Showing papers in "Nature Reviews Genetics in 2020"

Engineering adeno-associated virus vectors for gene therapy.

Abstract: Adeno-associated virus (AAV) vector-mediated gene delivery was recently approved for the treatment of inherited blindness and spinal muscular atrophy, and long-term therapeutic effects have been achieved for other rare diseases, including haemophilia and Duchenne muscular dystrophy. However, current research indicates that the genetic modification of AAV vectors may further facilitate the success of AAV gene therapy. Vector engineering can increase AAV transduction efficiency (by optimizing the transgene cassette), vector tropism (using capsid engineering) and the ability of the capsid and transgene to avoid the host immune response (by genetically modifying these components), as well as optimize the large-scale production of AAV. Adeno-associated virus (AAV) vector-mediated gene delivery has had long-term therapeutic effects for several diseases, including haemophilia and Duchenne muscular dystrophy. Genetically modifying AAV vectors to increase their transduction efficiency, vector tropism and ability to avoid the host immune response may further increase the success of AAV gene therapy.

Long-read human genome sequencing and its applications.

Abstract: Over the past decade, long-read, single-molecule DNA sequencing technologies have emerged as powerful players in genomics. With the ability to generate reads tens to thousands of kilobases in length with an accuracy approaching that of short-read sequencing technologies, these platforms have proven their ability to resolve some of the most challenging regions of the human genome, detect previously inaccessible structural variants and generate some of the first telomere-to-telomere assemblies of whole chromosomes. Long-read sequencing technologies will soon permit the routine assembly of diploid genomes, which will revolutionize genomics by revealing the full spectrum of human genetic variation, resolving some of the missing heritability and leading to the discovery of novel mechanisms of disease.

Determinants of enhancer and promoter activities of regulatory elements.

Abstract: The proper activities of enhancers and gene promoters are essential for coordinated transcription within a cell. Although diverse methodologies have been developed to identify enhancers and promoters, most have tacitly assumed that these elements are distinct. However, studies have unexpectedly shown that regulatory elements may have both enhancer and promoter functions. Here we review these results, focusing on the factors that determine the promoter and/or enhancer activity of regulatory elements. We discuss emerging models that define regulatory elements by accessible DNA and their non-mutually-exclusive abilities to drive transcription initiation (promoter activity) and/or to enhance transcription at other such regions (enhancer activity).

Regulation of gene expression by cis-acting long non-coding RNAs.

Abstract: Long non-coding RNAs (lncRNAs) are diverse transcription products emanating from thousands of loci in mammalian genomes. Cis-acting lncRNAs, which constitute a substantial fraction of lncRNAs with an attributed function, regulate gene expression in a manner dependent on the location of their own sites of transcription, at varying distances from their targets in the linear genome. Through various mechanisms, cis-acting lncRNAs have been demonstrated to activate, repress or otherwise modulate the expression of target genes. We discuss the activities that have been ascribed to cis-acting lncRNAs, the evidence and hypotheses regarding their modes of action, and the methodological advances that enable their identification and characterization. The emerging principles highlight lncRNAs as transcriptional units highly adept at contributing to gene regulatory networks and to the generation of fine-tuned spatial and temporal gene expression programmes.

Context is everything: aneuploidy in cancer

Abstract: Cancer is driven by multiple types of genetic alterations, which range in size from point mutations to whole-chromosome gains and losses, known as aneuploidy. Chromosome instability, the process that gives rise to aneuploidy, can promote tumorigenesis by increasing genetic heterogeneity and promoting tumour evolution. However, much less is known about how aneuploidy itself contributes to tumour formation and progression. Unlike some pan-cancer oncogenes and tumour suppressor genes that drive transformation in virtually all cell types and cellular contexts, aneuploidy is not a universal promoter of tumorigenesis. Instead, recent studies suggest that aneuploidy is a context-dependent, cancer-type-specific oncogenic event that may have clinical relevance as a prognostic marker and as a potential therapeutic target. Aneuploidy contributes to tumorigenesis, but the underlying processes are not well understood. This Review explains the context dependency of aneuploidy in cancer and discusses its clinical potential as a prognostic marker and a therapeutic target.

mRNAs, proteins and the emerging principles of gene expression control.

