The Enigma of Liver Steatosis: Insights from Archaeogenetics
The Origins, Evolution, and Global Distribution of a Genetic Variant Linked to Fatty Liver Disease
Liver steatosis, characterized by the accumulation of fat in the liver, presents a spectrum of conditions from benign steatosis to inflammatory steatohepatitis. Understanding the genetic underpinnings of this condition is crucial due to its widespread prevalence and potential for severe health consequences, including liver fibrosis and cancer. Recent research1 conducted by interdisciplinary teams from Würzburg University Hospital (UKW), Homburg University Hospital (UKS), and the Max Planck Institute for Evolutionary Anthropology in Leipzig (MPI-EVA) aims to shed light on the genetic basis of liver steatosis through an archaeogenetic lens.
The Significance of Liver Steatosis:
The liver, as the central organ responsible for carbohydrate and fat metabolism, plays a pivotal role in maintaining metabolic homeostasis. Excess fat deposition in the liver, which occurs under conditions of overnutrition, poses significant health risks. From benign steatosis, which affects up to 30% of modern populations, to the more severe steatohepatitis, liver fat accumulation can lead to inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma.
Genetic Predisposition to Liver Steatosis:
Among the genetic factors implicated in liver steatosis, a common variant in the PNPLA3 gene stands out. This variant has been robustly associated with an increased risk of developing fatty liver disease. Despite its detrimental effects on health, this variant exhibits a remarkably high global prevalence, particularly in regions such as Mesoamerica.
Evolutionary Origins of the PNPLA3 Variant:
To trace the evolutionary history of the PNPLA3 variant, researchers embarked on a comprehensive analysis of ancient and modern human DNA. By examining samples from diverse populations, including Neanderthals and Denisovans, researchers aimed to elucidate the origins and spread of this genetic variant. Surprisingly, the risk allele of the PNPLA3 gene was present in ancient hominin populations, suggesting an ancient origin predating the split of the human lineage.
Global Distribution and Trajectory of the Variant:
Through a meticulous examination of allele frequencies across geographic and temporal scales, researchers observed consistent patterns of distribution for the PNPLA3 variant. Despite fluctuations over time, the variant's prevalence remains notably high, especially in regions characterized by cold climates. This observation suggests potential adaptive advantages conferred by the variant in such environments, underscoring the complex interplay between genetic predisposition and environmental factors in the development of metabolic diseases.
Implications for Human Health and Evolution:
The findings from this study have profound implications for understanding the evolutionary basis of metabolic diseases. While the absence of recent genetic selection signals raises questions about the role of natural selection in shaping the prevalence of the PNPLA3 variant, further investigation is warranted to explore its evolutionary implications. Moreover, the study underscores the need for interdisciplinary collaboration between medical and archaeogenetic experts to unravel the mysteries of human health and evolution.
Insights from Neanderthal Genome Analysis:
Questions arise regarding the potential contribution of Neanderthal genetic heritage to the prevalence of the PNPLA3 variant in modern humans. Although evidence suggests a minimal role for Neanderthal introgression in shaping the variant's distribution, ongoing research aims to elucidate the genetic legacy of our ancient relatives and its impact on modern human health.
Concluding Remarks:
The collaborative effort between medical and archaeogenetic experts provides valuable insights into the evolutionary basis of metabolic diseases and sheds light on unexpected physiological aspects of genetic variants. As researchers continue to unravel the mysteries of liver steatosis, this interdisciplinary approach promises to uncover novel insights into human health and evolution, paving the way for innovative approaches to disease prevention and treatment.
Geier, A., Trost, J., Wang, K., Schmid, C., Krawczyk, M., & Schiffels, S. (2024). PNPLA3fatty liver allele was fixed in Neanderthals and segregates neutrally in humans. Gut, gutjnl-2023-331594. https://doi.org/10.1136/gutjnl-2023-331594