**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 & Miller, 2006).

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 but not in the nuclear genome model.
