Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations

The SOD1 gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of SOD1 variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.

To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the SOD1 locus in worldwide human populations.

We analyzed genomic variation spanning the SOD1 region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (π), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate SOD1 orthologs.

The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (p < 0.05 in all populations). Population differentiation was low (mean FST ≈ 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.

The SOD1 locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.