Biology subjects

Adelson, D. L.

Publications and source records attributed to Adelson, D. L..

4 recordsLinked to original sources

bioRxiv2018

Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

Alzheimers disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional inversion into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of A{beta}. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

bioinformatics↗

bioRxiv2017

Superior ab initio Identification, Annotation and Characterisation of TEs and Segmental Duplications from Genome Assemblies.

Transposable Elements (TEs) are mobile DNA sequences that make up significant fractions of amniote genomes. However, they are difficult to detect and annotate ab initio because of their variable features, lengths and clade-specific variants. We have addressed this problem by refining and developing a Comprehensive ab initio Repeat Pipeline (CARP) to identify and cluster TEs and other repetitive sequences in genome assemblies. The pipeline begins with a pairwise alignment using krishna, a custom aligner. Single linkage clustering is then carried out to produce families of repetitive elements. Consensus sequences are then filtered for protein coding genes and then annotated using Repbase and a custom library of retrovirus and reverse transcriptase sequences. This process yields three types of family: fully annotated, partially annotated and unannotated. Fully annotated families reflect recently diverged/young known TEs present in Repbase. The remaining two types of families contain a mixture of novel TEs and segmental duplications. These can be resolved by aligning these consensus sequences back to the genome to assess copy number vs. length distribution. Our pipeline has three significant advantages compared to other methods for ab initio repeat identification: 1) we generate not only consensus sequences, but keep the genomic intervals for the original aligned sequences, allowing straightforward analysis of evolutionary dynamics, 2) consensus sequences represent low-divergence, recently/currently active TE families, 3) segmental duplications are annotated as a useful by-product. We have compared our ab initio repeat annotations for 7 genome assemblies (1 unpublished) to other methods and demonstrate that CARP compares favourably with RepeatModeler, the most widely used repeat annotation package.\n\nAuthor summaryTransposable elements (TEs) are interspersed repetitive DNA sequences, also known as jumping genes, because of their ability to replicate in to new genomic locations. TEs account for a significant proportion of all eukaryotic genomes. Previous studies have found that TE insertions have contributed to new genes, coding sequences and regulatory regions. They also play an important role in genome evolution. Therefore, we developed a novel, ab initio approach for identifying and annotating repetitive elements. The idea is simple: define a \"repeat\" as any sequence that occurs at least twice in the genome. Our ab initio method is able to identify species-specific TEs with high sensitivity and accuracy including both TEs and segmental duplications. Because of the high degree of sequence identity used in our method, the TEs we find are less diverged and may still be active. We also retain all the information that links identified repeat consensus sequences to their genome intervals, permiting direct evolutionary analysis of the TE families we identify.

bioinformatics↗

bioRxiv2017

Divergent genome evolution caused by regional variation in DNA gain and loss between human and mouse

The forces driving the accumulation and removal of non-coding DNA and ultimately the evolution of genome size in complex organisms are intimately linked to genome structure and organisation. Our analysis provides a novel method for capturing the regional variation of lineage-specific DNA gain and loss events in their respective genomic contexts. To further understand this connection we used comparative genomics to identify genome-wide individual DNA gain and loss events in the human and mouse genomes. Focusing on the distribution of DNA gains and losses, relationships to important structural features and potential impact on biological processes, we found that in autosomes, DNA gains and losses both followed separate lineage-specific accumulation patterns. However, in both species chromosome X was particularly enriched for DNA gain, consistent with its high L1 retrotransposon content required for X inactivation. We found that DNA loss was associated with gene-rich open chromatin regions and DNA gain events with gene-poor closed chromatin regions. Additionally, we found that DNA loss events tended to be smaller than DNA gain events suggesting that they were more tolerated in open chromatin regions. GO term enrichment in human gain hotspots showed terms related to cell cycle/metabolism, human loss hotspots were enriched for terms related to gene silencing, and mouse gain hotspots were enriched for terms related to transcription regulation. Interestingly, mouse loss hotspots were strongly enriched for terms related to developmental processes, suggesting that DNA loss in mouse is associated with phenotypic changes in mouse morphology. This is consistent with a model in which DNA gain and loss results in turnover or \"churning\" of regulatory regions that are then subjected to selection, resulting in the differences we now observe, both genomic and phenotypic/morphological.

evolutionary biology↗

bioRxiv2016

Similar evolutionary trajectories for retrotransposon accumulation in mammals

The factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their non-autonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analysed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalise retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organisation, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.

evolutionary biology↗