Biology subjects

Fabian, D. K.

Publications and source records attributed to Fabian, D. K..

7 recordsLinked to original sources

bioRxiv2025

Expansion of chromosome F heterochromatin in parthenogenetic Drosophila mercatorum

The dramatic transition to parthenogenetic reproduction is often accompanied by similarly dramatic changes in genome organization. Genomic changes may precede or succeed the onset of parthenogenesis and may directly or indirectly contribute to the success of this reproductive transition and fitness of parthenogenetic animals. To gain greater understanding of genomic changes accompanying the transition to parthenogenetic reproduction, we have characterized genomic differences between a sexually reproducing and parthenogenetic strain of Drosophila mercatorum. This revealed three large (2.6-9 Mbp) inversions present on Muller element B and a 30-fold length expansion of heterochromatin on Muller element F. Comparisons of these genomic changes and parthenogenetic ability in 18 D. mercatorum strains collected in South America, North America, Hawaii, and Africa indicates no clear correlation of these genomic changes with geographical origin. However, these changes are minimal in strains collected in Brazil suggesting this is the origin for the ancestral strain and that both chromosome inversions and increased heterochromatin have likely preceded the transition to parthenogenetic reproduction. Parthenogenetic ability correlates most strongly with expansion of chromosomal element F. We speculate that this increased heterochromatic environment of genes on element F influences gene expression to either enhance parthenogenesis directly or redirect the activity of another factor contributing to it, in a manner analogous to the known influence of heterochromatin on gene activity in position effect variegation.

evolutionary biology↗

bioRxiv2024

Large-Scale Comparative Transcriptomic Analysis of CHO Cell Functional Adaptation to Recombinant Monoclonal Antibody Production

To comparatively evaluate cellular constraints on recombinant monoclonal antibody (mAb) production by Chinese Hamster Ovary (CHO) cells, we analysed the transcriptomes of 24 clonally derived CHO cell lines engineered with PiggyBac transposon technology to stably produce four recombinant monoclonal antibodies (mAbs) at varying specific production rates. Fed-batch cultures were sampled at exponential (day 5) and stationary (day 10) phases of culture for analysis by RNA-Seq. Recombinant mRNAs accounted for a large proportion of total mRNA across all clones, and efficient use of heavy chain (HC) mRNA to synthesise recombinant mAb (qP per HC mRNA) varied significantly with respect to both mAb product and cell line. Comparative bioinformatic analyses of CHO transcriptomes focussed on mAb specific production rate and utilised both data-driven and hypothesis-led approaches, specifically (i) production or non-production of recombinant mAb, (ii) changes in the abundance of functional groups of mRNAs abundance with mAb specific production rate and (iii) comparative analysis of informatically-mined gene subsets associated with cellular functions hypothesised to impact recombinant mAb synthesis and secretion. These analyses revealed widespread constitutive and adaptive changes in mRNA abundance associated with mAb production across a variety of cellular functions. Typically, most mechanistically consistent changes in mRNA abundance co-varying with mAb production were evident at the stationary phase sample point. These data revealed both recombinant mAb-specific limitations on cellular synthetic capacity and a generic adaptive strategy used by CHO cells to support high-level mAb production. The latter was achieved by directed and permissive regulation of endoplasmic reticulum and other processes to accommodate increased synthetic flux.

bioengineering↗

bioRxiv2022

Virgin Birth: A genetic basis for facultative parthenogenesis

Sexual reproduction evolved 1-2 billion years ago and underlies the biodiversity of our planet. Nevertheless, devolution of sexual into asexual reproduction can occur across all phyla of the animal kingdom. The genetic basis for how parthenogenesis can arise is completely unknown. To understand the mechanism and benefits of parthenogenesis, we have sequenced the genome of the facultative parthenogen, Drosophila mercatorum, and compared its organisation and expression pattern during parthenogenetic or sexual reproduction. We identified three genes, desat2, Myc, and polo in parthenogenetic D. mercatorum that when mis-regulated in a non-parthenogenetic species, D. melanogaster, enable facultative parthenogenetic reproduction. This simple genetic switch leads us to propose that sporadic facultative parthenogenesis could evolve as an escape route preserving the genetic lineage in the face of sexual isolation.

evolutionary biology↗

bioRxiv2021

Drosophila Evolution over Space and Time (DEST) - A New Population Genomics Resource

