Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases as mitochondria are essential to neuronal function. The mitochondrial genome encodes a small number of core respiratory chain proteins, whereas the vast majority of mitochondrial proteins are encoded by the nuclear genome. Here we focus on establishing a profile of nuclear-mitochondrial transcriptional relationships in healthy human central nervous system tissue data, before examining perturbations of these processes in Alzheimer&#8217s disease using transcriptomic data originating from affected human brain tissue. Through cross- central nervous system analysis of mitochondrial-nuclear gene pair relationships, we find that the cell type composition underlies regional variation, and variation is driven at the subcellular level by heterogeneity of nuclear-mitochondrial coordination in post-synaptic regions. We show that nuclear genes causally implicated in sporadic Parkinson&#8217s disease and Alzheimer&#8217s disease show much stronger relationships with the mitochondrial genome than expected by chance, and that nuclear-mitochondrial relationships are significantly perturbed in Alzheimer&#8217s disease cases, particularly amongst genes involved in synaptic and lysosomal pathways. Finally, we present MitoNuclearCOEXPlorer, a web tool designed to allow users to interrogate and visualise key mitochondrial-nuclear relationships in multi-dimensional brain data. We conclude that mitochondrial-nuclear relationships differ significantly across regions of the healthy brain, which appears to be driven by the functional specialisation of different cell types. We also find that mitochondrial-nuclear co-expression in critical pathways is disrupted in Alzheimer&#8217s disease, potentially implicating the regulation of energy balance and removal of dysfunctional mitochondria in the etiology or progression of the disease and making the case for the relevance of bi-genomic co-ordination in the pathogenesis of neurodegenerative diseases.

48In this study, we used long-PCR amplification combined with Next-Generation Sequencing (NGS) to 49 obtain complete mitochondrial genomes of individual ticks and performed precise annotation of these 50 genomes. These annotations were confirmed by the PacBio full-length transcriptome data to cover both 51 entire strands of the mitochondrial genomes without any gaps or overlaps. Based on these annotations, most 52 of our findings were consistent with those from previous studies. Moreover, two important findings were 53 reported for the first time, contributing fundamental knowledge to mitochondrial biology. The first was the 54 discovery of a transposon-like element that may reveal the mechanisms of mitochondrial gene order 55 rearrangement and genomic structural variation. Another finding was that Short Tandem Repeat (STRs) are 56 the dominant variation type causing mitochondrial sequence diversity within an individual tick, insect, 57 mouse and human. Comparisons between interindividual and intraindividual variation showed that 58 polynucleotides and STRs with longer repeat units had the same variation pattern. Particularly, mitochondria 59 containing deleterious mutations can accumulate in cells and deleterious STR mutations irreversibly change 60 the proteins made from their mRNAs. Therefore, we proposed that deleterious STR mutations in 61 mitochondria cause aging and diseases. This finding helped to ultimately reveal the mechanisms of 62 mitochondrial DNA variation and its consequences (e.g., aging and diseases) in animals. Our study will give 63 rise to the reconsideration of the importance of STRs and a unified study of STR variation with longer and 64 shorter repeat units (particularly polynucleotides) in both nuclear and mitochondrial genomes. The complete 65 mitochondrial genome sequence of Dermacentor silvarum is available at the NCBI GenBank database under 66 the accession number MN347015 and the raw data is available at the NCBI SRA database under the 67 accession number SRP178347 . 68 69 70 71 72 73 74 75 76 77 78 79 80