The evolution of psychiatric disorders and human personality traits

In a new paper pub­lished in Evol­u­tion Let­ters, a research team from Tohoku Uni­ver­sity reveal the evol­u­tion of a gene related to human-unique psy­chi­at­ric traits. Here, authors Daiki Sato and Masakado Kawata tell us more about their findings.

How and why unique human char­ac­ter­ist­ics, such as highly social beha­vi­or, lan­guages, and com­plex cul­tures, have evolved is a long-stand­ing ques­tion. In our labor­at­ory, we have focused on prob­lems as to what factors facil­it­ate and/or con­strain evol­u­tion using mainly non-human organ­isms. How­ever, dur­ing recent years, a large amount of gen­om­ic data, espe­cially for human gen­ome, have been accu­mu­lated, and thus, we can now attempt to resolve the mech­an­isms under­ly­ing human evol­u­tion using vari­ous meth­ods to detect the sig­na­ture of vari­ous forms of nat­ur­al selec­tion in the human genome.

The first motiv­a­tion for our study came from the hypo­thes­is that some psy­chi­at­ric dis­orders (PDs) have evolved as mal­ad­apt­ive byproducts of adapt­ive human evol­u­tion. In addi­tion, recent stud­ies have shown sig­ni­fic­ant genet­ic cor­rel­a­tions between PDs and human per­son­al­ity traits, such as neur­oticism, extro­ver­sion, open­ness, con­scien­tious­ness, and agree­able­ness, pos­ing the ques­tion of how adapt­ive evol­u­tion has shaped our psy­chi­at­ric and/or per­son­al­ity traits. Thus, among PD-related genes, we searched for those that have been favored by nat­ur­al selec­tion in the human lin­eage and iden­ti­fied three as pos­it­ively evolved genes asso­ci­ated with some PDs, although sev­er­al stud­ies using the same approach could not identi­fy these genes. Of the three genes iden­ti­fied, we focused on SLC18A1 because it has inter­est­ing known vari­ants that affect PDs. SLC18A1 encodes vesi­cu­lar monoam­ine trans­port­er 1 (VMAT1), which is involved in the uptake of monoam­ine neur­o­trans­mit­ters, such as sero­ton­in, dopam­ine, and nore­pineph­rine, into syn­aptic ves­icles. VMAT1 has vari­ants of two dif­fer­ent amino acids, threon­ine (Thr) and iso­leu­cine (Ile), at site 136 (Thr136Ile). Sev­er­al stud­ies have shown that these vari­ants are asso­ci­ated with PDs, includ­ing schizo­phrenia, bipolar dis­order, anxi­ety, and neur­oticism. Indi­vidu­als with 136Thr tend to be more anxious, more depressed and have high­er neur­oticism scores. Our paper showed that oth­er mam­mals have 136Asn at this site, but 136Thr had been favored over 136Asn dur­ing human evol­u­tion. Moreover, 136Ile vari­ant had ori­gin­ated nearly at the Out-of-Africa migra­tion, and then both 136Thr and 136Ile vari­ants were main­tained by nat­ur­al selec­tion in non-Afric­an populations.

Our res­ults provide two import­ant implic­a­tions for human psy­chi­at­ric evol­u­tion. First, through pos­it­ive selec­tion, the evol­u­tion from Asn to Thr at site 136 on SLC18A1 might have led to more anxious and depressed human minds in the course of evol­u­tion from ances­tral prim­ates to humans. Inoue-Maruyama et al. (2001) spec­u­lated from an ana­lys­is of sero­ton­in-trans­port­er vari­ants that anxi­ety has been favored through­out human evol­u­tion. Raghanti et al. (2018) pro­posed a neuro­chem­ic­al hypo­thes­is that selec­tion favored a human dopamine–dominated stri­atum (DDS) per­son­al­ity style in our earli­est ancest­ors, which led to extern­ally driv­en beha­vi­or and amp­li­fied sens­it­iv­ity to social cues that pro­mote con­form­ity, empathy, and altru­ism. The res­ults of their study showed that the con­cen­tra­tion of dopam­ine in the stri­atum was par­tic­u­larly elev­ated in humans, and that acet­ylcholine was lowered. The 136Thr vari­ant might be favored for inter­act­ing with such com­plex neuro­chem­ic­al changes dur­ing the evol­u­tion of human psy­chi­at­ric and emo­tion­al features.

Second, we showed that the two vari­ants of Thr136Ile have been main­tained by nat­ur­al selec­tion using sev­er­al dif­fer­ent meth­ods. Any form of nat­ur­al selec­tion that main­tains genet­ic diversity with­in pop­u­la­tions is called “bal­an­cing selec­tion”. Thus, our res­ults sug­gest that some com­pon­ents of per­son­al­ity traits in human pop­u­la­tions that are affected by genet­ic vari­ants are main­tained by bal­an­cing selec­tion. Indi­vidu­al dif­fer­ences in per­son­al­ity traits are observed in vari­ous human pop­u­la­tions, and some of these per­son­al­ity traits are also found in non-human prim­ates. This sug­gests that genes asso­ci­ated with per­son­al­ity traits could gen­er­ally be main­tained by bal­an­cing selec­tion, although there is no clear evid­ence for this pro­cess in human neur­o­trans­mit­ter genes (Taub and Page, 2016). Bal­an­cing selec­tion can be caused by sev­er­al factors, such as het­ero­zy­gote advant­age, neg­at­ive frequency–dependent selec­tion, environment–genotype inter­ac­tions, and int­ra­locus sexu­al con­flict. Detect­ing bal­an­cing selec­tion from gen­ome sequences is often dif­fi­cult because bal­an­cing selec­tion often does not con­tin­ue over long peri­ods of time and might be tran­si­ent. In par­tic­u­lar, phen­o­typ­ic and fit­ness effects of PD-related genes are expec­ted to change depend­ing on the envir­on­ments and their sur­round­ing social inter­ac­tions. These com­plex inter­ac­tions some­times cause emer­gent over­dom­in­ance (het­ero­zy­gote advant­age emerges by aver­aging over dif­fer­ent pop­u­la­tions, envir­on­ments, or gen­er­a­tions; Delph and Kelly, 2014). In these cases, the strength and effects of bal­an­cing selec­tion can often be incon­stant. In our study, bal­an­cing selec­tion for Thr136Ile vari­ants was detec­ted in only sev­er­al non-Afric­an pop­u­la­tions; there­fore, this pro­cess might depend on one’s phys­ic­al and/or social envir­on­ments. Taken togeth­er, we pro­pose that genes asso­ci­ated with per­son­al­ity traits have actu­ally been main­tained by vary­ing the pro­cess of bal­an­cing selec­tion, but detect­ing this would be dif­fi­cult using pre­vi­ous meth­ods. We must now con­sider how to detect weak select­ive pres­sure in the evol­u­tion of diverse indi­vidu­al­ity and per­son­al­ity traits.

In our ongo­ing research, we are attempt­ing to identi­fy the phen­o­typ­ic and fit­ness effects of Thr136Ile vari­ants and cla­ri­fy how and why the vari­ants are main­tained by bal­an­cing selection.

Daiki X. Sato is a PhD stu­dent and Masakado Kawata is Pro­fess­or at the Gradu­ate School of Life Sci­ences, Tohoku Uni­ver­sity. Their ori­gin­al study is freely avail­able to read and down­load here.