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A genomic study was conducted to identify the effects of urbanization and environmental contaminants with heavy metals on selection footprints in dairy cattle populations reared in the megacity of Bengaluru, South India. Dairy cattle reared along the rural–urban interface of Bengaluru with/without access to roughage from public lakeshores were selected. The genotyped animals were subjected to the cross-population–extended haplotype homozygosity (XP-EHH) methodology to infer selection sweeps caused by urbanization (rural, mixed, and urban) and environmental contamination with cadmium and lead. We postulated that social-ecological challenges contribute to mechanisms of natural selection. A number of selection sweeps were identified when comparing the genomes of cattle located in rural, mixed, or urban regions. The largest effects were identified on BTA21, displaying pronounced peaks for selection sweeps for all three urbanization levels (urban_vs_rural, urban_vs_mixed and rural_vs_mixed). Selection sweeps are located in chromosomal segments in close proximity to the genes lrand rab interactor 3 (RIN3), solute carrier family 24 member 4 (SLC24A4), tetraspanin 3 (TSPAN3), and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). Functional enrichment analyses of the selection sweeps for all three comparisons revealed a number of gene ontology (GO) and KEGG terms, which were associated with reproduction, metabolism, and cell signaling-related functional mechanisms. Likewise, a number of the chromosomal segments under selection were observed when creating cattle groups according to cadmium and lead contaminations. Stronger and more intense positive selection sweeps were observed for the cadmium contaminated group, i.e., signals of selection on BTA 16 and BTA19 in close proximity to genes regulating the somatotropic axis (growth factor receptor bound protein 2 (GRB2) and cell ion exchange (chloride voltage-gated channel 6 (CLCN6)). A few novel, so far uncharacterized genes, mostly with effects on immune physiology, were identified. The lead contaminated group revealed sweeps which were annotated with genes involved in carcass traits (TNNC2, SLC12A5, and GABRA4), milk yield (HTR1D, SLCO3A1, TEK, and OPCML), reproduction (GABRA4), hypoxia/stress response (OPRD1 and KDR), cell adhesion (PCDHGC3), inflammatory response (ADORA2A), and immune defense mechanism (ALCAM). Thus, the findings from this study provide a deeper insight into the genomic regions under selection under the effects of urbanization and environmental contamination. [ABSTRACT FROM AUTHOR]