Abstract: Gene expression involves transcription, translation and the turnover of mRNAs and proteins. The degree to which protein abundances scale with mRNA levels and the implications in cases where this dependency breaks down remain an intensely debated topic. Here we review recent mRNA-protein correlation studies in the light of the quantitative parameters of the gene expression pathway, contextual confounders and buffering mechanisms. Although protein and mRNA levels typically show reasonable correlation, we describe how transcriptomics and proteomics provide useful non-redundant readouts. Integrating both types of data can reveal exciting biology and is an essential step in refining our understanding of the principles of gene expression control.

Cell-free gene expression: an expanded repertoire of applications.

Abstract: Cell-free biology is the activation of biological processes without the use of intact living cells. It has been used for more than 50 years across the life sciences as a foundational research tool, but a recent technical renaissance has facilitated high-yielding (grams of protein per litre), cell-free gene expression systems from model bacteria, the development of cell-free platforms from non-model organisms and multiplexed strategies for rapidly assessing biological design. These advances provide exciting opportunities to profoundly transform synthetic biology by enabling new approaches to the model-driven design of synthetic gene networks, the fast and portable sensing of compounds, on-demand biomanufacturing, building cells from the bottom up, and next-generation educational kits. Cell-free gene expression systems have long been used to address fundamental research questions. Now, owing to technological advances, these systems are finding wider applications in the field of synthetic biology, including in biosensing, biomanufacturing, education and the design of gene networks.

Methods for mapping 3D chromosome architecture.

Abstract: Determining how chromosomes are positioned and folded within the nucleus is critical to understanding the role of chromatin topology in gene regulation. Several methods are available for studying chromosome architecture, each with different strengths and limitations. Established imaging approaches and proximity ligation-based chromosome conformation capture (3C) techniques (such as DNA-FISH and Hi-C, respectively) have revealed the existence of chromosome territories, functional nuclear landmarks (such as splicing speckles and the nuclear lamina) and topologically associating domains. Improvements to these methods and the recent development of ligation-free approaches, including GAM, SPRITE and ChIA-Drop, are now helping to uncover new aspects of 3D genome topology that confirm the nucleus to be a complex, highly organized organelle.

Structural variation in the sequencing era.

Abstract: Identifying structural variation (SV) is essential for genome interpretation but has been historically difficult due to limitations inherent to available genome technologies. Detection methods that use ensemble algorithms and emerging sequencing technologies have enabled the discovery of thousands of SVs, uncovering information about their ubiquity, relationship to disease and possible effects on biological mechanisms. Given the variability in SV type and size, along with unique detection biases of emerging genomic platforms, multiplatform discovery is necessary to resolve the full spectrum of variation. Here, we review modern approaches for investigating SVs and proffer that, moving forwards, studies integrating biological information with detection will be necessary to comprehensively understand the impact of SV in the human genome. To map the full extent of structural variation in the human genome, detection methods are needed that improve on short-read approaches. This Review discusses how ensemble algorithms and emerging sequencing technologies are helping to resolve the full spectrum of structural variations.

Lineage tracing meets single-cell omics: opportunities and challenges.

Abstract: A fundamental goal of developmental and stem cell biology is to map the developmental history (ontogeny) of differentiated cell types. Recent advances in high-throughput single-cell sequencing technologies have enabled the construction of comprehensive transcriptional atlases of adult tissues and of developing embryos from measurements of up to millions of individual cells. Parallel advances in sequencing-based lineage-tracing methods now facilitate the mapping of clonal relationships onto these landscapes and enable detailed comparisons between molecular and mitotic histories. Here we review recent progress and challenges, as well as the opportunities that emerge when these two complementary representations of cellular history are synthesized into integrated models of cell differentiation.

