**2. Devil's triangle of human genetics – Epidemiological facts of schizophrenia**

We describe here three epidemiological facts of schizophrenia – high prevalence, high heritability and low reproductive fitness. These properties form a Devil's triangle; any combination of the two tends to exclude the third, and in this triangle most diseases vanish except for schizophrenia, suggesting that schizophrenia has a unique etiological basis among the many human diseases.

#### **2.1 Schizophrenia as a common disease**

Substantial evidence of epidemiology shows that schizophrenia crosses all cultures and tribes in different continents at a relatively high prevalence (approximately 0.7%; 95%

Impact of Epidemiology on Molecular Genetics of Schizophrenia 115

**3. Persistence problem and mutation-selection balance in schizophrenia** 

The three epidemiological characteristics of schizophrenia mentioned above give a paradox. How has a highly heritable disease associated with a remarkable biological disadvantage never been extinct in the long human history? And how can it persist at a relatively high prevalence? This 'persistence problem of schizophrenia' (or 'schizophrenia paradox') has puzzled scientists for long years (Huxley et al., 1964; Crow, 1995; Brüne, 2004; Keller &

In this section, we discuss that the only plausible mechanism for the persistence is mutationselection balance with or without heterozygote advantage. Based on the consistent epidemiological findings on the fertility of patients with schizophrenia and their family members, we show that heterozygote advantage works in the mitochondrial genome model

**3.1 Mutation-selection balance is the only plausible mechanism for the persistence**  From an evolutionary viewpoint, four explanations are possible for the persistence: (i) ancestral neutrality, (ii) negative frequency-dependent selection, (iii) heterozygote

'Ancestral neutrality' assumes that reproductive fitness of affected individuals and/or their relatives was higher in ancient environments and that selection coefficients of pathogenic alleles were close to zero. Because the effective population size in ancient times might be much smaller than now, pathogenic but neutral or almost neutral alleles could be fixed by genetic drift. While this hypothesis explains that schizophrenia has not been extinct in the long human history, ancestral neutrality itself provides no explanation for the apparently stable prevalence of the disease across generations today; although 'ancestral neutrality' might be plausible, it needs another mechanism to account for the persistence in modern environments, where the effective population size has been expanded and the influence of

advantage (balancing selection or pleiotropy), and (iv) mutation-selection balance.

negative selection pressure may be much stronger than ever before.

Fig. 1. Devil's triangle of human genetics (Doi et al., 2009)

Miller, 2006).

but not in the nuclear genome model.

Confidence Interval 0.3% - 2.7%) (Saha et al., 2005); the prevalence of schizophrenia, at the macro-level, varies within narrow limits (Jablensky, 1995), and appears to be stable across generations in several countries (Harrison et al., 1991; Osby et al., 2001). This epidemiological fact suggests that schizophrenia has an ancient origin.
