increase in expression is observed with an EST gene (AK149307), which is located immediately upstream of the Pcdhg cluster (Figures 4F–G and Table S1). Sequence analyses revealed that this gene is a relic of the B-type Pcdhg isoforms, and its promoter region also contains a conserved sequence element (CSE) found in most Pcdh genes (Figures S4C–E). The expression levels of most Pcdhg isoforms are not affected by the deletion of C-type genes except for a few neighboring ones which are upregulated, and quantification of constant exon reads indicated that the combinatorial expression levels of the remaining Pcdhg genes in Pcdhgtcko/tcko mice are ~75% of the wild type levels (Figures 4F–G and Table S1). Thus, the loss of function of the C-type isoforms cannot be compensated by other Pcdhg isoforms. Many Pcdhb genes (as well as AK149307) are marginally upregulated in the Pcdhgtcko/tcko mice, likely also due to the action of the Pcdhb cluster enhancer as mentioned above. In addition, no neomorphic Pcdhg variants were detected in Pcdhgtcko/tcko mutants with splice junction analysis of the RNA-Seq data (Table S2). The striking phenotypic similarities in contrast to the vastly distinct Pcdh repertoires in Pcdhgtcko/tcko and Pcdhgdel/del mutants suggest that lack of the
