratory combines population genetics and cellular genomic approaches, with computational modelling and development of new statistical frameworks.

At this point, I would like to thank the real players in this research, those who have been with me since the beginning and those who have joined me more recently; in short, all those who have contributed or are still contributing to this great team adventure. It is a privilege for me to be able to work with such people. I would also like to thank the Institut Pasteur and the Centre National de la Recherche Scientifique (CNRS) for their kindness and for having encouraged and supported us from the beginning, as well as funding agencies and foundations, with special thanks to the Fondation pour la Recherche Médicale (FRM). Finally, I would like to reserve a special mention for the person who, de facto, co-directs the laboratory with me, my teammate Étienne Patin, a brilliant, generous, altruistic man who always puts the scientific question to be solved before all else.

Humans and microbes: a double-edged relationship

The link between natural selection, immune response and infectious diseases has been the second major focus of our research. Humans and microbes have a longstanding, double-edged relationship (Siddle and Quintana-Murci, 2014). They can complement each other and maintain a state of homeostasis, as in the gut microbiota, for example, but microorganisms can also sometimes be pathogenic, causing disease. Just as famine and war have continually inflicted a massive mortality burden on humans, so too has the threat of pathogenic infections had an overwhelming effect. Ancient diseases such as malaria and tuberculosis, or more recent ones such as the Black Death and Spanish flu, have killed millions of people throughout human history.

Mortality rates from infection remained high until the late nineteenth century, when hygiene improved and vaccines and antibiotics began to be developed (Cairns, 1997; Casanova and Abel, 2005). At the end of the nineteenth century, for example, only 35% of Europeans reached the age of 40, illustrating the heavy burden of infection and the harsh law that had prevailed until then in the history of our species. Even Louis Pasteur, the father of the microbial theory, lost three of his daughters to what was then known as “fever”. Retrospectively, it is tempting to speculate that they died of an infectious disease (Fig. 5). This illustrious family is representative of most families at the time: it was not uncommon for at least half the siblings in a family to die of infection. The question that arises from this observation is: why this half? In Pasteur’s family, one son and one daughter survived into adulthood, although they had probably been exposed to at least one of the microbes that killed their sisters. It is therefore possible that the three daughters who died carried some form of genetic predisposition to infectious disease.

The first to establish a causal link between mortality, infectious diseases and natural selection were John B.S. Haldane and Anthony Allison, in the 1950s. They hypothesized that red blood cell disorders, such as thalassaemia and sickle-cell disease, could provide protection against malaria (Allison, 1954; Haldane, 1949). Since that early work, a growing number of population genetics studies have shown that genes involved in immune functions display among the strongest signatures of natural selection of the genome, underlining the major role played by pathogens in the evolution of our species.

It was with these questions in mind that, around fifteen years ago, through Philippe Kourilsky, Professor of the Collège de France and, at the time, Director of the Institut Pasteur, I had the good fortune to meet Jean-Laurent Casanova and Laurent Abel. Together, we pioneered a new multidisciplinary approach to the study of infection, integrating clinical genetics, epidemiological genetics and evolutionary genetics (Alcais et al., 2010; Casanova et al., 2013; Quintana-Murci, 2016; Quintana-Murci, 2019). The detection of the molecular signatures of selection in genes involved in immunity, or the absence of such signatures (neutrality), combined with clinical and epidemiological data, has enabled us to assess the biological relevance of the corresponding genes in natura and to determine whether they are essential, redundant or adaptable (Fig. 6).

Immunology, human genetics and precision medicine

The third strand of our research, which began in the early 2010s, concerns the link between human immunology, genetics, and precision medicine. Our aim is to gain a better understanding of how genetic diversity, on the one hand, and non-genetic factors such as sex, age, nutrition, microbiota, epigenetic factors and lifestyle, on the other, can alter our immune responses (Fig. 7). In the long term, this information could pave the way to treatments that are better adapted to individuals and are more effective, with fewer side effects.

The study of the genetic architecture of gene expression, through the characterization of expression quantitative trait loci (eQTLs), has revealed its full value in establishing links between genetic diversity, intermediate phenotypes such as gene expression, and ultimate phenotypes such as susceptibility to infection (Dermitzakis, 2012; Fairfax and Knight, 2014). In recent years, we have started several projects involving the use of expression data, whether from protein-coding genes or small regulatory RNAs, combined with a model of immune activation, such as the infection of cells by infectious agents like the tuberculosis bacillus or influenza virus (Quach et al., 2016; Rotival et al., 2019; Siddle et al., 2014; Siddle et al., 2015). These studies should ultimately help us to better understand how variation in immune phenotypes has contributed to human adaptation to pathogen pressures.

For example, we characterized the transcriptional responses of monocytes to different bacterial and viral stimuli in individuals of African and European ancestry, all living in Belgium, in order to homogenize environmental exposure as much as possible (Quach et al., 2016). We have shown that there is indeed population differences: Africans and Europeans differ in the magnitude and extent of their immune response, particularly for certain genes involved in inflammatory and antiviral responses. These differences are largely due to genetic variants that modulate gene expression and that present different frequencies between the two populations. This work has also shown that natural selection may have favoured some of these mutations, leading each of these populations to better adaptation. Interestingly, through independent processes, selection favoured the same immune phenotype in Africans and Europeans: a reduction of the inflammatory response. This example of “convergent evolution” supports the notion that an overly strong immune response, as in the case of autoimmune diseases or allergies, should be avoided, even if it provides effective protection against infection.