Drosophila melanogaster is a leading model in population genetics and genomics, and a growing number of whole-genome datasets from natural populations of this species have been published over the last 20 years. A major challenge is the integration of these disparate datasets, often generated using different sequencing technologies and bioinformatic pipelines, which hampers our ability to address questions about the evolution and population structure of this species. Here we address these issues by developing a bioinformatics pipeline that maps pooled sequencing (Pool-Seq) reads from D. melanogaster to a hologenome consisting of fly and symbiont genomes and estimates allele frequencies using either a heuristic (PoolSNP) or a probabilistic variant caller (SNAPE-pooled). We use this pipeline to generate the largest data repository of genomic data available for D. melanogaster to date, encompassing 271 population samples from over 100 locations in >20 countries on four continents based on a combination of 121 unpublished and 150 previously published genomic datasets. Several of these locations have been sampled at different seasons across multiple years. This dataset, which we call Drosophila Evolution over Space and Time (DEST), is coupled with sampling and environmental meta-data. A web-based genome browser and web portal provide easy access to the SNP dataset. Our aim is to provide this scalable platform as a community resource which can be easily extended via future efforts for an even more extensive cosmopolitan dataset. Our resource will enable population geneticists to analyze spatio-temporal genetic patterns and evolutionary dynamics of D. melanogaster populations in unprecedented detail.

genomics↗

bioRxiv2020

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes. HighlightsO_LITranscriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespan C_LIO_LIThe major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolism C_LIO_LIGene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing C_LI

genomics↗

bioRxiv2019

Transposable element landscape in Drosophila populations selected for longevity

Transposable elements (TEs) inflict numerous negative effects on health and fitness as they replicate by integrating into new regions of the host genome. Even though organisms employ powerful mechanisms to demobilize TEs, transposons gradually lose repression during aging. The rising TE activity causes genomic instability and was implicated in age-dependent neurodegenerative diseases, inflammation and the determination of lifespan. It is therefore conceivable that long-lived individuals have improved TE silencing mechanisms resulting in reduced TE expression relative to their shorter-lived counterparts and fewer genomic insertions. Here, we test this hypothesis by performing the first genome-wide analysis of TE insertions and expression in populations of Drosophila melanogaster selected for longevity through late-life reproduction for 50-170 generations from four independent studies. Contrary to our expectation, TE families were generally more abundant in long-lived populations compared to non-selected controls. Although simulations showed that this was not expected under neutrality, we found little evidence for selection driving TE abundance differences. Additional RNA-seq analysis revealed a tendency for reducing TE expression in selected populations, which might be more important for lifespan than regulating genomic insertions. We further find limited evidence of parallel selection on genes related to TE regulation and transposition. However, telomeric TEs were genomically and transcriptionally more abundant in long-lived flies, suggesting improved telomere maintenance as a promising TE-mediated mechanism for prolonging lifespan. Our results provide a novel viewpoint indicating that reproduction at old age increases the opportunity of TEs to be passed on to the next generation with little impact on longevity.

evolutionary biology↗

bioRxiv2018

A clinal polymorphism in the insulin signaling transcription factor foxo contributes to life-history adaptation in Drosophila

A fundamental aim of adaptation genomics is to identify polymorphisms that underpin variation in fitness traits. In D. melanogaster latitudinal life-history clines exist on multiple continents and make an excellent system for dissecting the genetics of adaptation. We have previously identified numerous clinal SNPs in insulin/insulin-like growth factor signaling (IIS), a pathway known from mutant studies to affect life history. However, the effects of natural variants in this pathway remain poorly understood. Here we investigate how two clinal alternative alleles at foxo, a transcriptional effector of IIS, affect fitness components (viability, size, starvation resistance, fat content). We assessed this polymorphism from the North American cline by reconstituting outbred populations, fixed for either the low- or high-latitude allele, from inbred DGRP lines. Since diet and temperature modulate IIS, we phenotyped alleles across two temperatures (18{degrees}C, 25{degrees}C) and two diets differing in sugar source and content. Consistent with clinal expectations, the high-latitude allele conferred larger body size and reduced wing loading. Alleles also differed in starvation resistance and expression of InR, a transcriptional target of FOXO. Allelic reaction norms were mostly parallel, with few GxE interactions. Together, our results suggest that variation in IIS makes a major contribution to clinal life-history adaptation.

evolutionary biology↗