Beyond Dosage Compensation: Re-evaluating the Lyon Hypothesis in X-chromosome Reactivation, Meiotic Fidelity, and Female Fertility

Abstract

The Lyon hypothesis established the classical framework for understanding X-chromosome inactivation as a dosage-compensation mechanism in female mammals. However, recent advances in molecular and cellular biology indicate that X-chromosome regulation during germ-cell development involves more dynamic processes than previously recognized. This review re-examines the Lyon hypothesis in light of emerging evidence from transcriptomic studies, meiotic-entry regulators such as STRA8 and MEIOSIN, synaptonemal complex assembly pathways, and checkpoint-mediated chromosome-segregation mechanisms. Recent findings demonstrate that meiotic initiation depends on coordinated transcriptional networks rather than single-gene activation events, while hierarchical synaptonemal complex organisation plays an essential role in homolog pairing, recombination fidelity, and genome stability. In addition, centrosome-associated regulators, spindle-alignment factors, and cohesin-mediated chromosome-segregation pathways reveal conserved interactions between mitotic and meiotic chromosome-control systems. These observations suggest that X-chromosome behaviour during female germ-cell differentiation reflects an integrated regulatory framework involving chromatin remodelling, recombination dynamics, and checkpoint surveillance beyond classical dosage compensation alone. By synthesising historical genetic theory with recent mechanistic discoveries across vertebrate model systems, this review provides an updated conceptual perspective on sex-chromosome regulation during meiosis and highlights its implications for reproductive biology, developmental stability, and inheritance.