In a more general context, identifying the various genetic and non-genetic factors behind the variability of the immune system is the core of the “Milieu intérieur” consortium, which I have been coordinating since 2011, first with Matthew Albert and then with Darragh Duffy (Thomas et al., 2015). This project brings together the multidisciplinary expertise of researchers in the fields of immunology, human and quantitative genetics, microbiology and computational biology. It takes its name from the concept of “internal environment”, developed by the physiologist and founder of experimental medicine, Claude Bernard, according to whom the internal environment – that is, the main internal fluids essential for living organisms – governs the very principles of life. The aim of this project is to establish the parameters that characterize the immune system of healthy individuals, paving the way for precision medicine.

To this end, we have recruited a cohort of 1,000 healthy individuals, which includes 500 women and 500 men, stratified by age classes between 20 and 70 years (Thomas et al., 2015). In recent years, we have obtained a large number of immune phenotypes, including the characterization of the proportions of immune cells in the blood, the gene and protein expression of hundreds of genes after stimulation by around thirty immune stimuli, and the characterization of faecal and nasal microbiota (Duffy et al., 2014; Patin et al., 2018; Piasecka et al., 2018; Scepanovic et al., 2019; Urrutia et al., 2016). In addition, a large number of health parameters, serologies for chronic infections (CMV, EBV, influenza, Helicobacter pylori, toxoplasmosis, etc.), vaccination and medical histories, socio-economic and lifestyle variables have been obtained, including diet, smoking habits, sports activities, sleep quality, and so on (Thomas et al., 2015).

Let me share with you two examples of this work. First, we focused on studying the factors driving the variability of cell types circulating in the blood (Patin et al., 2018). For this, we used flow cytometry to measure a large number of immunophenotypes. Of the 140 variables tested that could explain the variability of immune cells in our blood, only five had a real impact: human genetics, chronic cytomegalovirus infection, smoking, age and sex. Secondly, we showed that genetic factors influence primarily the variability of cell populations of the innate immune system, while non-genetic factors mostly affect cell variability of the adaptive immune system.

The second study investigated the factors driving the variability of the immune response to some infectious agents, such as the bacteria Escherichia coli, staphylococcus aureus, BCG (often used as a vaccine against tuberculosis), the influenza virus, or the fungus Candida albicans (Piasecka et al., 2018). Our study of the 1,000 individuals revealed that about 10% of the variance in immune response was explained by the cumulative effects of genetics, while sex and age accounted for about 5% of the total variance.

Although our understanding of the genetic, intrinsic, and environmental sources of immune response variation is growing, a significant proportion of inter-individual immune variance remains unexplained. Further research is therefore needed, which will take into account more complex forms of genetic control, such as the role of epistatic interactions or rare variants, interactions with age and sex, and the impact of the environment on gene expression, all using cutting-edge technologies such as single-cell sequencing.

The future of evolutionary biology: an ode to diversity

In conclusion, ladies and gentlemen, genomic approaches, combined with the principles and models developed in population genetics, have enabled us to identify key, essential immune functions and to distinguish them from others presenting higher levels of immunological redundancy. Genes whose variation has been beneficial to the survival of our species have also been identified, some of which harbour mutations that have been acquired through admixture with both archaic humans and between modern populations. Nevertheless, there are still many links to be explored between population genetics and evolution, on the one hand, and human immunology, on the other. This is the case not only for the effects of natural selection on immune phenotypes and disease risk at various time-scales, but also for the way in which adaptation to fight infection in the past can, following environmental or lifestyle changes, lead to “maladaptation” and, consequently, to pathology.

The study of ancient DNA from humans who have lived before or after major events, such as the transition to sedentary, farming-based lifestyles or epidemics that, like the plague, wiped out millions of people over the last millennium, could help us to better understand the factors underlying the susceptibility to, or severity of, infectious diseases. New statistical methods also need to be developed to identify more subtle forms of natural selection, such as polygenic selection and even polygenic introgression, which are still difficult to detect.

Finally, it should be pointed out that most genomic studies focus on large continental populations. By way of comparison, populations of European ancestry represent only 16% of the world’s inhabitants, whereas they make up more than 78% of the categories taken into account in genetic studies (Sirugo et al., 2019). For both scientific and societal reasons, it is therefore time to include more populations of non-European ancestry in these genomic studies, particularly the so-called “neglected” populations, in order to improve the representation of human genetic diversity as a whole. These multidisciplinary efforts, including approaches based on population genetics, functional genomics and genetic epidemiology, are needed to shed light on the links between migration history, natural selection, cultural factors and disease.

But it is time to return to the notion of diversity, a subject that has fascinated me since childhood. I am a Parisian, but also a Catalan, a Spaniard, a Frenchman, and above all, a European. This attraction to the diversity of languages, cultures and individuals led me, I believe, to population genetics, a discipline that is an ode to plurality, travel and diversity. It is diversity, and diversity alone, in fact, that drives evolution and underpins our species adaptation to environmental changes. As I hope to have shown you in this inaugural lecture, and as I will be going into in greater depth throughout my lectures, the study of genetic diversity makes it possible to answer key questions in evolutionary biology – questions that have major repercussions on human health.

If there is any merit in our experimental approach, it is that it seeks to unveil the most imposing and immediate experience that has ever existed: that of Nature.