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Showing papers in "Annual Review of Genetics in 2004"


Journal ArticleDOI
TL;DR: The precautions and criteria necessary to ascertain to the greatest extent possible that results represent authentic ancient DNA sequences are discussed, which highlight some significant results and areas of promising future research.
Abstract: ▪ Abstract About 20 years ago, DNA sequences were separately described from the quagga (a type of zebra) and an ancient Egyptian individual. What made these DNA sequences exceptional was that they were derived from 140- and 2400-year-old specimens. However, ancient DNA research, defined broadly as the retrieval of DNA sequences from museum specimens, archaeological finds, fossil remains, and other unusual sources of DNA, only really became feasible with the advent of techniques for the enzymatic amplification of specific DNA sequences. Today, reports of analyses of specimens hundreds, thousands, and even millions of years old are almost commonplace. But can all these results be believed? In this paper, we critically assess the state of ancient DNA research. In particular, we discuss the precautions and criteria necessary to ascertain to the greatest extent possible that results represent authentic ancient DNA sequences. We also highlight some significant results and areas of promising future research.

1,146 citations


Journal ArticleDOI
TL;DR: Current ideas on the protein and DNA components of this transcriptional memory system are reviewed and how they interact dynamically with each other to orchestrate cellular memory for several hundred genes are reviewed.
Abstract: During the development of multicellular organisms, cells become different from one another by changing their genetic program in response to transient stimuli. Long after the stimulus is gone, "cellular memory" mechanisms enable cells to remember their chosen fate over many cell divisions. The Polycomb and Trithorax groups of proteins, respectively, work to maintain repressed or active transcription states of developmentally important genes through many rounds of cell division. Here we review current ideas on the protein and DNA components of this transcriptional memory system and how they interact dynamically with each other to orchestrate cellular memory for several hundred genes.

1,050 citations


Journal ArticleDOI
TL;DR: Progress toward understanding the biology of uncultured Bacteria, Archaea, and viruses through metagenomic analyses is described.
Abstract: ▪ Abstract Uncultured microorganisms comprise the majority of the planet's biological diversity. Microorganisms represent two of the three domains of life and contain vast diversity that is the product of an estimated 3.8 billion years of evolution. In many environments, as many as 99% of the microorganisms cannot be cultured by standard techniques, and the uncultured fraction includes diverse organisms that are only distantly related to the cultured ones. Therefore, culture-independent methods are essential to understand the genetic diversity, population structure, and ecological roles of the majority of microorganisms. Metagenomics, or the culture-independent genomic analysis of an assemblage of microorganisms, has potential to answer fundamental questions in microbial ecology. This review describes progress toward understanding the biology of uncultured Bacteria, Archaea, and viruses through metagenomic analyses.

1,017 citations


Journal ArticleDOI
TL;DR: Plants utilize several families of photoreceptors to fine-tune growth and development over a large range of environmental conditions, and the molecular mechanisms involved include light-regulated subcellular localization of the photoreception, a large reorganization of the transcriptional program, and light- regulated proteolytic degradation of several photoreceptor and signaling components.
Abstract: Plants utilize several families of photoreceptors to fine-tune growth and development over a large range of environmental conditions. The UV-A/blue light sensing phototropins mediate several light responses enabling optimization of photosynthetic yields. The initial event occurring upon photon capture is a conformational change of the photoreceptor that activates its protein kinase activity. The UV-A/blue light sensing cryptochromes and the red/far-red sensing phytochromes coordinately control seedling establishment, entrainment of the circadian clock, and the transition from vegetative to reproductive growth. In addition, the phytochromes control seed germination and shade-avoidance responses. The molecular mechanisms involved include light-regulated subcellular localization of the photoreceptors, a large reorganization of the transcriptional program, and light-regulated proteolytic degradation of several photoreceptors and signaling components.

