Brownian motion: a paradigm of soft matter and biological physics

This is a pedagogical introduction to Brownian motion on the occasion of the 100th anniversary of Einstein's 1905 paper on the subject. After briefly reviewing Einstein's work in its contemporary context, we pursue some lines of further developments and applications in soft condensed matter and biology. Over the last century Brownian motion became promoted from an odd curiosity of marginal scientific interest to a guiding theme pervading all of the modern (live) sciences.Comment: 30 pages, revie

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL- 12–dependent IFN-? immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL- 12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL- 23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that aß T, ?d T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-? in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-? in response to IL-23. We also show that the development of IFN-?–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rß2–deficient than IL-12Rß1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-?, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-?–dependent immunity to mycobacteria, both individually and much more so cooperatively

Investigation of pathogenic mutations by whole exome sequencing analyses of large cohorts of patients : application to tuberculosis

Le cadre général de mon projet se situe dans la recherche de gènes contribuant à la prédisposition ou à la résistance à la tuberculose en se servant des exomes non seulement de patients tuberculeux mais aussi de ceux de patients MSMD. Il s’agit en particulier de comprendre pourquoi, lorsque des individus sont infectés par M. tuberculosis, certains (~10%) vont développer la maladie clinique (qui peut être plus ou moins sévère) alors que d’autres (~90%) ne présentent aucune symptomatologie (infection latente). Nous décrivons dans cette thèse la découverte d’une nouvelle étiologie génétique du MSMD au sein du gène IFNG, gouvernant le seul axe immunologique de défense anti-mycobactérienne connu. Nous rapportons aussi la première étiologie monogénique relativement commune de la tuberculose. Cette découverte est un des premiers exemples faisant le lien entre étiologies monogéniques à effets forts et variants communs obtenus par analyses GWAS. Compte tenu de l’histoire de la tuberculose, ce variant aurait pu être responsable à lui tout seul de la mort de 10 millions d’individus au cours des 2,000 dernières années. Finalement, nous étendons l’horizon d’étude de la tuberculose par la recherche d’étiologies digéniques à partir du développement d’une nouvelle méthode statistique. Elle est appropriée à l’étude de maladies dites monogéniques qui ne sont pourtant pas complètement expliquées par une seule lésion monogénique. La robustesse et la puissance de cette approche à identifier des interactions entre deux régions génétiques indépendantes ont été démontrées et réalisées tant sur des données simulées comme sur des données réelles (craniosynostose).The thesis aimed at finding new genetic etiologies of tuberculosis disease using whole exome sequencing data of tuberculosis patients as well as MSMD patients. Since the beginning of the XXth century researchers have tried to understand why infected individuals would (~10%) in some cases develop diseases while others (~90%) would remain asymptomatic. We herein describe the first genetic etiology of MSMD in the IFNG gene, the core gene controlling host’s immune systeme against mycobacterial infections. We also describe the first common monogenic etiology of tuberculosis in the TYK2 gene, bridging the gap between monogenic variants with strong effect and more common variants obtained with GWAS. Looking back at the history of TB, it would be estimated that about 10 million people died due to this one TYK2 mutation. We finally expanded the study of the genetics of tuberculosis by developing a new methodology to study digenic effects on disease susceptibility. It is in particular appropriate to the study of so far assumed monogenic diseases that are not fully explained by a monogenic lesion. Robustness and power of this approach to find interaction between independent genomic regions were shown in both extensive simulated data and real exome data (craniosynostosis)

Paléogénomique et évolution du système immunitaire humain au cours des dix derniers millénaires

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The genetic and evolutionary determinants of COVID-19 susceptibility

International audienceDevastating pandemics, such as that due to COVID-19, can provide strong testimony to our knowledge of the genetic and evolutionary determinants of infectious disease susceptibility and severity. One of the most remarkable aspects of such outbreaks is the stunning interindividual variability observed in the course of infection. In recent decades, enormous progress has been made in the field of the human genetics of infectious diseases, and an increasing number of human genetic factors have been reported to explain, to a great extent, the observed variability for a large number of infectious agents. However, our understanding of the cellular, molecular, and immunological mechanisms underlying such disparities between individuals and ethnic groups, remains very limited. Here, we discuss recent findings relating to human genetic predisposition to infectious disease, from an immunological or population genetic perspective, and show how these and other innovative approaches have been applied to deciphering the genetic basis of human susceptibility to COVID-19 and the severity of this disease. From an evolutionary perspective, we show how past demographic and selection events characterizing the history of our species, including admixture with archaic humans, such as Neanderthals, facilitated modern human adaptation to the threats imposed by ancient pathogens. In the context of emerging infectious diseases, these past episodes of genetic adaptation may contribute to some of the observed population differences in the outcome of SARS-CoV-2 infection and the severity of COVID-19 illness

New insights into human immunity from ancient genomics

International audiencePopulation genetic studies have clearly indicated that immunity and host defense are among the functions most frequently subject to natural selection, and increased our understanding of the biological relevance of the corresponding genes and their contribution to variable immune traits and diseases. Herein, we will focus on some recently studied forms of human adaptation to infectious agents, including hybridization with now-extinct hominins, such as Neanderthals and Denisovans, and admixture between modern human populations. These studies, which are partly enabled by the technological advances in the sequencing of DNA from ancient remains, provide new insight into the sources of immune response variation in contemporary humans, such as the recently reported link between Neanderthal heritage and susceptibility to severe COVID-19 disease. Furthermore, ancient DNA analyses, in both humans and pathogens, allow to measure the action of natural selection on immune genes across time and to reconstruct the impact of past epidemics on the evolution of human immunity

Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years

International audienceTuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians $30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting$2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

International audienceThe human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96–10.31, P = 2 × 10−3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans