Relaxed Selection Limits Lifespan by Increasing Mutation Load

Cui, Rongfeng; Medeiros, Tania; Willemsen, David; Iasi, Leonardo Nicola Martin; Collier, Glen E.; Graef, Martin; Reichard, Martin; Valenzano, Dario Riccardo

doi:10.1016/j.cell.2020.02.038

Cited by 30 publications

(48 citation statements)

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“…The killifish is a newly co-opted vertebrate model for aging studies, because of its exceptionally short lifespan [25,26]. Recent studies are beginning to explore causal factors of its accelerated aging, including in the brain [27][28][29][30][31]. The fast aging in N. furzeri is hypothesized by some authors to be a trade-off to rapid larval and juvenile growth, but this lead remains mechanistically unexplored [32].…”

Section: Discussionmentioning

confidence: 99%

Mosaic Heterochrony in Neural Progenitors Sustains Accelerated Brain Growth and Neurogenesis in the Juvenile Killifish N. furzeri

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Mosaic Heterochrony in Neural Progenitors Sustains Accelerated Brain Growth and Neurogenesis in the Juvenile Killifish N. furzeri

et al. 2020

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“…Finally, at least some of the difference between locus structures in different species is likely to be attributable to differences in assembly quality; for example, the characterisation of medaka constant regions presented here contains many fewer unusual or incomplete constant regions than that presented in the published medaka IGH locus 12 , primarily due to the increased quality of the more recent medaka genome assemblies. Issues with assembly quality could also account for the apparent complexity of the Nothobranchius orthonotus locus, as the genome of this species was assembled from a wild-caught individual with a high degree of heterozygosity 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Cladograms of teleost species (Fig. 1 and 5a) were constructed using phylogenetic information from Cui et al 40 (for African killifishes) and Hughes et al 19 (for other species) and visualised using the ggtree R package 64 .…”

Section: Methodsmentioning

confidence: 99%

Extreme genomic volatility characterises the evolution of the immunoglobulin heavy chain locus in teleost fishes

Bradshaw

Valenzano

2019

Preprint

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8The evolution of the adaptive immune system has provided vertebrates with a uniquely sophisticated immune 9 toolkit, enabling them to mount precise immune responses against a staggeringly diverse range of antigens. 10 Like other vertebrates, teleost fishes possess a complex and functional adaptive immune system; however, our 11 knowledge of the complex antigen-receptor genes underlying its functionality has been restricted to a small 12 number of experimental and agricultural species, preventing a systematic investigation of how these crucial 13 gene loci evolve. Here, we analyse the genomic structure of the immunoglobulin heavy chain (IGH) gene 14 loci in the cyprinodontiforms, a diverse and important group of teleosts present in many different habitats 15 across the world. We reconstruct the complete IGH loci of the turquoise killifish (Nothobranchius furzeri) 16 and the southern platyfish (Xiphophorus maculatus) and analyse their in vivo gene expression, revealing the 17 presence of species-specific splice isoforms of transmembrane IGHM. We further characterise the IGH constant 18 regions of ten additional cyprinodontiform species, including guppy, amazon molly, mummichog and mangrove 19 killifish. Phylogenetic analysis of these constant regions reveals multiple independent rounds of duplication and 20 deletion of the teleost-specific antibody class IGHZ in the cyprinodontiform lineage, demonstrating the extreme 21 volatility of IGH evolution. Focusing on the cyprinodontiforms as a model taxon for comparative evolutionary 22 immunology, this work provides novel genomic resources for studying adaptive immunity and sheds light on 23 the evolutionary history of the adaptive immune system. 24 29 sequence 1-3 . By combining this enormous diversity in antigen specificities with antigen-dependent clonal 30 expansion and long-term immune memory 4,5 , vertebrates can progressively improve their protection against 31 recurrent immune challenges while also coping effectively with rapidly-evolving pathogenic threats 6 , dramati-32 cally improving their ability to survive and thrive in a complex immune environment.The immunoglobulin heavy chain (IGH) is one of the most important antigen-receptor genes in the adaptive 34 immune system, determining both the effector function and the majority of the antigen-specificity of the anti-35 bodies produced by each B-cell 7,8 . The native structure of the IGH gene locus has a profound effect on adaptive 36 immunity in a species, determining the range of gene segment choices available for the VDJ recombination pro-37 cess giving rise to novel antigen-receptor sequences 2 , the possible antibody classes (or isotypes) available, and 38 the relationship between VDJ recombination and isotype choice 9 . Understanding the structure of this locus is 39 therefore essential for understanding adaptive-immune function in any given vertebrate species, while compar-40 ing loci between species can provide important insight into the adaptive immune system's complex evolutionary 41 Atherinomor...

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“…Moreover, population sampling biases and recent population bottleneck effects can lead to misinterpretation of variant frequencies when determining pathogenicity (Keinan and Clark 2012;Zuk et al 2014;Chheda et al 2017;Landry et al 2018). A lack of selection against variants that might act in a deleterious manner at the post-reproductive stage of life also makes likely the possibility that some mtDNA changes will contribute to age-related phenotypes while avoiding clear association with mitochondrial disease (Medawar 1952;Williams 1957;Maklakov et al 2015;Cui et al 2019).…”

Section: Introductionmentioning

confidence: 99%

A novel phylogenetic analysis and machine learning predict pathogenicity of human mtDNA variants

Dunn

Akpinar

Carlson³

et al. 2020

Preprint

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Linking mitochondrial DNA (mtDNA) mutations to patient outcomes remains a formidable challenge. The multicopy nature and potential heteroplasmy of the mitochondrial genome, differential distribution of mutant mtDNAs among various tissues, genetic interactions among alleles, and environmental effects currently hamper clinical efforts to diagnose mitochondrial disease. Multiple sequence alignments are often deployed to estimate the potential significance of mitochondrial variants. However, factors including sample set bias, alignment errors, and sequencing errors currently limit the utility of multiple sequence alignments in pathogenicity prediction. Here, we describe an approach to assessment of site-specific conservation and variant acceptability that is reliant upon ancestral phylogenetic predictions and minimizes current alignment limitations. Using the output of our approach, we deploy machine learning in order to predict the pathogenicity of thousands of human mtDNA variants not yet linked to disease. Our work demonstrates that a substantial portion of mtDNA variants not yet characterized as harmful are, in fact, likely to be deleterious. Our findings will be of direct relevance to those at risk of mitochondria-associated illness, but the general applications of our methodology also extend beyond the context of mitochondrial disorders.

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Relaxed Selection Limits Lifespan by Increasing Mutation Load

Cited by 30 publications

References 0 publications

Mosaic Heterochrony in Neural Progenitors Sustains Accelerated Brain Growth and Neurogenesis in the Juvenile Killifish N. furzeri

Mosaic Heterochrony in Neural Progenitors Sustains Accelerated Brain Growth and Neurogenesis in the Juvenile Killifish N. furzeri

Extreme genomic volatility characterises the evolution of the immunoglobulin heavy chain locus in teleost fishes

A novel phylogenetic analysis and machine learning predict pathogenicity of human mtDNA variants

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