Harnessing genomics to fast-track genetic improvement in aquaculture.

Abstract: Aquaculture is the fastest-growing farmed food sector and will soon become the primary source of fish and shellfish for human diets. In contrast to crop and livestock production, aquaculture production is derived from numerous, exceptionally diverse species that are typically in the early stages of domestication. Genetic improvement of production traits via well-designed, managed breeding programmes has great potential to help meet the rising seafood demand driven by human population growth. Supported by continuous advances in sequencing and bioinformatics, genomics is increasingly being applied across the broad range of aquaculture species and at all stages of the domestication process to optimize selective breeding. In the future, combining genomic selection with biotechnological innovations, such as genome editing and surrogate broodstock technologies, may further expedite genetic improvement in aquaculture.

Polygenic adaptation: a unifying framework to understand positive selection

Abstract: Most adaption processes have a polygenic genetic basis, but even with the recent explosive growth of genomic data we are still lacking a unified framework describing the dynamics of selected alleles Building on recent theoretical and empirical work we introduce the concept of adaptive architecture, which extends the genetic architecture of an adaptive trait by factors influencing its adaptive potential and population genetic principles Because adaptation can be typically achieved by many different combinations of adaptive alleles (redundancy), we describe how two characteristics — heterogeneity among loci and non-parallelism between replicated populations — are hallmarks for the characterization of polygenic adaptation in evolving populations We discuss how this unified framework can be applied to natural and experimental populations Increased capacities for sequencing and genotyping are enabling a more comprehensive understanding of the genetics of adaptation for diverse species In this Perspective, Barghi, Hermisson and Schlotterer describe how polygenic adaptation can be studied using a framework of ‘adaptive architecture’ that unifies principles from the traditionally disparate fields of quantitative genetics and molecular population genetics

Towards a comprehensive catalogue of validated and target-linked human enhancers

Abstract: The human gene catalogue is essentially complete, but we lack an equivalently vetted inventory of bona fide human enhancers. Hundreds of thousands of candidate enhancers have been nominated via biochemical annotations; however, only a handful of these have been validated and confidently linked to their target genes. Here we review emerging technologies for discovering, characterizing and validating human enhancers at scale. We furthermore propose a new framework for operationally defining enhancers that accommodates the heterogeneous and complementary results that are emerging from reporter assays, biochemical measurements and CRISPR screens. In this Review, Gasperini, Tome and Shendure discuss the evolving definitions of transcriptional enhancers, as well as diverse modern experimental tools to identify them. The authors describe how these diverse mindsets and methods provide differing but complementary insights into enhancers, each with notable strengths and caveats. They discuss how such views and approaches might be combined in a comprehensive catalogue of functional enhancers.

The evolving metabolic landscape of chromatin biology and epigenetics.

Abstract: Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs — which include both nutrient availability as a result of diet and growth factor signalling — are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions. Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.

Phylogenetic tree building in the genomic age.

Abstract: Knowing phylogenetic relationships among species is fundamental for many studies in biology. An accurate phylogenetic tree underpins our understanding of the major transitions in evolution, such as the emergence of new body plans or metabolism, and is key to inferring the origin of new genes, detecting molecular adaptation, understanding morphological character evolution and reconstructing demographic changes in recently diverged species. Although data are ever more plentiful and powerful analysis methods are available, there remain many challenges to reliable tree building. Here, we discuss the major steps of phylogenetic analysis, including identification of orthologous genes or proteins, multiple sequence alignment, and choice of substitution models and inference methodologies. Understanding the different sources of errors and the strategies to mitigate them is essential for assembling an accurate tree of life.

