Panhong Liu

Human peripheral blood exhibits molecular and cellular heterogeneity across populations, yet the underlying mechanisms remain unclear. We present the Chinese Immune Multi-Omics Atlas (CIMA), characterizing molecular variations linked to sex, age, and genetic variants through multi-omics analysis of more than 10 million circulating immune cells from 428 Chinese adults. CIMA established an enhancer-driven gene regulatory network comprising 237 robust regulons; identified 9600 eGenes and 52,361 caPeaks at cell type resolution; and revealed pleiotropic associations among immune-related disease risk loci, cis-expression quantitative trait loci (QTLs), and chromatin accessibility QTLs. Furthermore, the cell language model CIMA-CLM predicted chromatin accessibility and evaluated the effects of noncoding variants from chromatin sequences and gene expression. CIMA provides a comprehensive reference for immune-related disease research.

Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1⁺ memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.

Since the release of the complete human genome, the priority of human genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid human genome from a Han Chinese male individual (CN1), in which the assemblies of both haploids achieve the telomere-to-telomere (T2T) level. Comparison of this diploid genome with the CHM13 haploid T2T genome revealed significant variations in the centromere. Outside the centromere, we discovered 11,413 structural variations, including numerous novel ones. We also detected thousands of CN1 alleles that have accumulated high substitution rates and a few that have been under positive selection in the East Asian population. Further, we found that CN1 outperforms CHM13 as a reference genome in mapping and variant calling for the East Asian population owing to the distinct structural variants of the two references. Comparison of SNP calling for a large cohort of 8869 Chinese genomes using CN1 and CHM13 as reference respectively showed that the reference bias profoundly impacts rare SNP calling, with nearly 2 million rare SNPs miss-called with different reference genomes. Finally, applying the CN1 as a reference, we discovered 5.80 Mb and 4.21 Mb putative introgression sequences from Neanderthal and Denisovan, respectively, including many East Asian specific ones undetected using CHM13 as the reference. Our analyses reveal the advances of using CN1 as a reference for population genomic studies and paleo-genomic studies. This complete genome will serve as an alternative reference for future genomic studies on the East Asian population.

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19.