FTLD targets brain regions expressing recently evolved genes

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and normative human regional transcriptomic data to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions expressing recently evolved genes. In addition, we asked whether genes expressed in FTLD-targeted brain regions are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions that express overlapping and distinct genes, including many linked to neuromodulatory functions. Genes whose normative brain regional expression pattern correlated with FTLD cortical atrophy were strongly associated with HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by NIH grants K99-AG065457 and R00-AG065457 to LP; P30AG062422, P01AG019724, U01AG057195, and U19AG063911 (WWS), as well as the Rainwater Charitable Foundation and the Bluefield Project to Cure FTD (WWS); GBHI ALZ UK-21-720973 and AACSF-21-850193 as well as JR20/0018 and PI21/00791 to IIG; 2021-A-023-FEL to AF; Gladstone Institutes and R01MH123178 to KSP. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: In accordance with the declaration of Helsinki, patients or their surrogates provided written informed consent prior to participation, including consent for brain donation. The UCSF Committee on Human Research approved the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes In house Python 2.7.16 (), R 4.1.2 (), and MATLAB R2021a () scripts were used for the analyses. W-score maps averaged for each FTLD subtype are publicly available on NeuroVault[88][1]. The gene lists used to generate the findings are available as Supplementary Data . Further data that support the findings of this study are available on request from the corresponding author. Correspondence should be directed to Lorenzo Pasquini or William W. Seeley. [1]: #ref-88