Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

Abstract

Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders.

Figure 1

Schematic representation of 22q11.2 deletions and duplications in individuals with schizophrenia (blue bars) or ASD (red bars). Cases and boundaries are based on published studies with dense probes.^,,,–,, The blue and pink frames indicate chromosomal segments that are commonly deleted in schizophrenia and ASD cases, respectively. A boundary with a pale color indicates individually variable ends.

Figure 2

Organization and location of corresponding genes between human 22q11.2 and murine 16. Mouse models of segmental overexpression and deletions are shown. Purple (social interaction), green (working memory), blue (PPI) and orange (anxiety) bars represent chromosomal segments whose murine copy number variation results in phenotypes consistent (see red arrows) and inconsistent (see black arrows) with 22q11.2 CNVs in humans or no effect (see black horizontal lines). The blue frame represents a segment whose deletion is commonly seen in mouse models with a PPI phenotype consistent with that in humans. PPI, prepulse inhibition; WM, working memory; SI, social interaction; Anx, anxiety. (1) Hiroi et al.; (2) Suzuki et al.; (3) Stark et al.; (4) Kimber et al.; (5) Paylor et al.; (6) Paylor et al.; (7) Long et al.; (8) Stark et al.

Figure 3

Mosaic pattern of phenotypes caused by deletion of specific genes in mouse models. Phenotypes consistent (red) and inconsistent (gray) with what is seen in 22q11.2 hemizygous patients are shown; black squares represent cases where a gene deletion caused no effect. Blank squares represent cases where phenotyping was not conducted. PPI, prepulse inhibition; WM, working memory; SI, social interaction; Anx, anxiety. (1) Long et al.; (2) Gogos et al.; (3) Paterlini et al.; (4) Hsu et al.; (5) Mukai et al.; (6) Stark et al.; (7) Gogos et al.; (8) Papaleo et al.; (9) Babovic et al.; (10) O’Tuathaigh et al.; (11) O’Tuathaigh et al.; (12) Paylor et al.; (13) Hiramoto et al.; (14) Suzuki et al.; (15) Harper et al.

Figure 4

Shifts in data structure of various phenotypes caused by Tbx1 heterozygosity. Figures are based on raw data of our published study. Black circles represent WT mice and open circles represent HT mice for the three graphs. (a) For PPI, Tbx1 heterozygosity shifts data lower so that the cumulative data curve shows a parallel shift to the left, with many HT cases below the lowest data point of WT mice. (b) Vocal calls: Tbx1 heterozygosity shifts the average of data slightly to the left, but data largely overlap between WT and HT mice. (c) Social interaction: Tbx1 heterozygosity shifts the data distribution of WT to the left, with a minimal overlap between HT and WT mice. Note that variance is also reduced in HT mice.

Figure 5

Hypothetical genotype–phenotype relation. Three dimensions indicate genes, phenotypes and Z-scores of phenotypic expression. The yellow–green zones indicate average scores exhibited in organisms at a normal gene dose. Lower (blue) and higher (red) Z-scores indicate more severe phenotypic deviation. The plane expands as more genes are involved in a CNV and more phenotypes are affected. (a) A hypothetical impact of a CNV on phenotypes. (b) Genetic background and/or environmental factors evenly shift the impact of a CNV on all phenotypes, compared to panel a. (c) Genetic background and/or environmental factors selectively shift the impact of a CNV on a specific phenotype (see phenotype 3), compared to panel a. (d) Genetic background and/or environmental factors selectively shift the impact of a specific gene (see gene a), compared to panel a. Not depicted here is a developmental trajectory along which a gene-dose alteration starts to affect a phenotypic score.