Biology subjects

McLysaght, A.

Publications and source records attributed to McLysaght, A..

10 recordsLinked to original sources

bioRxiv2026

A Duplicate Resolved Paddlefish Genome Provides Insights into the Mechanisms of Rediploidisation and Hox Cluster Evolution

Whole-genome duplication (WGD; or polyploidy) has played a major role in the evolution of many lineages however, our understanding of the processes that shape genome evolution following WGD remains incomplete. While polyploidy duplicates the entire genome sequence, it is rediploidisation that establishes independent duplicated genes. Rediploidisation proceeds through suppression of meiotic recombination across polysomic loci thus restoring disomic inheritance, a process that is not synchronised across the genome. Despite its importance, the mechanisms underlying this process remain poorly understood. The slowly evolving genomes of paleopolyploid Acipenseriformes paddlefish and sturgeon provide an invaluable system for investigating this, as rediploidisation was highly asynchronous in these lineages. In both genomes ohnologs tend to segregate into blocks on the chromosomes according to rediploidisation timing, a pattern that suggests links between chromosomal structure and rediploidisation. Here, we analyse a newly-produced duplicate-resolved paddlefish genome assembly and show a strong concordance between genome rearrangement and rediploidisation timing. We also find that topologically associated domain (TAD) boundaries are associated with rediploidisation block boundaries. Together these results indicate that rediploidisation in acipenseriformes occurred through a process of genome rearrangements that was subject to functional constraints imposed by 3D genome architecture. We investigate the evolution of Hox clusters in these lineages, revealing a previously overlooked duplicate HoxC region in paddlefish, and both ancestral and lineage-specific Hox cluster rediploidisation with substantially different timings. These findings highlight a complex evolutionary history following WGD in Acipenseriformes with implications for understanding short-term adaptations to polyploidy as well as longer-term diversification of lineages.

evolutionary biology↗

bioRxiv2026

An automated pipeline for reconstructing whole genome duplications

Whole genome duplications leave lasting traces in our genomes. How these present in terms of gene content and order varies over time. While collinear blocks of paralogs, long stretches of conserved gene order and content termed microsynteny, are a distinctive feature of comparatively recent WGD and have been integral in reconstructing the history of ancestral duplication events, this signal degrades over time, making analysis of older events non-trivial. While gene order degrades quickly, gene content is often better conserved and recent work takes advantage of this to reconstruct older events and ancestral pre-WGD and post-WGD chromosomes. However, these new methods are complicated and not well-documented. Here we develop an automated and user-friendly pipeline for reconstructing ancestral chromosomes before and after WGD, and use the conservation of gene content to infer chromosomal rearrangement events in this timeframe. We verify the efficacy of our tool by reconstructing the ancestral acipenseriform, a model system for vertebrate WGD and rediploidisation. Our pipeline should serve to make ancestral reconstruction more accessible and provide a solid foundation for future analysis.

evolutionary biology↗

bioRxiv2025

Pervasive Chromosomal Instability Drives the Karyotypic Evolution of Hypodiploid Tumours

Tumours frequently exhibit extreme levels of aneuploidy. While increases in ploidy are well-characterised, the opposite phenomenon--extensive chromosome loss leading to hypodiploidy-- remains underexplored. Here, we analyse over 17,000 cancer genomes from 34 cancer types and perform a pan-cancer analysis of karyotypic evolution in hypodiploid tumours. We find that hypodiploidy is widespread and associated with a generalised chromosomal instability phenotype, marked by significantly elevated rates of genome doubling, intrachromosomal copy number alterations, chromothripsis, and intra-tumour heterogeneity. These tumours are hypoxic and strongly enriched for TP53 mutations. However, we also identify a subset of cancers--acute lymphoblastic leukaemia (ALL), kidney chromophobe, and adrenocortical carcinoma--that exhibit stable hypodiploidy, with stereotyped chromosome loss patterns, low chromosomal instability, and distinct evolutionary origins. We exploit this stability to develop a simple method of distinguishing poor-prognosis masked hypodiploid from good-prognosis hyperdiploid ALL using only cytogenetic data, enabling more precise risk stratification. Finally, we show that hypodiploidy predicts poor prognosis across cancers. Genome doubling does not confer a fitness advantage in low-hypodiploid tumours, nor do these tumours evolve to avoid loss of dosage-sensitive genes. Together, these findings provide the first pan-cancer characterization of hypodiploidy as a widespread and clinically relevant phenomenon often driven by pervasive chromo-somal instability, and illustrate the remarkable ability of cancer cells to tolerate and evolve under extreme dosage imbalance.

