The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and 
highly conserved from Drosophila to human. It has important roles in 
transcriptional insulation and the formation of a high-dimensional chromatin 
structure. CTCF has a paralog called "Brother of Regulator of Imprinted Sites" 
(BORIS) or "CTCF-like" (CTCFL). It binds DNA at sites similar to those of CTCF. 
However, the expression profiles of the two proteins are quite different. We 
investigated the evolutionary trajectories of the two proteins after the 
duplication event using a phylogenomic and interactomic approach. We find that 
CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all 
interactors already existed before the emergence of CTCF and CTCFL. The unique 
secondary loss of CTCF from several nematodes is paralleled by a loss of two of 
its interactors, the polycomb repressive complex subunit SuZ12 and the 
multifunctional transcription factor TYY1. In contrast to earlier studies 
reporting the absence of BORIS from birds, we present evidence for a multigene 
synteny block containing CTCFL that is conserved in mammals, reptiles, and 
several species of birds, indicating that not the entire lineage of birds 
experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic 
neighbors seem to be partitioned into two nested chromatin loops. The high 
expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible 
link between CTCFL, meiotic recombination, and fertility-associated phenotypes. 
Using the 65,700 exomes and the 1000 genomes data, we observed a higher number 
of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in 
CTCF, suggesting a reduced strength of purifying selection, perhaps due to less 
functional constraint.