The Evolutionary Genetics of Schizophrenia

Updates, clarifications, and corrections

Schizophrenia Is the Price We Pay for Minds Poised Near the Edge of a Cliff

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Since publication of the post “Schizophrenia Is the Price We Pay for Minds Poised Near the Edge of a Cliff,” friends and readers have reached out to me to highlight various problems with this hypothesis. It is perhaps not surprising at all that scientific details are complicated and recent research findings have cast doubt on some older reports. As I understand it, high polygenicity of schizophrenia (hundreds and thousands of alleles are involved), mechanistic heterogeneity (there is no single mechanism), and schizophrenia alleles being under current negative selection or common variants being very weak are all compatible with the cliff-edged dynamics theorized. What would favor or disfavor cliff-edge dynamics rests on a) whether there is good evidence of positive selection of schizophrenia alleles in the evolutionary past and b) whether the weak size of common variants is better seen as evidence of very weak positive selection in those not affected or as a deleterious effect so weak that it flies under the radar of natural selection.

Here are some important updates, clarifications, and corrections.

The evidence for positive selection of schizophrenia alleles in the evolutionary past is not robust and has been challenged.

Several studies had suggested that schizophrenia risk alleles might have undergone positive selection in our evolutionary past, but those findings haven’t held up well under further research. Subsequent research suggests that what we’re seeing is the residue of negative selection and background selection processes. Risk alleles for schizophrenia do not appear to be enriched in regions of the genome under positive selection.

Chenxing Liu and colleagues note in their 2019 paper:

“The enrichment of schizophrenia SNPs in pHAR regions and NSS regions was identified by Xu et al. (2015) and Srinivasan et al. (2016), respectively. Srinivasan attributed their observation to the effect of positive selection after the divergence of humans and Neanderthals. However, the most recent study by Pardiñas et al. (2018) has emphasized the role of background selection in the persistence of risk alleles for schizophrenia. Contrary to the perspective in Srinivasan’s study, Pardiñas et al. (2018) suggested that SNPs under positive selection are less likely to be associated with schizophrenia. Our findings are consistent with those reported by Pardiñas et al. (2018) in that our results support negative selection and corresponding background selection of schizophrenia risk alleles rather than positive selection.”

Schizophrenia as a “by-product”

Liu et al. 2019 support a by-product hypothesis, with schizophrenia arising as a harmful byproduct of “the development of the social brain, language, and high-order cognitive functions (Crow, 2000; Burns, 2004).”

“Aligned with this notion, we speculate that around 100,000 – 150,000 years ago (Burns, 2004), before the migration of modern humans out-of-Africa (Stringer and Andrews, 1988), there was a “turning point” at which time the number of schizophrenia risk alleles plateaued. Thereafter, risk alleles for schizophrenia have been progressively but slowly eliminated from the modern human genome while undergoing negative selection pressure.”

In other words, as Nesse (2023) puts it,

“the development of social brain, language and high-order cognitive functions transformed many neutral alleles into risk alleles for schizophrenia.”

Selection considerations differ based on rare variants (of large effect) vs common variants (of weak effect), and given the complex origins of schizophrenia, different evolutionary mechanisms are not mutually exclusive.

Milica Nesic and colleagues (2019):

“For instance, rare schizophrenia risk variants, such as de novo mutations that are usually deleterious and are under negative selection, continue to arise due to erroneous genetic machinery and stochastic processes. Certain copy number variations that are also deleterious and under negative selection continue to emerge due to intrinsic vulnerability of our ‘uniquely evolved’ genomes. They could, therefore, be a result of a trade-off between a specific course of human genome evolution and chromosomal instability. Certain common variations, such as SNP, are maintained not necessarily because they increase fitness, but because they do not decrease it significantly. This is possible due to evolutionary mechanisms that allow for alleles that are mildly deleterious to go ‘unnoticed’ by selection. Furthermore, mechanisms operating beyond the nuclear genome sequence, such as altered epigenetic regulation or mutations in mitochondrial DNA, might add to the complexity of phenotypic variation, thus lessening the purifying power of selection. Finally, it may be that specific schizophrenia-risk variants offer certain advantage to relatives of affected persons (e.g. enhanced creativity) that counterbalance their detrimental effects on a population level. In general, most of the new genetic and genomic data, understood from the evolutionary perspective, imply that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but that has been a mildly deleterious by-product of specific patterns of the evolution of the human brain.”

Mutation-selection balance and genetic drift remain valid and commonly accepted explanations for schizophrenia variants.

Michael Owen (2023):

“Schizophrenia is relatively common and highly heritable but is associated with markedly reduced fecundity [42]. Some light has been thrown upon this so-called ‘evolutionary paradox’ [43] by recent genomic studies. The evolutionary explanation for highly penetrant fitness-reducing mutations is likely to be mutation selection-balance [44] and evidence to support this has come from studies of schizophrenia risk CNVs [45]. Regarding common schizophrenia risk alleles, genomic studies have shown that weak purifying selection is pervasive [46,47] and that, when the effects of background selection are controlled for, there is little evidence for positive selection [47]. These findings, while not excluding a role for balancing selection at some loci, suggest that mutation-selection-drift is a more generally applicable explanation for the presence of common risk alleles in the face of reduced fecundity [44,47].”

And something I should’ve realized but hadn’t was that in recent years Randolph Nesse himself has moved on from the cliff-edge fitness function hypothesis to a “wrenching transition” hypothesis for schizophrenia

(although he continues to believe cliff-edge fitness approach is important to understand why evolution has left us vulnerable to serious psychiatric diseases)

Here’s Nesse is a 2023 paper for World Psychiatry:

“A different approach considers the possible role of rapid selection for traits that became useful during the major transition to the social cultural niche in the past few hundred thousand years. T.J. Crow wrote extensively about the possibility that psychosis could be the price we pay for the capacity for language (461, 462). We now are on the verge of confirming that some health problems can be attributed to wrenching major transitions in which a new niche or strategy selects strongly for traits that make other traits vulnerable because of anatomic, physiologic or pleiotropic constraints. The exemplar is the transition to bipedality and its legacy of vulnerability to hernias, hemorrhoids, back pain, knee pain, plantar fasciitis, varicose veins, and omental torsion (463). It is painful to imagine how prevalent these problems must have been in the first million years of bipedality.

The wrenching transition to the cognitive social niche may have created even more severe problems, considering the path-dependent interactions of multiple alleles that influence brain development pathways (464-466). Imagine a new allele changing the chemical gradients that influence neuronal migration during brain development in ways that give a benefit, perhaps something like more expressive vocalization. If this gives a net selective advantage, the allele will be selected for, despite negative effects that slightly disrupt multiple other adaptations that evolved previously.”

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As a conceptually minded clinical psychiatrist, I am somewhat out of my depth here with regard to the scientific complexities of the evolutionary and genetics literature, but I can’t help being fascinated by this either, and I hope my efforts to make sense of this and my efforts at self-correction are of some value to readers as well.

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