Previous studies have highlighted significant genetic structure among Southeast Asian populations, with Northern Borneo natives closely related to Austronesians from Taiwan and the Philippines, and Peninsular Malaysia indigenous populations potentially linked to the indigenous Andamanese. In this study, we analyzed 96 genomes from indigenous populations in Peninsular Malaysia, genotyped with approximately 2 million genome-wide autosomal SNPs, alongside datasets from Singapore cosmopolitan Malays and five native populations from Sabah, Northern Borneo. Our findings reveal distinct genetic structures between indigenous populations and Malays, despite their shared habitat. The Malays exhibit substantial admixture with East Asian, Austronesian, and indigenous Peninsular Malaysian ancestral components. Indigenous populations showed lower within-population diversity and longer linkage disequilibrium compared to benchmark populations. Estimated divergence times suggest that the Semang represent an earlier branching population (similar to 10,000 years ago), followed by Northern Borneo natives (similar to 7,600-6,H800 years ago), with Malays diverging more recently. These results support a scenario of successive migration waves into Southeast Asia, providing insights into the genetic history and population structure of the region.
BACKGROUND AND AIMS:PNPLA3 variants are associated with increased hepatocellular carcinoma (HCC) risk. We examined the association between a combination of the PNPLA3 I148M genotype and clinical risk factors with HCC risk using data from a large, ongoing, population-based, prospective cohort study, the Singapore Chinese Health Study. APPROACH AND RESULTS:This study included 24,979 participants (54.2% female). The primary outcome was incident HCC. Fine-Grey models were used to examine the association between a combination of the PNPLA3 I148M genotype and clinical risk factors and risk of HCC. After a median follow-up of 19.8 years, we identified 214 HCC incident cases. Males who were homozygous carriers for PNPLA3 I148M (adjusted hazard ratio [aHR] = 9.23, 95% confidence interval [CI]: 4.81-17.70) had a nine-fold risk of HCC, while heterozygous male carriers (aHR 4.83, CI: 2.63-8.89) had a five-fold risk of HCC, compared to non-carrier females. Homozygous carriers who were overweight (aHR = 2.92, 95% CI: 1.74-4.89) had a three-fold risk of HCC compared to non-carriers who were not overweight. Participants with diabetes and who were homozygous carriers (aHR 2.83, 95% CI: 1.21-6.61) had an approximately three-fold risk of HCC compared to non-carriers without diabetes. CONCLUSION:The frequency of rs738409-G alleles was associated with a dose-dependent increase in HCC risk and was independent of other clinical risk factors. Among participants who were male, overweight, and those with diabetes, the risk of HCC was further elevated among those with rs738409-G alleles. These data may be helpful for the development of future risk stratification strategies.
Epstein-Barr virus (EBV) infects more than 95% of adults worldwide but is associated with endemic nasopharyngeal carcinoma (NPC) specifically in southern China1-4. Here, through a stepwise host-EBV genome interaction analysis, we identify a genetic interaction between HLA-A*11:01 and the high-risk EBV variant 85841G as a key determinant of NPC risk. Individuals carrying a susceptible HLA-A background (HLA-A*11:01- or HLA-A*02:07+) and infected with the high-risk 85841G EBV form a dual-risk subgroup with substantially elevated, interaction-driven NPC risk, far exceeding the effects of host or virus alone. This dual-risk subgroup comprises 20.5% of the population and accounts for approximately 47% of NPC cases. We show that EBV 85841G encodes an EBNA3B peptide that binds to HLA-A*11:01 and elicits specific T cell responses capable of lysing EBV+ B cells transformed by 85841G-carrying strains, and is associated with reduced salivary viral load and lower NPC risk among A*11:01 carriers. Evolutionary analysis reveals that 85841G arose via ancient recombination events between northern and southern EBV and subsequently underwent clonal expansion in southern China, leading to co-enrichment of interacting host and viral risk factors that, in turn, contribute to NPC endemicity. These findings reveal a markedly stratified, interaction-driven risk architecture in NPC and highlight opportunities for precision prevention.
Foundation models in genomics have shown mixed success compared to their counterparts in natural language processing. Yet, the reasons for their limited effectiveness remain poorly understood. In this work, we investigate the role of entropy as a fundamental factor limiting the capacities of such models to learn from their training data and develop foundational capabilities. We train ensembles of models on text and DNA sequences and analyze their predictions, static embeddings, and empirical Fisher information flow. We show that the high entropy of genomic sequences – from the point of view of unseen token prediction – leads to near-uniform output distributions, disagreement across models, and unstable static embeddings, even for models that are matched in architecture, training and data. We then demonstrate that models trained on DNA concentrate Fisher information in embedding layers, seemingly failing to exploit inter-token relationships. Our results suggest that self-supervised training from sequences alone may not be applicable to genomic data, calling into question the assumptions underlying current methodologies for training genomic foundation models.
Mitochondrial electron transport and oxidative respiration are required for immunity and host tolerance, but how the ETC contributes to viral infection-where proinflammatory antiviral responses must be finely balanced with host-protective anti-inflammatory mechanisms-remains unclear. Here, we show that H1N1 influenza infection causes murine macrophages to reduce Complex III levels by downregulating the early CIII assembly factor COMB. Using Brawnin (Br/UQCC6) knockout mice, which lack COMB complexes and have reduced Complex III, we found that Br KO bone marrow-derived macrophages exhibited reduced inflammation due to decreased CIII Qo-site ROS production. Following non-lethal H1N1 infection, Br KO mice showed reduced lung immune pathology, lower viral burden, enhanced survival, and improved recovery. Single-cell RNA-seq revealed reduced accumulation of hyperinflammatory monocytes and diminished monocyte chemotaxis in infected Br KO lungs. Together, these findings demonstrate that ETC Complex III suppression is an adaptive innate immune response to viral infection and may represent a therapeutic strategy to limit host inflammation in acute respiratory viral disease. ### Competing Interest Statement The authors have declared no competing interest.