cancer biology↗

bioRxiv2024

Evolution of dosage-sensitive genes by tissue-restricted expression changes

Dosage-sensitive genes have characteristic patterns of evolution that include being refractory to small-scale duplication, depleted on human benign copy number variants (CNVs) and enriched on pathogenic CNVs. This intolerance to copy number change is likely due to an expression constraint that exists in one or more tissues. While genomic copy number changes alter the encompassed genes expression across all tissues, expression quantitative trait loci (eQTLs) -genomic regions harbouring sequence variants that influence the expression level of one or more genes- can act in a tissue-specific manner. In this work we examine expression variation of presumed dosage-sensitive and non-dosage-sensitive genes to discover how the locus duplicability constraints translate into gene expression constraints. Here we test the hypothesis that expression changes due to the presence of eQTLs acting in unconstrained tissues will not be deleterious and thus allow dosage-sensitive genes to vary expression while obeying constraints in other tissues. Using eQTLs across 48 human tissues from The Genotype-Tissue Expression (GTEx) project, we find that dosage-sensitive genes are enriched for being affected by eQTLs and that the eQTLs affecting dosage-sensitive genes are biased towards having narrow tissue-specificity with these genes having fewer eQTL-affected tissues than non-dosage-sensitive genes. Additionally, we find that dosage-sensitive genes are depleted for being affected by broad tissue breadth eQTLs, likely due to the increased chance of these eQTLs conflicting with expression constraints and being removed by purifying selection. These patterns suggest that dosage-sensitivity shapes the evolution of these genes by precluding copy number evolution and restricting their evolutionary trajectories to changes in expression regulation compatible with their functional constraints. Thus deeper interpretation of the patterns of constraints can be informative of the temporal or spatial location of the gene dosage sensitivity and contribute to our understanding of functional genomics. Author summaryGene duplication is an important and powerful evolutionary force that is responsible for the expansion of the coding capacity of genomes ultimately resulting in great genetic novelty. However, the opportunity for this evolutionary change can be limited by dosage constraints on some genes, meaning they are not normally duplicable, except in a balanced, whole genome event. This results in important, biologically relevant, differences between genes that are retained from whole genome duplication events versus those retained from small scale duplications, especially in terms of dosage sensitivity. We explored how the different dosage sensitivity in these sets of genes relates to quantitative expression variation present in populations. We found that while dosage-sensitive genes are more likely to have their expression levels influenced by genetic variation, these changes are often specific a small number of tissues. In contrast, genes that are less sensitive to dosage changes show greater variation in expression levels across multiple tissues. Our findings suggest that dosage-sensitive genes evolve through fine-tuned adjustments in their expression levels in specific tissues, thus bypassing constraints operating on other tissues. This understanding sheds light on how dosage-sensitive genes evolve and could have implications for understanding human diseases caused by these genes.

evolutionary biology↗

bioRxiv2024

A punctuated burst of massive genomic rearrangements by chromosome shattering and the origin of non-marine annelids

The genomic basis of cladogenesis and adaptive evolutionary change has intrigued biologists for decades. Here, we show that the tectonics of genome evolution in clitellates, a clade composed of most freshwater and all terrestrial species of the phylum Annelida, is characterised by extensive genome-wide scrambling that resulted in a massive loss of macrosynteny between marine annelids and clitellates. These massive rearrangements included the formation of putative neocentromeres with newly acquired transposable elements and preceded a further period of genome-wide reshaping events, potentially triggered by the loss of genes involved in genome stability and homeostasis of cell division. Notably, while these rearrangements broke short-range interactions observed between Hox genes in marine annelids, they were reformed as long-range interactions in clitellates. Our findings reveal extensive genomic reshaping in clitellates at both the linear (2D) and three-dimensional (3D) levels, suggesting that, unlike in other animal lineages where synteny conservation constrains structural evolution, clitellates exhibit a remarkable tolerance for chromosomal rearrangements. Our study thus suggests that the genomic landscape of Clitellata resulted from a rare burst of genomic changes that ended a long period of stability that persists across large phylogenetic distances.

evolutionary biology↗

bioRxiv2023

Synthetic autotetraploid Caenorhabditis elegans resist severe cold stress by escaping cold induced death at the gravid adult stage.

