An evolutionary perspective on complex neuropsychiatric disease

Abstract

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

Keywords: 22q11 deletion; OCD; assortative mating; autism; bipolar disorder; causality; clinical heterogeneity; complex neuropsychiatric disease; consanguinity; de novo mutation; evolution; genetic drift; genetics; genomics; migration; polygenic inheritance; rare alleles; schizophrenia; selection; somatic mutation.

Fig 1.. Somatic mutations and mental illness.

Somatic mutations may appear de novo at any time during development of gametes, embryonic or fetal development, or after birth. The nature and severity of the illness depend both on the mutation and its timing of occurrence during development. As shown in the figure, for genes critical to brain development, the earlier the time of occurrence of the mutation during development (red dots in top panels), the greater the proportion of brain cells that are affected (red cells in lower panels). Somatic mutations are an extremely common cause of disease; for example, almost all cancers involve somatic mutations in critical genes in critical tissues. The role of somatic mutations in severe mental illness has been much more difficult to evaluate, because somatic mutations causing mental illness are likely to arise in brain, which is virtually inaccessible in living patients.

Fig 2.. Human-specific duplications of SRGAP2 and evolution of the neocortex.

The SRGAP2 gene on chromosome 1 encodes the SLIT-ROBO Rho GTPase-Activating Protein, which controls migration of neurons and dendritic formation in the cortex. SRGAP2 has been duplicated three times during human evolution. (A) Timing of SRGAP2 duplication events. ~3.4 million years ago (mya), SRGAP2 was partially duplicated to form the less active SRGAP2B; ~2.4 mya, SRGAP2B was duplicated to form SRGAP2C, which lacks the GTPase activating domain of SRGAP2 and acts antagonistically to it; and ~1.0 mya SRGAP2C was duplicated to form SRGAP2D, a pseudogene. (B) RNA expression levels of SRGAP2 genes in various tissues of human, chimpanzee, and rhesus monkey. Expression levels are based on RNA-Seq data mapped using gene-specific sequences. SRGAP2A is expressed in brain of all three species, but SRGAP2B and SRGAP2C are expressed only in human brain. (SRGAP2D is a pseudogene.) (C.) Effects of differences in SRGAP2 protein levels on neuronal migration. SRGAP2 protein regulates neurite formation and branching by forming filopodia on neurons in the ventricular zone (VZ) and subventricular zone (SVZ) of the cortex. In a mouse model, high levels of SRGAP2 protein inhibit migration of neurons to the cortical plate (CP), compared to control. In contrast, SRGAP2C protein binds to and antagonizes SRGAP2, leading to prolonged period of neuronal migration to the cortical plate. In the mouse model, reduction of SRGAP2 was associated with the emergence of human-like features in the neocortex, including a prolonged phase of maturation of dendritic spines and therefore a prolonged phase of maturation of the neocortex. (Data and figure from references –.)

Fig. 3.. Human Accelerated Regions (HARs) are enriched for neurodevelopmental enhancer elements.

HARs are genomic regions that are conserved across all human populations but differ between humans and all other species. In human neuroprogenitor cells (NPC) and neurons, HARs that are potentially regulatory (i.e. are DNase I hypersensitive sites) are more likely than other DNase I hypersensitive sites to include active regulatory elements (i.e. H3K4me1 signals of methylation or H3k27ac signals of acetylation). *P<0.001; Z test for proportions. (Figure from reference .)

Fig. 4.. Genetic variation in human populations as a function of distance from East Africa.

Heterozygosity genome-wide is highest in East Africa and decreases worldwide with distance from that point. The reason for the richness of human genetic variation in Africa is that people have lived in Africa longer than anywhere else. (Figure from reference .)

Fig 5.. Genetic heterogeneity of severe mental illness.

Individually rare and de novo point mutations and structural variants (deletions, duplications, inversions, and translocations) inn many different genes have been causally associated with schizophrenia (red), autism (blue), or both (black). The list of affected genes is growing rapidly. No individual damaging variant appears in more than a small number of cases. Hotspots for structural variants include chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2. Figure updated from McClelland and King with data from Turner et al., Singh et al., Zhou et al., and Marshall et al.

Fig. 6.. Clinical heterogeneity and pleiotropy among patients with deletion of chromosome 22q11.2.

Prevalence rates by age for several neuropsychiatric disorders among 1402 individuals with 22q11.2 deletions, evaluated by the International 22q11DS Brain Behavior Consortium (IBBC).