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Both environmental factors and genetic factors influence human immunity. Albert and colleagues leverage data from the Milieu Intérieur Consortium to comprehensively describe the effects of lifestyle, environment and genetics on human innate and adaptive immunity.

Variation in responses to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda suggests population-level divergence under natural selection, with hunter-gatherers disproportionately showing signatures of positive selection.

Many studies assess epigenetic marks in white blood cells, but it is unclear how much immune factors affect the epigenome. Here, the authors show that fine-scale blood cell composition and cytomegalovirus infection affect the DNA methylome of adults.

Population differences in immune responses to SARS-CoV-2 can be explained by environmental exposures, but also by local adaptation acting through genetic variants acquired after admixture with archaic hominin forms.

The recent increase in available human population genetic data is revealing signatures of selection at immunity-related genes. This Review discusses how studies of genome evolution are contributing to our understanding of how pathogens have shaped the human genome and immune response.

Genomic analyses of human populations in the Pacific provide insights into the peopling history of the region and reveal episodes of biological adaptation relating to the immune system and lipid metabolism through introgression from archaic hominins and polygenic adaptation.

Population genetics informs about how genes have evolved under varying selective pressures. The analysis of such selection signatures in innate immune genes, including genes encoding pattern-recognition receptors and their downstream effector molecules, provides helpful insight into the roles of these genes in host immunity and their links to disease.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Genetic ancestry might influence immunological response to infection at different regulatory levels. Here, the authors use RNA-Seq to investigate the variability of alternative splicing patterns in resting and stimulated monocytes of African- and European-descent.

Alternative polyadenylation (APA) has a key role in the post-transcriptional regulation of most human genes but is understudied in cells of the immune system. Here, the authors construct an atlas of cell type-specific APA events in various immune cell-types and stimulation conditions, providing evidence of widespread stimulation-responsiveness and association with immune-related traits.

A survey of 136 factors that may influence cytokine secretion identify smoking, cytomegalovirus latent infection and body mass index as influential factors, with varying effects on innate and adaptive immunity.

Agriculture emerged in West Africa 5,000 years ago but how this impacted the population of rainforest hunter-gatherers (RHGs) is unknown. Here, the authors show that modern-day RHG populations present up to 50% of farmer ancestry but admixture only occurred in the last 1,000 years.

Here, Brotherton and colleagues sequence 39 mitochondrial genomes from ancient human remains. They track population changes across Central Europe and find that the foundations of the European mitochondrial DNA pool were formed during the Neolithic rather than the post-glacial period.

The innate immune system affects viral evolution. Here, the authors use experimental evolution to ask how different immune pathways impact viral genetic diversity and virulence using Drosophila melanogaster and its natural pathogen Drosophila C virus.

Herpes simplex virus-1 encephalitis is linked to variants in a small nucleolar RNA, suggesting a new mechanism for antiviral immunity in cortical neurons.

Genetic and environmental factors affect genome-wide patterns of epigenetic variation. Here, the authors show that while current habitat and historical lifestyle impact the methylome of rainforest hunter-gatherers and sedentary farmers, the biological functions affected and the degree of genetic control differ.

Paleogenomics can help elucidate the genetic basis of modern diseases, including inborn errors of immunity that impair the response to infections, providing a tool for drug development.

High-coverage exomes from 300 central African hunter-gatherers and farmers reveal recent population trends and gene flow, as well as insight into the effects these trends have had on their respective mutational loads.

Immunogenomics studies have been largely limited to individuals of European ancestry, restricting the ability to identify variation in human adaptive immune responses across populations. Inclusion of a greater diversity of individuals in immunogenomics studies will substantially enhance our understanding of human immunology.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Current methods to identify the geographical origin of humans based on DNA data present limited accuracy. Here, the authors develop a new algorithm, the Genographic Population Structure (GPS), and demonstrate its ability to place worldwide individuals within their country or, in some cases, village of origin.

Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.

The COVID Human Genetic Effort examines the molecular, cellular and immunological determinants of the various SARS-CoV-2-related disease manifestations by searching for causal errors of immunity.

In this Perspective, Spaan and colleagues propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.