A decade of advances in transposon-insertion sequencing

Abstract: It has been 10 years since the introduction of modern transposon-insertion sequencing (TIS) methods, which combine genome-wide transposon mutagenesis with high-throughput sequencing to estimate the fitness contribution or essentiality of each genetic component in a bacterial genome. Four TIS variations were published in 2009: transposon sequencing (Tn-Seq), transposon-directed insertion site sequencing (TraDIS), insertion sequencing (INSeq) and high-throughput insertion tracking by deep sequencing (HITS). TIS has since become an important tool for molecular microbiologists, being one of the few genome-wide techniques that directly links phenotype to genotype and ultimately can assign gene function. In this Review, we discuss the recent applications of TIS to answer overarching biological questions. We explore emerging and multidisciplinary methods that build on TIS, with an eye towards future applications.

The genetics of human ageing

Abstract: The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans. Bringing together different strands of genetic research, including results from recent large-scale genome-wide association studies relevant to human ageing, the authors highlight how genetics can further our understanding of the underlying mechanisms of ageing.

Measuring and interpreting transposable element expression.

Abstract: Transposable elements (TEs) are insertional mutagens that contribute greatly to the plasticity of eukaryotic genomes, influencing the evolution and adaptation of species as well as physiology or disease in individuals Measuring TE expression helps to understand not only when and where TE mobilization can occur but also how this process alters gene expression, chromatin accessibility or cellular signalling pathways Although genome-wide gene expression assays such as RNA sequencing include transposon-derived transcripts, most computational analytical tools discard or misinterpret TE-derived reads Emerging approaches are improving the identification of expressed TE loci and helping to discriminate TE transcripts that permit TE mobilization from chimeric gene–TE transcripts or pervasive transcription Here we review the main challenges associated with the detection of TE expression, including mappability, insertional and internal sequence polymorphisms, and the diversity of the TE transcriptional landscape, as well as the different experimental and computational strategies to solve them Computational tools to analyse RNA sequencing data often disregard or even misinterpret reads derived from transposable elements This Review highlights the main challenges associated with the detection of transposable element expression, including mappability, sequence polymorphisms and transcript diversity, and discusses the experimental and computational strategies to overcome them

Pan-genomics in the human genome era

Abstract: Since the early days of the genome era, the scientific community has relied on a single ‘reference’ genome for each species, which is used as the basis for a wide range of genetic analyses, including studies of variation within and across species. As sequencing costs have dropped, thousands of new genomes have been sequenced, and scientists have come to realize that a single reference genome is inadequate for many purposes. By sampling a diverse set of individuals, one can begin to assemble a pan-genome: a collection of all the DNA sequences that occur in a species. Here we review efforts to create pan-genomes for a range of species, from bacteria to humans, and we further consider the computational methods that have been proposed in order to capture, interpret and compare pan-genome data. As scientists continue to survey and catalogue the genomic variation across human populations and begin to assemble a human pan-genome, these efforts will increase our power to connect variation to human diversity, disease and beyond. Although single reference genomes are valuable resources, they do not capture genetic diversity among individuals. Sherman and Salzberg discuss the concept of ‘pan-genomes’, which are reference genomes that encompass the genetic variation within a given species. Focusing particularly on large eukaryotic pan-genomes, they describe the latest progress, the varied methodological approaches and computational challenges, as well as applications in fields such as agriculture and human disease.

Evolutionary entanglement of mobile genetic elements and host defence systems: guns for hire.

Abstract: All cellular life forms are afflicted by diverse genetic parasites, including viruses and other types of mobile genetic elements (MGEs), and have evolved multiple, diverse defence systems that protect them from MGE assault via different mechanisms. Here, we provide our perspectives on how recent evidence points to tight evolutionary connections between MGEs and defence systems that reach far beyond the proverbial arms race. Defence systems incur a fitness cost for the hosts; therefore, at least in prokaryotes, horizontal mobility of defence systems, mediated primarily by MGEs, is essential for their persistence. Moreover, defence systems themselves possess certain features of selfish elements. Common components of MGEs, such as site-specific nucleases, are ‘guns for hire’ that can also function as parts of defence mechanisms and are often shuttled between MGEs and defence systems. Thus, evolutionary and molecular factors converge to mould the multifaceted, inextricable connection between MGEs and anti-MGE defence systems. Incessant encounters of all cellular life forms with mobile genetic elements (MGEs) have driven the evolution of diverse defence mechanisms, including CRISPR–Cas and restriction–modification systems. In this Perspective, Koonin, Makarova, Wolf and Krupovic describe the surprisingly intricate interplay between MGEs and host defence systems. Not only do defence systems commonly show high horizontal mobility but many molecular components are ‘guns for hire’ that have been co-opted by defence systems from MGEs and vice versa.