885 citations


Journal ArticleDOI
TL;DR: Recently studies showing defects in homologous recombination and double-strand break repair in several human cancer-prone syndromes have emphasized the importance of this repair pathway in maintaining genome integrity.
Abstract: ▪ Abstract The process of homologous recombination promotes error-free repair of double-strand breaks and is essential for meiosis. Central to the process of homologous recombination are the RAD52 group genes (RAD50, RAD51, RAD52, RAD54, RDH54/TID1, RAD55, RAD57, RAD59, MRE11, and XRS2), most of which were identified by their requirement for the repair of ionizing radiation-induced DNA damage in Saccharomyces cerevisiae. The Rad52 group proteins are highly conserved among eukaryotes. Recent studies showing defects in homologous recombination and double-strand break repair in several human cancer-prone syndromes have emphasized the importance of this repair pathway in maintaining genome integrity. Herein, we review recent genetic, biochemical, and structural analyses of the genes and proteins involved in recombination.

827 citations


Journal ArticleDOI
TL;DR: Concept and technological advances in gene duplication research from this early research in comparative cytology up to recent research on whole genomes, "transcriptomes," and "interactomes" are document.
Abstract: ▪ Abstract Over 35 years ago, Susumu Ohno stated that gene duplication was the single most important factor in evolution (97). He reiterated this point a few years later in proposing that without duplicated genes the creation of metazoans, vertebrates, and mammals from unicellular organisms would have been impossible. Such big leaps in evolution, he argued, required the creation of new gene loci with previously nonexistent functions (98). Bold statements such as these, combined with his proposal that at least one whole-genome duplication event facilitated the evolution of vertebrates, have made Ohno an icon in the literature on genome evolution. However, discussion on the occurrence and consequences of gene and genome duplication events has a much longer, and often neglected, history. Here we review literature dealing with the occurence and consequences of gene duplication, begining in 1911. We document conceptual and technological advances in gene duplication research from this early research in comparat...

824 citations


Journal ArticleDOI
TL;DR: How traditional genetics, modern forward genetics and in vitro biochemical analyses have combined to produce an intriguing story on the role and actions of a gene family in a living organism is shown.
Abstract: ▪ Abstract The first mouse microphthalmia transcription factor (Mitf ) mutation was discovered over 60 years ago, and since then over 24 spontaneous and induced mutations have been identified at the locus. Mitf encodes a member of the Myc supergene family of basic helix-loop-helix zipper (bHLH-Zip) transcription factors. Like Myc, Mitf regulates gene expression by binding to DNA as a homodimer or as a heterodimer with another related family member, in the case of Mitf the Tfe3, Tfeb, and Tfec proteins. The study of Mitf has provided many insights into the biology of melanocytes and helped to explain how melanocyte-specific gene expression and signaling is regulated. The human homologue of MITF is mutated in patients with the pigmentary and deafness disorder Waardenburg Syndrome Type 2A (WS2A). The mouse Mitf mutations therefore serve as a model for the study of this human disease. Mutations and/or aberrant expression of several MITF family member genes have also been reported in human cancer, including me...

719 citations


Journal ArticleDOI
TL;DR: Repairs of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, and must be sufficiently accurate and efficient to preserve genome stability compatible with long-term cellular viability.
Abstract: ▪ Abstract Living organisms dependent on water and oxygen for their existence face the major challenge of faithfully maintaining their genetic material under a constant attack from spontaneous hydrolysis and active oxygen species and from other intracellular metabolites that can modify DNA bases. Repair of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, and must be sufficiently accurate and efficient to preserve genome stability compatible with long-term cellular viability. The size of the mammalian genome has necessitated an increased complexity of repair and diversification of key enzymes, as revealed by gene knock-out mouse models. The genetic instability characteristic of cancer cells may be due, in part, to mutations in genes whose products normally function to ensure DNA integrity.

