Model for the evolution of the SCAN, SCAN-KRAB and KRAB C2H2-ZNF subfamilies. A) Sequential events leading to the birth of SCAN and SCAN-KRAB and KRAB C2H2-ZNF subfamilies. Most of the SCAN, SCAN-KRAB and KRAB C2H2-ZNF genes have the exon-intron structure shown (boxes represent exons). Birth of new families may have occurred presumably by an exon shuffling mechanism leading first to the acquisition of a SCAN domain by a C2H2-ZNF gene and later of a KRAB domain by a SCAN C2H2-ZNF gene. In most SCAN-KRAB C2H2-ZNF genes, a single exon is found in between the exon encoding the KRAB A box (identified as KRAB) and the exon encoding the zinc finger domain (ZNF). This exon encodes in most instances the so-called KRAB B, b, or C boxes. KRAB C2H2-ZNF subfamily emergence involved the loss of the SCAN domain from SCAN-KRAB gene (s). B) Dynamic evolution of C2H2-ZNF genes after birth of the SCAN and SCAN-KRAB subfamilies through gene duplication and recurrent loss of effector domains. A first SCAN C2H2-ZNF gene appeared in an ancestor of vertebrates following the gain of a SCAN domain by a C2H2-ZNF gene; duplication then led to the establishment of the SCAN C2H2-ZNF subfamily. The gain of a KRAB domain at the emergence of tetrapods by a SCAN C2H2-ZNF gene gave rise to a SCAN-KRAB C2H2-ZNF gene. This was followed by duplication and establishment of the SCAN-KRAB subfamily. Loss of the SCAN domain by deletion or sequence degeneration from some SCAN-KRAB C2H2-ZNF genes followed in many instances by duplication of the resulting KRAB C2H2-ZNF genes led to the expansion of the KRAB C2H2-ZNF subfamily. Loss of SCAN or KRAB domains by deletion or degeneration from SCAN, SCAN-KRAB and KRAB C2H2-ZNF subfamilies is seen as a recurrent theme shaping the repertoires of the C2H2-ZNF subfamilies.