Abstract: The genetic structure and population history of ethno-linguistically diverse populations from the Yunnan-Guizhou Plateau remain underrepresented in human genomic research. We analyzed genome-wide data from 239 individuals in Guizhou, combined with modern and ancient datasets, to investigate their fine-scale genetic structure, demographic events, and functional consequences of adaptive genomic signatures. Our findings revealed three genetically distinct groups corresponding to linguistic categories, shaped by differential gene flow from ancient millet farmers and southern Chinese populations. We identified population-specific adaptive candidate genomic regions associated with immune, metabolic, and hematological functions. Additionally, we detected clinically relevant variants with implications for disease risk prediction and precision medicine. These findings underscore the importance of genetic diversity in understanding human adaptation and health disparities, offering a framework for equitable genomic research in underrepresented populations.

Key words: Guizhou populations, genetic structure, admixture, disease susceptibility, precision medicine.