**5.3.8 Genomic instability**

It is generally thought that a major cause of DNA damage that leads to mutations is reactive oxygen species, which are generated as a normal part of oxygen metabolism but are also produced by ionising radiation, metabolism of exogenous compounds (Hussain et al., 2003; Finkel, 2003). It has been shown that endogenous mitochondrial oxidative stress can induce many types of DNA damage including double strand breaks, end-to-end fusions, base and sugar modifications, DNA-protein cross-links, and gross chromosomal rearrangements (Ragu et al., 2007; Samper et al., 2003).

Therefore, the hypothesis predicts that the enhanced oxidative stress may cause genomic instability during meiosis and/or early phase of ontogeny, producing increased rates of random point mutations and/or structural variants of the nuclear genome in the

Therefore, the hypothesis predicts that the risk of preeclampsia, eclampsia, or stillbirth may be increased in the birth of patients with schizophrenia as well as in the pregnancies of women with schizophrenia. Indeed, an excess of stillbirths and neonatal deaths among women with schizophrenia has been reported by several investigators (Sobel, 1961; Rieder et

Furthermore, there has been a body of evidence for an increased risk of obstetric complications in the birth of patients with schizophrenia (Dalman et al., 1999; Cannon et al., 2002). A meta-analysis of population-based data (Cannon et al., 2002) found significant estimates for three main categories of obstetric complications: (1) complications of pregnancies, (2) abnormal fetal growth and development, and (3) complications in delivery. Among all, preeclampsia was the strongest individual risk factor detected in the largest

Although obstetrical events in schizophrenia are often considered as having a direct causative effect, none of the available data can refute the hypothesis that they are merely markers of some other causal process (Rapoport et al., 2005), such as mitochondrial

Since the positive selection of the schizophrenia-associated alleles mentioned above occurs only in the predisposed matrilineal pedigrees, a ubiquitous subpopulation in humans, frequencies of those alleles may not be so high in the general population as if the selection

Thus, the hypothesis predicts that every schizophrenia-associated nuclear gene shows an apparent signature as if it had been subject to a positive selection in the recent evolutionary history of humans. Recent two reports (Lo et al, 2007; Crespi et al., 2007) seem to be in line

On the other hand, the nuclear genome model predicts that every schizophrenia-associated nuclear gene shows an apparent signature of negative selection due to the strong negative

It is generally thought that a major cause of DNA damage that leads to mutations is reactive oxygen species, which are generated as a normal part of oxygen metabolism but are also produced by ionising radiation, metabolism of exogenous compounds (Hussain et al., 2003; Finkel, 2003). It has been shown that endogenous mitochondrial oxidative stress can induce many types of DNA damage including double strand breaks, end-to-end fusions, base and sugar modifications, DNA-protein cross-links, and gross chromosomal rearrangements

Therefore, the hypothesis predicts that the enhanced oxidative stress may cause genomic instability during meiosis and/or early phase of ontogeny, producing increased rates of random point mutations and/or structural variants of the nuclear genome in the

**5.3.7 An apparent signature of positive selection in schizophrenia-associated** 

al., 1975; Modrzewska, 1980; Webb et al., 2005).

dysfunction which is implicated in this hypothesis.

had occurred *recently* in the general population.

**genes** 

with this prediction.

selection pressure.

**5.3.8 Genomic instability** 

(Ragu et al., 2007; Samper et al., 2003).

single population-based cohort study to date (Dalman et al., 1999).

predisposed population. In addition, genomic instability may be more pronounced in males due to lack of antioxidant protection by estrogen.

There have been numerous reports of associations between schizophrenia and chromosomal abnormalities including fragile sites, reciprocal translocations, inversions, insertions, deletions, disomy and trisomy in many autosomes, and sex chromosome aneuploidies (Macintyre et al, 2003). However, with an exception of 22q11 deletion, none of these have been consistently replicated, and with another exception of (1,11) (q42;q14.3) balanced translocation, none provides convincing evidence for the location of a 'susceptibility' gene (Kirov et al., 2005).

A popular explanation in the nuclear genome model may be that most of these structural variants are coincidental findings of no clinical significance. Alternatively, those alterations may indicate genomic instability in schizophrenia. An increased risk of schizophrenia in individuals with 22q11 deletion (Pulver et al., 1994; Murphy et al., 1999) might be due to haplodeficiency of presumptive resistance genes of gain-offunction type and/or presumptive facilitating genes of loss-of-function type aggregated on 22q11.

More recently, it has been reported that rare structural variants such as microdeletions or microduplications of sizes ranging from 100kb to 15MB throughout the genome are more frequent among individuals with schizophrenia than unaffected individuals (Walsh et al., 2008). While many of those structural variants duplicate or delete genes in neurodevelopmental pathways, one third of those do not disrupt genes, leaving their role in causation of the disease unwarranted. Another recent report (Xu et al., 2008) has shown that *de novo* copy number mutations are increased in sporadic schizophrenia. However, the cytobands of those copy number mutations are diverse among the affected individuals and their roles in the pathogenesis still remain unclear. Therefore, no available data can refute the possibility that those structural variants and copy number mutations are not the causes of schizophrenia but the results of the genomic instability in schizophrenia predicted by our hypothesis.

Indeed, direct measure of the de novo mutation rates shows an increased mutation rate in schizophrenia (Awadalla et al., 2010), and genomic and epigenomic instability has been suggested in schizophrenia (Smith et al., 2010). Furthermore, it has been shown that blood cells from patients with schizophrenia present a higher rate of folate-sensitive fragile sites, and that male patients exhibit twice as many fragile sites as females while there are no age effects (Demirhan et al., 2006). This sex difference may indicate that increased fragile sites expression (genomic instability) is the results of enhanced oxidative stress in patients with schizophrenia.
