A study on the 2023 monkeypox (mpox) epidemic reveals that the subclade IIb MPXV lineage, traced back to Nigeria in 1971, has higher person-to-person transmission than clade I or subclade IIa MPXV. The research highlights significant variation in short tandem repeats within the low-complexity regions (LCRs) of the MPXV genome. LCRs, previously dismissed as uninformative, show higher entropy than single-nucleotide polymorphisms (SNPs) and are not randomly distributed. In silico analyses suggest that LCRs may influence the expression, translation, and function of orthopoxvirus genes, consistent with the "genomic accordion" evolutionary strategy. The study proposes that LCR variability should be considered in future MPXV genomic analyses to understand the unusual epidemiology of the 2022 subclade IIb MPXV. The MPXV genome is a linear, 197-kb double-stranded DNA with covalently closed hairpin ends. It contains orthologous poxvirus genes (OPGs) distributed in a central conserved region and flanking terminal regions. LCRs, which include short tandem repeats and homopolymers, are located in areas of high variation and may play a crucial role in MPXV biology and evolution. The study provides a comprehensive genomic characterization of LCRs during the mpox outbreak, showing that LCRs are non-randomly distributed and have higher entropy than SNPs. Three specific gene candidates are highlighted for further investigation in relation to transmissibility and adaptation. The study also demonstrates that LCRs are not associated with defective genomes, as no stop codons were detected in any allele within LCRs. The analysis of LCRs and SNPs revealed that LCRs have significantly higher diversity than SNPs. The study further shows that LCRs are non-randomly distributed in the MPXV genome, with a significant purifying selection force against introducing LCRs in central conserved regions. The findings suggest that LCRs may be more phylogenetically informative than SNPs for inter-host sequence analysis. The study also highlights the conservation and variation in proteins encoded by OPGs and codon usage analysis in OPG LCRs. The results indicate that LCRs may influence the translational landscape of MPXV, providing intriguing avenues for further investigation. The study concludes that LCRs are of functional importance in the MPXV genome and should be considered in future genomic analyses to understand the dynamics of the currently circulating viral clades.A study on the 2023 monkeypox (mpox) epidemic reveals that the subclade IIb MPXV lineage, traced back to Nigeria in 1971, has higher person-to-person transmission than clade I or subclade IIa MPXV. The research highlights significant variation in short tandem repeats within the low-complexity regions (LCRs) of the MPXV genome. LCRs, previously dismissed as uninformative, show higher entropy than single-nucleotide polymorphisms (SNPs) and are not randomly distributed. In silico analyses suggest that LCRs may influence the expression, translation, and function of orthopoxvirus genes, consistent with the "genomic accordion" evolutionary strategy. The study proposes that LCR variability should be considered in future MPXV genomic analyses to understand the unusual epidemiology of the 2022 subclade IIb MPXV. The MPXV genome is a linear, 197-kb double-stranded DNA with covalently closed hairpin ends. It contains orthologous poxvirus genes (OPGs) distributed in a central conserved region and flanking terminal regions. LCRs, which include short tandem repeats and homopolymers, are located in areas of high variation and may play a crucial role in MPXV biology and evolution. The study provides a comprehensive genomic characterization of LCRs during the mpox outbreak, showing that LCRs are non-randomly distributed and have higher entropy than SNPs. Three specific gene candidates are highlighted for further investigation in relation to transmissibility and adaptation. The study also demonstrates that LCRs are not associated with defective genomes, as no stop codons were detected in any allele within LCRs. The analysis of LCRs and SNPs revealed that LCRs have significantly higher diversity than SNPs. The study further shows that LCRs are non-randomly distributed in the MPXV genome, with a significant purifying selection force against introducing LCRs in central conserved regions. The findings suggest that LCRs may be more phylogenetically informative than SNPs for inter-host sequence analysis. The study also highlights the conservation and variation in proteins encoded by OPGs and codon usage analysis in OPG LCRs. The results indicate that LCRs may influence the translational landscape of MPXV, providing intriguing avenues for further investigation. The study concludes that LCRs are of functional importance in the MPXV genome and should be considered in future genomic analyses to understand the dynamics of the currently circulating viral clades.