In a groundbreaking revelation with profound implications for evolutionary biology and infectious disease resistance, researchers have unveiled compelling evidence of positive selection acting on a genetic variant in Sardinia that modulates cyclin D3 expression in erythroid cells. This variant, known as the rs112233623-T allele in the CCND3 gene, exhibits a unique distribution pattern across global populations, being notably common in Sardinia while virtually absent in many other regions. The study, recently published in Nature, illuminates the evolutionary trajectory and adaptive significance of this allele, shedding light on how genetic factors contribute to malaria protection.
The rs112233623-T allele’s frequency presents a striking geographical gradient. Within the SardiNIA cohort, it occurs at a minor allele frequency (MAF) of approximately 10%, whereas in mainland Italy, its occurrence diminishes to around 2%. Its prevalence fades further in northern European and South Asian populations, where it registers below 1%, and it remains undetected in African and East Asian groups. This pattern alone raises questions about the selective pressures uniquely shaping Sardinia’s genetic landscape.
To dissect whether the heightened frequency in Sardinia is the product of positive selection or merely a result of random genetic drift, the investigators deployed a battery of population-genetic analyses. The degree of allele frequency differentiation, measured by F_ST, between Sardinians and European populations from the 1000 Genomes (1KG EUR) project was remarkable—0.094, ranking in the 99.9th genomic percentile. This pronounced differentiation strongly hints at non-neutral evolutionary forces sculpting the allele’s distribution.
Delving deeper, the study employed the integrated haplotype score (iHS) metric, a powerful method to detect recent positive selection based on extended haplotype homozygosity. The rs112233623-T allele stands out with an iHS value of 2.16 in the SardiNIA population, positioning it in the 99.1st percentile when compared to frequency-matched variants across the genome. Such extended haplotype homozygosity implies that the allele rose swiftly in frequency, outpacing recombination and thereby preserving a large genomic segment—a classic hallmark of positive selection.
The reduction in haplotype diversity among Sardinians carrying this allele, further confirmed via cross-population extended haplotype homozygosity (xp-EHH) analysis yielding a value of 1.99 (99.4th percentile), indicates a recent selective sweep that differentiated Sardinians from broader European populations. In other words, the genetic signature echoes a scenario where the rs112233623-T allele conferred a survival advantage, rapidly proliferating in the population.
Complementing these population genetic diagnostics, the authors reconstructed allele frequency trajectories over time through the use of a local ancestral recombination graph, analyzed via the CLUES framework. This approach revealed a consistent increase in the allele’s frequency trailing toward modern times, accompanied by a robust selection coefficient estimate of s = 0.026. This value lies within the 99.5th percentile among comparable genomic variants, underscoring the strength of evolutionary pressures favoring this locus.
At the biological level, the rs112233623-T allele reduces the expression of cyclin D3 in erythroid progenitor cells, a subtle yet potentially transformative effect. Cyclin D3 is critical for regulating cell cycle progression in erythrocyte development. The study suggests that diminished cyclin D3 expression modulates red blood cell properties in a manner that confers resistance to malaria, mirroring the principle of balancing selection seen in other protective variants such as those affecting hemoglobin.
The uniqueness of the Sardinian genetic milieu, shaped partly by geographic isolation and demographic history, provided a natural laboratory for this evolutionary event. The genetic drift characteristic of such populations often obscures selection signals, but the meticulous statistical framework in this study carefully disentangled drift from selection, offering robust evidence that the rs112233623-T allele experienced positive selection rather than being a neutral byproduct.
This discovery not only deepens our understanding of human adaptation to malaria, a formidable selective agent historically plaguing Mediterranean populations, but also highlights the intricate interplay between genetic regulation and pathogen resistance. The implications extend beyond Sardinia, inviting broader inquiries into whether similar mechanisms operate in other populations and how subtle gene regulatory modifications can shape disease susceptibility.
Moreover, this investigation exemplifies the power of population genomics combined with cutting-edge computational approaches to resolve the evolutionary dynamics of functional variants. By tracing allele frequency changes and haplotype structures, researchers can reconstruct the selective past, linking genotype to phenotype and fitness with unprecedented precision.
Future research avenues opened by this study may focus on elucidating the precise molecular mechanisms by which cyclin D3 reduction impacts parasite invasion or erythrocyte lifespan. Understanding these pathways will be crucial for translating genetic insights into potential therapeutic strategies or gene-targeted interventions, leveraging human evolutionary history to combat malaria today.
In sum, the rs112233623-T variant in CCND3 emerges as a paradigmatic example of how human populations have genetically fine-tuned physiological pathways in response to endemic infectious diseases. Its rarity outside Sardinia and moderate frequency within underscore the localized nature of evolutionary pressures, illuminating how geography, ecology, and human history coalesce to shape the genome.
As malaria continues to impose a staggering global health burden, insights gleaned from such evolutionary genetics investigations not only enrich our biological knowledge but may also rekindle hopes for novel approaches in malaria control. This study stands as a testament to the intricate narratives encoded within our DNA, stories of survival and adaptation woven through millennia.
The convergence of population genetics, molecular biology, and infectious disease research showcased here marks a compelling frontier in human genetics. It reveals that even slight modulations in gene expression—far from null effects—can echo through generations, sculpting the susceptibility landscape in ways that enhance population fitness against some of humanity’s most ancient foes.
These findings invite a reassessment of how subtle regulatory variants contribute to complex traits, spotlighting the CCND3 rs112233623-T allele as a beacon for future multidimensional studies integrating genomics, transcriptomics, and evolutionary theory.
Subject of Research: Evolutionary genetics of the CCND3 rs112233623-T allele and its role in malaria resistance in Sardinian populations.
Article Title: Reduced cyclin D3 expression in erythroid cells protects against malaria.
Article References:
Marini, M.G., Mingoia, M., Steri, M. et al. Reduced cyclin D3 expression in erythroid cells protects against malaria. Nature (2026). https://doi.org/10.1038/s41586-026-10110-9
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