Whole genome duplication (WGD) is a well-studied yet enigmatic phenomenon. While it has long been recognised as contributing numerous genes to many eukaryotic lineages and often implicated in evolutionary radiations, how these lineages overcome the known burdens of polyploidy is poorly understood. Circumstantial evidence of many WGD events coinciding with periods of otherwise mass extinction is consistent with the hypothesis that polyploidy is conditionally advantageous under stress conditions. While support for this comes from both theoretical work and field studies, direct evidence is lacking, especially in animals. Here we compare diploid and neo-tetraploid Caenorhabditis elegans and show that tetraploid animals exhibit increased resilience under specific stress conditions related to temperature changes. Most notably, under severe cold stress gravid neo-tetraploids massively escape cold-induced death, and generate more progeny, of similar quality, than diploid animals. This is the first demonstration of the effects of polyploidy on stress resistance and physiology in animals.

cell biology↗

bioRxiv2022

Extensive lineage-specific rediploidisation masks shared whole genome duplication in the sturgeon-paddlefish ancestor

Whole genome duplication (WGD) is a dramatic evolutionary event generating many new genes and which may play a role in survival through mass extinctions. Paddlefish and sturgeon are sister lineages that both show genomic evidence for ancient WGD. Until now this has been interpreted as two independent WGD events due to a preponderance of duplicate genes with independent histories. Here we show that although there is indeed a plurality of apparently independent gene duplications, these derive from a shared genome duplication event occurring close to the Permian-Triassic mass extinction period, followed by a prolonged process of reversion to stable diploid inheritance (rediploidisation). We show that the sharing of this WGD is masked by the fact that paddlefish and sturgeon lineage divergence occurred before rediploidisation had proceeded even half-way. Thus, for most genes the resolution to diploidy was lineage-specific. Because genes are only truly duplicated once diploid inheritance is established, the paddlefish and sturgeon genomes are a mosaic of shared and non-shared gene duplications resulting from a shared genome duplication event. This is the first time that lineage-specific resolution of genes from a common WGD event has been shown to affect such a large proportion of the genome.

evolutionary biology↗

bioRxiv2021

De novo birth of functional, human-specific microproteins

We now have a growing understanding that functional short proteins can be translated out of small Open Reading Frames (sORF). Such "microproteins" can perform crucial biological tasks and can have considerable phenotypic consequences. However, their size makes them less amenable to genomic analysis, and their evolutionary origins and conservation are poorly understood. Given their short length it is plausible that some of these functional microproteins have recently originated entirely de novo from non-coding sequence. Here we test the possibility that de novo gene birth can produce microproteins that are functional "out-of-the-box". We reconstructed the evolutionary origins of human microproteins previously found to have measurable, statistically significant fitness effects. By tracing the appearance of each ORF and its transcriptional activation, we were able to show that, indeed, novel small proteins with significant phenotypic effects have emerged de novo throughout animal evolution, including many after the human-chimpanzee split. We show that traditional methods for assessing the coding potential of such sequences often fall short, due to the high variability present in the alignments and the absence of telltale evolutionary signatures that are not yet measurable. Thus we provide evidence that the functional potential intrinsic to sORFs can be rapidly, and frequently realised through de novo gene birth.

evolutionary biology↗

bioRxiv2019

Synteny-based analyses indicate that sequence divergence is not the dominant source of orphan genes

The origin of "orphan" genes, species-specific sequences that lack detectable homologues, has remained mysterious since the dawn of the genomic era. There are two dominant explanations for orphan genes: complete sequence divergence from ancestral genes, such that homologues are not readily detectable; and de novo emergence from ancestral non-genic sequences, such that homologues genuinely do not exist. The relative contribution of the two processes remains unknown. Here, we harness the special circumstance of conserved synteny to estimate the contribution of complete divergence to the pool of orphan genes. By separately comparing yeast, fly and human genes to related taxa using conservative criteria, we find that complete divergence accounts, on average, for at most a third of eukaryotic orphan and taxonomically restricted genes. We observe that complete divergence occurs at a stable rate within a phylum but at different rates between phyla, and is frequently associated with gene shortening akin to pseudogenization. Two cancer-related human genes, DEC1 and DIRC1, have likely originated via this route in a primate ancestor.

evolutionary biology↗

bioRxiv2019

De novo emergence of adaptive membrane proteins from thymine-rich intergenic sequences

Recent evidence demonstrates that novel protein-coding genes can arise de novo from intergenic loci. This evolutionary innovation is thought to be facilitated by the pervasive translation of intergenic transcripts, which exposes a reservoir of variable polypeptides to natural selection. Do intergenic translation events yield polypeptides with useful biochemical capacities? The answer to this question remains controversial. Here, we systematically characterized how de novo emerging coding sequences impact fitness. In budding yeast, overexpression of these sequences was enriched in beneficial effects, while their disruption was generally inconsequential. We found that beneficial emerging sequences have a strong tendency to encode putative transmembrane proteins, which appears to stem from a cryptic propensity for transmembrane signals throughout thymine-rich intergenic regions of the genome. These findings suggest that novel genes with useful biochemical capacities, such as transmembrane domains, tend to evolve de novo within intergenic loci that already harbored a blueprint for these capacities.

evolutionary biology↗