Notably, 22q11.2 hemizygosity does not predict the actual mechanism of phenotypic expression, which would include several possibilities, none of which has been proven for 22qDS-schizophrenia. For example, haploinsufficiency refers to lower expression of a gene product that is inadequate for normal functioning when an otherwise-normal gene is present in only a single copy. However, for many genes, compensatory mechanisms can ensure sufficient protein expression even with only one copy of a gene (eg, with hemizygosity). Also, some genes may be expressed in ratios lower than the expected 0.5 ratio or have expression levels that are highly variable between individuals. Contiguous genes imply that genes that are physically close to each other in a chromosomal region act together to express certain phenotypic traits. Loss of heterozygosity would be the applicable term if a deletion combined with a mutational event within the normal allele on the intact chromosome and rendered the cell hemizygous for a deleterious allele.
Despite the current lack of definitive knowledge, accumulating evidence supports the likelihood that variants and/or hemizygosity of several genes within the 22q11.2 region may be necessary for expression of major 22qDS phenotypes and that variants of genes from other areas of the genome can modify the effects of 22q11.2 hemizygosity [25••
]. Murine models have revealed substantially different sensitivity to gene dosage in different tissues and at different times, underlying the importance of the developmental context within which gene dosage reduction occurs [39
]. Using a murine model of the 22q11.2 deletion, Meechan et al. [40
] showed that expression levels of at least nine genes are reduced in embryonic tissue and developing and adult brain tissue. The authors proposed a role for subtle but pervasive pathology of cortical circuits in 22qDS due to this decreased expression of multiple genes in a quantitatively stable cell population contributing to schizophrenia vulnerability in 22qDS [40
]. Another group using a murine model recently selected differentially expressed genes in hippocampal tissue for validation studies [41
]. Eight genes from the deletion region and 15 (56%) of 27 other genes were validated as true changes [41
]. Another study showed that phenotypic variability itself may be related to mRNA dosage [39
Meechan et al. [25••
] recently published a comprehensive review of 22qDS pathogenesis and how gene dosage effects may be involved. This review goes through each of three possibilities with respect to major phenotypic expression: 1) a single gene causing all phenotypes; 2) independent action of several contiguous genes at distinct sites, including the brain; or 3) combinational effects of multiple genes (ie, the cooperative nature of diminished gene dosage and synergy between subsets of genes expressed at distinct times) [25••
]. This review makes a case for the role of several subsets of genes in brain development: 1) those with unifying transcriptional control, 2) cell cycle genes, 3) mitochondrial genes, and 4) those with expression restricted to the adult brain. These subsets of genes could affect neuronal cell migration, synaptogenesis, and/or neurogenesis—all plausible mechanisms in schizophrenia.