Schematic of potential evolutionary pathways of mammalian sex-linked genes. From top to bottom: evolution of homologous genes originally located on the proto-sex chromosomes ( gray) to their full differentiation into Y-linked genes (Y) and genes on the active X (Xa) and inactive X (Xi). New genes have been acquired by the X and Y (mottled gray) and thus are not remnants of the proto-sex chromosomes; some may be unique to the Y (gene 7) or the X (gene 15), others may be acquired by both sex chromosomes (genes 5-6), depending on how much recombination between the sex chromosomes still occurred at that time. Pseudoautosomal region (PAR) genes are homologous on the sex chromosomes; however, note that PAR genes can also derive from additions to the sex chromosomes later in evolution. Gene 1 represents the sex determinant SRY derived from the X-linked gene SOX3, which becomes upregulated on the Xa (orange) and silenced on the Xi (white). Genes 2, 4-6, 8, 10-12, and 14-15 are examples of genes progressively lost from the Y. Genes 3 and 13 evolved from X/Y pairs by acquiring a testis function on the Y (mottled yellow/green). Their X paralog becomes silenced (gene 3) or escapes X inactivation (gene 13). Most genes on the Xa become upregulated (orange), but some do not (gene 12), and others acquire reproduction-related functions (mottled yellow/green) (genes 5, 6, 14, 15). A majority of genes (genes 1-6, 8, 10, 12, 14, 15) on the Xi become silenced (empty). A few genes escape X inactivation on the Xi (genes 9, 11, 13); some of these retain a functional Y paralog (gene 9, X/Y gene pair), resulting in equal sex expression, although expression is usually lower on the Xi and Y than on the Xa ( pale orange); others have lost the Y paralog (gene 11) or have a differentiated Y paralog expressed in testis (gene 13). Escape genes may acquire a female advantageous role (genes 11 and 13) (mottled purple/pink). Overall, both the Y and X chromosomes have acquired a number of new testis-specific (or reproduction-related) genes (mottled yellow/green).