Chromosome organization in bacteria: mechanistic insights into genome structure and function

Abstract: Bacterial chromosomes are folded to compact DNA and facilitate cellular processes. Studying model bacteria has revealed aspects of chromosome folding that are applicable to many species. Primarily controlled by nucleoid-associated proteins, chromosome folding is hierarchical, from large-scale macrodomains to smaller-scale structures that influence DNA transactions, including replication and transcription. Here we review the environmentally regulated, architectural and regulatory roles of nucleoid-associated proteins and the implications for bacterial cell biology. We also highlight similarities and differences in the chromosome folding mechanisms of bacteria and eukaryotes. Advances in sequencing- and imaging-based techniques for chromosome structure analysis have led to a mature understanding of bacterial chromosome structure and dynamics. In this Review, Dame, Rashid and Grainger discuss the hierarchical nature of bacterial chromosome structure and how it is influenced by diverse types of nucleoid-associated proteins. Furthermore, they describe roles for nucleoid-associated proteins and chromosome structure, including in gene expression, chromosome segregation and cell cycle regulation.

Overcoming challenges and dogmas to understand the functions of pseudogenes.

Abstract: Pseudogenes are defined as regions of the genome that contain defective copies of genes. They exist across almost all forms of life, and in mammalian genomes are annotated in similar numbers to recognized protein-coding genes. Although often presumed to lack function, growing numbers of pseudogenes are being found to play important biological roles. In consideration of their evolutionary origins and inherent limitations in genome annotation practices, we posit that pseudogenes have been classified on a scientifically unsubstantiated basis. We reflect that a broad misunderstanding of pseudogenes, perpetuated in part by the pejorative inference of the 'pseudogene' label, has led to their frequent dismissal from functional assessment and exclusion from genomic analyses. With the advent of technologies that simplify the study of pseudogenes, we propose that an objective reassessment of these genomic elements will reveal valuable insights into genome function and evolution.

The road ahead in genetics and genomics.

Abstract: In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.

Rights, interests and expectations: Indigenous perspectives on unrestricted access to genomic data

Abstract: Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

Emerging mechanisms of cell competition.

Abstract: The growth and survival of cells within tissues can be affected by 'cell competition' between different cell clones. This phenomenon was initially recognized between wild-type cells and cells with mutations in ribosomal protein (Rp) genes in Drosophila melanogaster. However, competition also affects D. melanogaster cells with mutations in epithelial polarity genes, and wild-type cells exposed to 'super-competitor' cells with mutation in the Salvador-Warts-Hippo tumour suppressor pathway or expressing elevated levels of Myc. More recently, cell competition and super-competition were recognized in mammalian development, organ homeostasis and cancer. Genetic and cell biological studies have revealed that mechanisms underlying cell competition include the molecular recognition of 'different' cells, signalling imbalances between distinct cell populations and the mechanical consequences of differential growth rates; these mechanisms may also involve innate immune proteins, p53 and changes in translation.

Animal domestication in the era of ancient genomics

Abstract: The domestication of animals led to a major shift in human subsistence patterns, from a hunter-gatherer to a sedentary agricultural lifestyle, which ultimately resulted in the development of complex societies. Over the past 15,000 years, the phenotype and genotype of multiple animal species, such as dogs, pigs, sheep, goats, cattle and horses, have been substantially altered during their adaptation to the human niche. Recent methodological innovations, such as improved ancient DNA extraction methods and next-generation sequencing, have enabled the sequencing of whole ancient genomes. These genomes have helped reconstruct the process by which animals entered into domestic relationships with humans and were subjected to novel selection pressures. Here, we discuss and update key concepts in animal domestication in light of recent contributions from ancient genomics.