699 citations


Journal ArticleDOI
TL;DR: Molecular analyses identified one form of teosinte (Zea mays ssp. parviglumis) as the progenitor of maize and a few loci of large effect that appear to represent key innovations during maize domestication.
Abstract: ▪ Abstract Maize and its closest wild relatives, the teosintes, differ strikingly in the morphology of their female inflorescences or ears. Despite their divergent morphologies, several studies indicate that some varieties of teosinte are cytologically indistinguishable from maize and capable of forming fully fertile hybrids with maize. Molecular analyses identified one form of teosinte (Zea mays ssp. parviglumis) as the progenitor of maize. Analyses of the inheritance of the morphological traits that distinguish maize and teosinte indicates that they are under the control of multiple genes and exhibit quantitative inheritance. Nevertheless, these analyses have also identified a few loci of large effect that appear to represent key innovations during maize domestication. Remaining challenges are to identify additional major and minor effect genes, the polymorphisms within these genes that control the phenotypes, and how the combination of the individual and epistatic effects of these genes transformed teo...

560 citations


Journal ArticleDOI
TL;DR: The functions of Cdc14 are reviewed and how this phosphatase is regulated to accomplish the coupling of mitotic processes.
Abstract: ▪ Abstract Completion of the cell cycle requires the temporal and spatial coordination of chromosome segregation with mitotic spindle disassembly and cytokinesis. In budding yeast, the protein phosphatase Cdc14 is a key regulator of these late mitotic events. Here, we review the functions of Cdc14 and how this phosphatase is regulated to accomplish the coupling of mitotic processes. We also discuss the function and regulation of Cdc14 in other eukaryotes, emphasizing conserved features.

449 citations


Journal ArticleDOI
TL;DR: A clearer understanding of the mechanism and efficiency of AAV integration, in terms of contributing viral and host-cell factors and circumstances, will provide a context in which to evaluate these potential benefits and risks.
Abstract: The driving interest in adeno-associated virus (AAV) has been its potential as a gene delivery vector. The early observation that AAV can establish a latent infection by integrating into the host chromosome has been central to this interest. However, chromosomal integration is a two-edged sword, imparting on one hand the ability to maintain the therapeutic gene in progeny cells, and on the other hand, the risk of mutations that are deleterious to the host. A clearer understanding of the mechanism and efficiency of AAV integration, in terms of contributing viral and host-cell factors and circumstances, will provide a context in which to evaluate these potential benefits and risks. Research to date suggests that AAV integration in any context is inefficient, and that the persistence of AAV gene delivery vectors in tissues is largely attributable to episomal genomes.

Journal ArticleDOI
TL;DR: The experimental basis for the current understanding of group II intron mobility mechanisms is discussed, beginning with genetic observations in yeast mitochondria, and culminating with a detailed understanding of molecular mechanisms shared by organellar and bacterial group II introns.
Abstract: Mobile group II introns, found in bacterial and organellar genomes, are both catalytic RNAs and retrotransposable elements. They use an extraordinary mobility mechanism in which the excised intron RNA reverse splices directly into a DNA target site and is then reverse transcribed by the intron-encoded protein. After DNA insertion, the introns remove themselves by protein-assisted, autocatalytic RNA splicing, thereby minimizing host damage. Here we discuss the experimental basis for our current understanding of group II intron mobility mechanisms, beginning with genetic observations in yeast mitochondria, and culminating with a detailed understanding of molecular mechanisms shared by organellar and bacterial group II introns. We also discuss recently discovered links between group II intron mobility and DNA replication, new insights into group II intron evolution arising from bacterial genome sequencing, and the evolutionary relationship between group II introns and both eukaryotic spliceosomal introns and non-LTR-retrotransposons. Finally, we describe the development of mobile group II introns into gene-targeting vectors, "targetrons," which have programmable target specificity.

Journal ArticleDOI
TL;DR: This work has identified a new component of the transcription machinery, DksA, that is absolutely required for regulation of rRNA promoter activity, and provides clues important for molecular understanding not only of r RNA transcription, but also of transcription in general.
Abstract: Ribosomal RNA transcription is the rate-limiting step in ribosome synthesis in bacteria and has been investigated intensely for over half a century. Multiple mechanisms ensure that rRNA synthesis rates are appropriate for the cell's particular growth condition. Recently, important advances have been made in our understanding of rRNA transcription initiation in Escherichia coli. These include (a) a model at the atomic level of the network of protein-DNA and protein-protein interactions that recruit RNA polymerase to rRNA promoters, accounting for their extraordinary strength; (b) discovery of the nonredundant roles of two small molecule effectors, ppGpp and the initiating NTP, in regulation of rRNA transcription initiation; and (c) identification of a new component of the transcription machinery, DksA, that is absolutely required for regulation of rRNA promoter activity. Together, these advances provide clues important for our molecular understanding not only of rRNA transcription, but also of transcription in general.

