Abstract：
In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of 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 human brain regional transcriptomic data from controls 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 linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy 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 with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites 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.
摘要：
额颞叶变性（FTLD），特定大脑区域的病理性蛋白质聚集与人类专门的社交情感和语言功能的下降有关。在大多数患者中，疾病蛋白聚集体含有TDP-43(FTLD-TDP)或tau(FTLD-tau)。这里,我们探讨了FTLD相关的区域变性模式是否与人类加速区（HARs）的区域基因表达有关，在最近的人类进化过程中经历了正选择的保守序列。为此,我们使用FTLD患者的结构神经成像和对照的人脑区域转录组数据来鉴定在FTLD靶向脑区表达的基因.然后，我们整合了灵长类动物的比较基因组数据，以检验我们的假设，即FTLD靶向与最近进化的基因表达水平相关的大脑区域。此外,我们询问当TDP-43功能受损时,其表达与FTLD萎缩相关的基因是否富集了进行隐秘剪接的基因.我们发现FTLD-TDP和FTLD-tau亚型靶向具有重叠和不同基因表达相关的大脑区域。突出了许多与神经调节功能相关的基因。对于HARs，FTLD萎缩相关基因强烈富集。与FTLD-tau中的萎缩相关基因相比，FTLD-TDP中的萎缩相关基因与TDP-43隐蔽剪接基因和具有更多TDP-43结合位点的基因显示出更大的重叠。富集了HAR基因的隐性剪接基因，反之亦然,但这种影响是由于基因长度的混杂影响。在个体患者水平进行的分析显示，在FTLD-TDP亚型中，HAR基因和假定的疾病发作区域内的潜在剪接基因的表达有所不同。
