Biology subjects
Publications and source records attributed to Danek, A..
High-quality sequence assembly is the ultimate representation of complete genetic information of an individual. Several ongoing pangenome projects are producing collections of high-quality assemblies of various species. Here, we show how to represent the sequenced genomes in 2-3 orders of magnitude smaller space, allowing easy and fast extraction of any contig or its part.
Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.
Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). We first identify distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and anteromedial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, effectively modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability.
SummaryThe VCF files with results of sequencing projects take a lot of space. We propose VCFShark squeezing them up to an order of magnitude better than the de facto standards (gzipped VCF and BCF). Availability and Implementationhttps://github.com/refresh-bio/vcfshark Contactsebastian.deorowicz@polsl.pl Supplementary informationSupplementary data are available at publishers Web site.
INTRODUCTIONBrain structural imaging is paramount for the diagnosis of behavioral variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. METHODSA total of 515 subjects from two different bvFTD databases (training and validation cohorts) were included to perform voxel-wise deformation-based morphometry analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from morphometric differences in isolation and together with bedside cognitive scores. RESULTSAverage ten-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In a separate validation cohort of genetically confirmed bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added cognitive scores. DISCUSSIONThe random forest classifier developed can accurately predict bvFTD at the individual subject level.
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of FTD, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,772 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic FTD Initiative study. No significant association was seen between (C9orf2, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. Between 1,000 and 5,000 genes showed a negative or positive correlation with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative correlation with genes involved in mitochondrial function, and a positive correlation with genes involved in vascular and glial cell function in each of the genetic groups. After adjusting for spatial autocorrelation, a set of 423 and 700 genes showed significant positive and negative correlation, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in FTD than previously assumed, and in the case of the positively-associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier respectively. Abbreviated summaryAltmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia.
SummaryNowadays large sequencing projects handle tens of thousands of individuals. The huge files summarizing the findings definitely require compression. We propose a tool able to compress large collections of genotypes as well as single samples in such projects to sizes not achievable to date.\n\nAvailability and Implementationhttps://github.com/refresh-bio/GTShark\n\nContactsebastian.deorowicz@polsl.pl\n\nSupplementary informationSupplementary data are available at publishers Web site.
SummaryKmer-db is a new tool for estimating evolutionary relationship on the basis of k-mers extracted from genomes or sequencing reads. Thanks to an efficient data structure and parallel implementation, our software estimates distances between 40,715 pathogens in less than 4 minutes (on a modern workstation), 44 times faster than Mash, its main competitor.\n\nAvailability and Implementationhttps://github.com/refresh-bio/kmer-db\n\nContactsebastian.deorowicz@polsl.pl\n\nSupplementary informationSupplementary data are available at publishers Web site
MotivationO_ST_ABSResultsC_ST_ABSWe present GTC, a novel compressed data structure for representation of huge collections of genetic variation data. GTC significantly outperforms existing solutions in terms of compression ratio and time of answering various types of queries. We show that the largest of publicly available database of about 60 thousand haplotypes at about 40 million SNPs can be stored in less than 4 Gbytes, while the queries related to variants are answered in a fraction of a second.\n\nAvailabilityGTC can be downloaded from https://github.com/refresh-bio/GTC or http://sun.aei.polsl.pl/REFRESH/GTC.\n\nContactsebastian.deorowicz@polsl.pl