Dissecting human population variation in single-cell responses to SARS-CoV-2.

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1-3, the genetic and immunological basis of which has begun to be deciphered4. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors of diverse ancestries-that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes.

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer's disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

Revisiting the Hygiene Hypothesis in the Context of Autoimmunity.

Initially described for allergic diseases, the hygiene hypothesis was extended to autoimmune diseases in the early 2000s. A historical overview allows appreciation of the development of this concept over the last two decades and its discussion in the context of evolution. While the epidemiological data are convergent, with a few exceptions, the underlying mechanisms are multiple and complex. A major question is to determine what is the respective role of pathogens, bacteria, viruses, and parasites, versus commensals. The role of the intestinal microbiota has elicited much interest, but is it a cause or a consequence of autoimmune-mediated inflammation? Our hypothesis is that both pathogens and commensals intervene. Another question is to dissect what are the underlying cellular and molecular mechanisms. The role of immunoregulatory cytokines, in particular interleukin-10 and TGF beta is probably essential. An important place should also be given to ligands of innate immunity receptors present in bacteria, viruses or parasites acting independently of their immunogenicity. The role of Toll-Like Receptor (TLR) ligands is well documented including via TLR ligand desensitization.

Disease transmission and introgression can explain the long-lasting contact zone of modern humans and Neanderthals.

Neanderthals and modern humans both occupied the Levant for tens of thousands of years prior to the spread of modern humans into the rest of Eurasia and their replacement of the Neanderthals. That the inter-species boundary remained geographically localized for so long is a puzzle, particularly in light of the rapidity of its subsequent movement. Here, we propose that infectious-disease dynamics can explain the localization and persistence of the inter-species boundary. We further propose, and support with dynamical-systems models, that introgression-based transmission of alleles related to the immune system would have gradually diminished this barrier to pervasive inter-species interaction, leading to the eventual release of the inter-species boundary from its geographic localization. Asymmetries between the species in the characteristics of their associated 'pathogen packages' could have generated feedback that allowed modern humans to overcome disease burden earlier than Neanderthals, giving them an advantage in their subsequent spread into Eurasia.

Immune Gene Diversity in Archaic and Present-day Humans.

Genome-wide analyses of two Neandertals and a Denisovan have shown that these archaic humans had lower genetic heterozygosity than present-day people. A similar reduction in genetic diversity of protein-coding genes (gene diversity) was found in exome sequences of three Neandertals. Reduced gene diversity, particularly in genes involved in immunity, may have important functional consequences. In fact, it has been suggested that reduced diversity in immune genes may have contributed to Neandertal extinction. We therefore explored gene diversity in different human groups, and at different time points on the Neandertal lineage, with a particular focus on the diversity of genes involved in innate immunity and genes of the Major Histocompatibility Complex (MHC).We find that the two Neandertals and a Denisovan have similar gene diversity, all significantly lower than any present-day human. This is true across gene categories, with no gene set showing an excess decrease in diversity compared with the genome-wide average. Innate immune-related genes show a similar reduction in diversity to other genes, both in present-day and archaic humans. There is also no observable decrease in gene diversity over time in Neandertals, suggesting that there may have been no ongoing reduction in gene diversity in later Neandertals, although this needs confirmation with a larger sample size. In both archaic and present-day humans, genes with the highest levels of diversity are enriched for MHC-related functions. In fact, in archaic humans the MHC genes show evidence of having retained more diversity than genes involved only in the innate immune system.

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans.

BACKGROUND: The 2'-5' oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. RESULTS: Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. CONCLUSIONS: We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.

Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

Antimicrobial Functions of Lactoferrin Promote Genetic Conflicts in Ancient Primates and Modern Humans.

Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with microbes remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by bacteria. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with opportunistic bacterial pathogens causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.

Neanderthal genomics suggests a pleistocene time frame for the first epidemiologic transition.

High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity, with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. As such Neanderthal genomes are an independent line of evidence of which infectious diseases Neanderthals were genetically adapted to. Sympathetically, human genome adaptive introgression is an independent line of evidence of which infectious diseases were important for AMH coming in to Eurasia and interacting with Neanderthals. The Neanderthals and Denisovans present interesting cases of hominin hunter-gatherers adapted to a Eurasian rather than African infectious disease package. Independent sources of DNA-based evidence allow a re-evaluation of the first epidemiologic transition and how infectious disease affected Pleistocene hominins. By combining skeletal, archaeological and genetic evidence from modern humans and extinct Eurasian hominins, we question whether the first epidemiologic transition in Eurasia featured a new package of infectious diseases or a change in the impact of existing pathogens. Coupled with pathogen genomics, this approach supports the view that many infectious diseases are pre-Neolithic, and the list continues to expand. The transfer of pathogens between hominin populations, including the expansion of pathogens from Africa, may also have played a role in the extinction of the Neanderthals and offers an important mechanism to understand hominin-hominin interactions well back beyond the current limits for aDNA extraction from fossils alone. Am J Phys Anthropol 160:379-388, 2016. © 2016 Wiley Periodicals, Inc.

TLRs of Our Fathers.

Two new studies published in The American Journal of Human Genetics (Dannemann et al., 2016; Deschamps et al., 2016) show that introgression of innate immune genes from Neandertals and Denisovans contributed to the modern genome of European and Asian, but not African, populations, and this might partly explain differences in susceptibility to immune-mediated diseases.

Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes.

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change-containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.

[Innate immunity and human diseases: from archaic introgression to natural selection]. / Immunité innée et maladies chez l'homme - De l'introgression archaïque à la sélection naturelle.

Throughout evolution, humans have had to face strong variation in environmental conditions, with pathogens being among the strongest threats that our species has encountered. The use of population genetic approaches provides novel insights into how natural selection imposed by pathogen pressures, in its different forms and intensities, has shaped the patterns of diversity of the human genome at the population level. These studies help to distinguish genes playing essential, non-redundant functions in host defence from genes variation in which has conferred selective advantages to specific human populations and/or has been acquired through admixture with archaic hominins, such as Neandertals. However, with the improvements in hygiene and the advent of antibiotics and vaccination, pressures imposed by pathogens have recently been relaxed. Accumulating evidence suggests that alleles having conferred an advantage against infection in the past may nowadays be associated with increased risk to develop immune-related disorders, such as autoimmunity and inflammation.

Distribution of HLA haplotypes across Japanese Archipelago: similarity, difference and admixture.

The human leukocyte antigen (HLA) region is the most polymorphic region in the human genome. The polymorphic nature of the HLA region is thought to have been shaped from balancing selection. The complex migration events during the Out-of-Africa expansion have influenced geographic patterns of HLA allele frequencies and diversities across present-day human populations. Differences in the HLA allele frequency may contribute geographic differences in the susceptibility to many diseases, such as infectious, autoimmune and metabolic diseases. Here we briefly reviewed characteristics of frequency distribution of HLA alleles and haplotypes in Japanese population. A large part of HLA alleles and haplotypes that are common in Japanese are shared with neighboring Asian populations. The differentiations in HLA alleles and haplotypes across Japanese regional populations may provide clues to model for peopling of Japanese Archipelago and for design of genetic association studies. Finally, we introduce recent topics that new HLA alleles derived from ancient admixtures with Neanderthals and Denisovans are thought to have played an important role in the adaptation of modern humans to local pathogens during Out-of-Africa expansion.