Mechanisms of tissue and cell-type specificity in heritable traits and diseases

Abstract: Hundreds of heritable traits and diseases that are caused by germline aberrations in ubiquitously expressed genes manifest in a remarkably limited number of cell types and tissues across the body. Unravelling mechanisms that govern their tissue-specific manifestations is critical for our understanding of disease aetiologies and may direct efforts to develop treatments. Owing to recent advances in high-throughput technologies and open resources, data and tools are now available to approach this enigmatic phenomenon at large scales, both computationally and experimentally. Here, we discuss the large prevalence of tissue-selective traits and diseases, describe common molecular mechanisms underlying their tissue-selective manifestation and present computational strategies and publicly available resources for elucidating the molecular basis of their genotype–phenotype relationships. The pathology of heritable human traits and diseases often affects a narrow range of tissues, even when causal genes are expressed widely across the body. In this Review, Hekselman and Yeger-Lotem discuss the latest understanding of tissue specificity in human traits and disease, including the diverse underlying molecular mechanisms, experimental and bioinformatics resources to leverage omics data, and implications for understanding disease aetiology.

Haematopoietic stem cell self-renewal in vivo and ex vivo.

Abstract: The self-renewal capacity of multipotent haematopoietic stem cells (HSCs) supports blood system homeostasis throughout life and underlies the curative capacity of clinical HSC transplantation therapies. However, despite extensive characterization of the HSC state in the adult bone marrow and embryonic fetal liver, the mechanism of HSC self-renewal has remained elusive. This Review presents our current understanding of HSC self-renewal in vivo and ex vivo, and discusses important advances in ex vivo HSC expansion that are providing new biological insights and offering new therapeutic opportunities. Wilkinson and colleagues discuss haematopoietic stem cell (HSC) self-renewal in mice and humans. Experimental techniques for assaying HSC self-renewal are addressed, along with biological mechanisms regulating HSC self-renewal in vivo and ex vivo, and the therapeutic implications of this understanding.

Host-parasite co-evolution and its genomic signature.

Abstract: Studies in diverse biological systems have indicated that host-parasite co-evolution is responsible for the extraordinary genetic diversity seen in some genomic regions, such as major histocompatibility (MHC) genes in jawed vertebrates and resistance genes in plants. This diversity is believed to evolve under balancing selection on hosts by parasites. However, the mechanisms that link the genomic signatures in these regions to the underlying co-evolutionary process are only slowly emerging. We still lack a clear picture of the co-evolutionary concepts and of the genetic basis of the co-evolving phenotypic traits in the interacting antagonists. Emerging genomic tools that provide new options for identifying underlying genes will contribute to a fuller understanding of the co-evolutionary process.

Gene regulatory programmes of tissue regeneration.

Abstract: Regeneration is the process by which organisms replace lost or damaged tissue, and regenerative capacity can vary greatly among species, tissues and life stages. Tissue regeneration shares certain hallmarks of embryonic development, in that lineage-specific factors can be repurposed upon injury to initiate morphogenesis; however, many differences exist between regeneration and embryogenesis. Recent studies of regenerating tissues in laboratory model organisms - such as acoel worms, frogs, fish and mice - have revealed that chromatin structure, dedicated enhancers and transcriptional networks are regulated in a context-specific manner to control key gene expression programmes. A deeper mechanistic understanding of the gene regulatory networks of regeneration pathways might ultimately enable their targeted reactivation as a means to treat human injuries and degenerative diseases. In this Review, we consider the regeneration of body parts across a range of tissues and species to explore common themes and potentially exploitable elements.