Laura Gramolini, Paolo Ciucci, Paolo Colangelo, Livia Chavko, Paolo Franchini, Leonardo Gentile, Alexandros Karamanlidis, Jonas Kindberg, Oddmund Kleven, Alexander Kopatz, Josè Vicente López-Bao, Lana Pađen, Slaven Reljic, Emanuela Solano, Tomasz Zwijacz-Kozica, Diana Lobo

The Apennine brown bear, a critically endangered population confined to the central Apennines in Italy, represents an extreme case of long-term demographic isolation and genetic erosion. Such conditions are expected to reduce adaptive potential through strong genetic drift, although epigenetic mechanisms may partly buffer this loss by enabling rapid phenotypic responses. Notably, recent studies revealed that Apennine bears display distinctive traits allegedly advantageous in human-dominated landscapes, including smaller body size, wider skulls, and reduced aggressiveness. To investigate how genomic erosion has shaped both genetic and epigenetic potential, we analysed 44 whole genomes and 35 RRBS-derived DNA methylation profiles representing most of the European brown bear populations. We found that Apennine bears exhibit the lowest heterozygosity and extensive allele fixation, including 21,748 population-specific SNPs overlapping 3,420 genes. Uniquely fixed SNPs are enriched for missense mutations (1.86× relative to the genomic background), affecting 123 genes involved in neurodevelopmental, cognitive, and growth-related processes, potentially linked to the population’s distinctive traits. To evaluate consequences for epigenetic regulation, we quantified SNPs that create or disrupt CpG dinucleotides. Apennine bears carry the lowest proportion of CpG-disruptive (17.5%) but the highest of CpG-creative (16.4%) SNPs, although fixed SNPs are disproportionately CpG-disruptive (23.9%). These epigenetic SNPs are enriched in highly methylated regions (>60% average methylation), consistent with high mutation rates potentially driven by deamination of methylated cytosines. Concordantly, Apennine bears display the highest CpG density and the lowest genome-wide methylation levels across European populations. Overall, although continued genomic erosion may constrain adaptive genetic potential, elevated CpG content may help sustain phenotypic plasticity under prolonged isolation.