Search arXiv⌕ Search
Home/Archive/arXiv

arXiv · 2501.00767

Infectious diseases, imposing density-dependent mortality on MHC/HLA variation, can account for balancing selection and MHC/HLA polymorphism

D. P. L. Green
View original source ↗Read source document ↗Export metadata ↓

Abstract

The human MHC transplantation loci (HLA-A, -B, -C, -DPB1, -DQB1, -DRB1) are the most polymorphic in the human genome. It is generally accepted this polymorphism reflects a role in presenting pathogen-derived peptide to the adaptive immune system. Proposed mechanisms for the polymorphism such as negative frequency-dependent selection (NFDS) and heterozygote advantage (HA) focus on HLA alleles, not haplotypes. Here, we propose a model for the polymorphism in which infectious diseases impose independent density-dependent regulation on HLA haplotypes. More specifically, a complex pathogen environment drives extensive host polymorphism through a guild of HLA haplotypes that are specialised and show incomplete peptide recognition. Separation of haplotype guilds is maintained by limiting similarity. The outcome is a wide and stable range of haplotype densities at steady-state in which effective Fisher fitnesses are zero. Densities, and therefore frequencies, emerge theoretically as alternative measures of fitness. A catalogue of ranked frequencies is therefore one of ranked fitnesses. The model is supported by data from a range of sources including a Caucasian HLA dataset compiled by the US National Marrow Donor Program (NMDP). These provide evidence of positive selection on the top 350-2000 5-locus HLA haplotypes taken from an overall NMDP sample set of 10E5. High-fitness haplotypes drive the selection of 137 high-frequency alleles spread across the 5 HLA loci under consideration. These alleles demonstrate positive epistasis and pleiotropy in the formation of haplotypes. Allelic pleiotropy creates a network of highly inter-related HLA haplotypes that account for 97% of the census sample. We suggest this network has properties of a quasi-species and is itself under selection. We also suggest this is the origin of balancing selection in the HLA system.

Explore related subjects

q-bio.PEq-bio.MN

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

D. P. L. Green. 2025-01-01. Infectious diseases, imposing density-dependent mortality on MHC/HLA variation, can account for balancing selection and MHC/HLA polymorphism. https://arxiv.org/abs/2501.00767

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

A conceptual predator-prey model with super-long transients

Drawing on the understanding of the logistic map, we propose a simple predator-prey model where predators and prey adapt to each other, leading to the co-evolution of the system. The special dynamics observed in periodic windows contribute to the coexistence of multiple time scales, adding to the complexity of the system. Typical dynamics in ecosystems, such as the persistence and coexistence of population cycles and chaotic behaviors, the emergence of super-long transients, regime shifts, and the quantifying of resilience, are encapsulated within this single model. The simplicity of our model allows for detailed analysis, reinforcing its potential as a conceptual tool for understanding ecosystems deeply.

q-bio.PE↗
arXiv2026

Mutation Order and Selection Shape Intratumor Heterogeneity in Tumor Evolution

Cancer progression often requires multiple driver mutations, but the same drivers may be acquired in different orders. How these pathways jointly shape tumor clonal structure remains unclear. We develop a multitype branching-process model in which malignant transformation requires two driver mutations, distinguishing malignant cells by mutation order and the independent transformation event that founded their clone. Under a successive exponential approximation, we establish point-process limits for pathway-specific clone sizes and derive a closed-form expression for the limiting expected Simpson's index of the combined malignant population. When both mutation orders yield malignant cells with the same net growth rate, the index decomposes into effective pathway weights, determined by mutation rates and birth-death dynamics at preceding stages, and within-pathway concentration terms, determined by intermediate-to-malignant growth-rate ratios. A driver's effect on heterogeneity thus depends critically on when it is acquired. A strong driver acquired early expands the intermediate lineage and increases the supply of independent malignant founders, whereas the same driver acquired last strengthens the growth and age advantage of early-founded malignant clones. Under additive fitness effects, these opposing mechanisms can produce a non-monotone relationship between selective advantage and clonal concentration. Threshold-like non-additive fitness effects can generate highly concentrated malignant populations, while order-dependent terminal fitness causes the faster-growing pathway to dominate asymptotically. These results show how mutation order, mutational accessibility, selection, and epistasis jointly determine lineage-level intratumor heterogeneity.

q-bio.PE↗
arXiv2026

Phase transitions in microbial lineage trees

Microbial populations exhibit high cell-to-cell variability, which fundamentally shapes population behavior. A striking consequence is the existence of phase transitions, where small genetic or environmental changes trigger abrupt shifts in population dynamics. While biological phase transitions have often been proposed, connecting observed behavior to the underlying physics has remained challenging. We combine population genetics with statistical physics to show how phase transitions arise naturally in microbial populations. We highlight the existence of a first-order transition in a model of bacterial plasmid engineering and find a strict lower bound on the number of plasmids that can be stably maintained in a population.

q-bio.PE↗