Journal ArticleDOI
TL;DR: This review aims to describe bacterial genome structures according to current knowledge and proposed hypotheses, and describes examples where mechanisms of genome evolution have acted in the adaptation of bacterial species to particular niches.
Abstract: ▪ Abstract Recent advances in DNA-sequencing technologies have made available an enormous resource of data for the study of bacterial genomes. The broad sample of complete genomes currently available allows us to look at variation in the gross features and characteristics of genomes while the detail of the sequences reveal some of the mechanisms by which these genomes evolve. This review aims to describe bacterial genome structures according to current knowledge and proposed hypotheses. We also describe examples where mechanisms of genome evolution have acted in the adaptation of bacterial species to particular niches.

Journal ArticleDOI
TL;DR: Comparison of mtDNA sequence data has provided insights into the radically diverse trends in mitochondrial genome evolution exhibited by different phylogenetically coherent groupings of eukaryotes, and has allowed us to pinpoint specific protist relatives of the multicellular eUKaryotic lineages.
Abstract: ▪ Abstract Over the past several decades, our knowledge of the origin and evolution of mitochondria has been greatly advanced by determination of complete mitochondrial genome sequences. Among the most informative mitochondrial genomes have been those of protists (primarily unicellular eukaryotes), some of which harbor the most gene-rich and most eubacteria-like mitochondrial DNAs (mtDNAs) known. Comparison of mtDNA sequence data has provided insights into the radically diverse trends in mitochondrial genome evolution exhibited by different phylogenetically coherent groupings of eukaryotes, and has allowed us to pinpoint specific protist relatives of the multicellular eukaryotic lineages (animals, plants, and fungi). This comparative genomics approach has also revealed unique and fascinating aspects of mitochondrial gene expression, highlighting the mitochondrion as an evolutionary playground par excellence.

Journal ArticleDOI
David Haig1
TL;DR: The phenotypes of reciprocal heterozygotes for Gnas knockouts provide provisional support for this hypothesis, as does some evidence from other imprinted genes (albeit more tentatively), which defy a unifying hypothesis in terms of the kinship theory.
Abstract: ▪ Abstract The kinship theory of genomic imprinting proposes that parent-specific gene expression evolves at a locus because a gene's level of expression in one individual has fitness effects on other individuals who have different probabilities of carrying the maternal and paternal alleles of the individual in which the gene is expressed. Therefore, natural selection favors different levels of expression depending on an allele's sex-of-origin in the previous generation. This review considers the strength of evidence in support of this hypothesis for imprinted genes in four “clusters,” associated with the imprinted loci Igf2, Igf2r, callipyge, and Gnas. The clusters associated with Igf2 and Igf2r both contain paternally expressed transcripts that act as enhancers of prenatal growth and maternally expressed transcripts that act as inhibitors of prenatal growth. This is consistent with predictions of the kinship theory. However, the clusters also contain imprinted genes whose phenotypes as yet remain unexpl...

Journal ArticleDOI
TL;DR: Current data indicate that scaffolding and cross pathway inhibition play key roles in the maintenance of fidelity, and potential mechanisms by which specificity could be achieved by signaling pathways that share components are described.
Abstract: ▪ Abstract Cells respond to a plethora of signals using a limited set of intracellular signal transduction components. Surprisingly, pathways that transduce distinct signals can share protein components, yet avoid erroneous cross-talk. A highly tractable model system in which to study this paradox is the yeast Saccharomyces cerevisiae, which harbors three mitogen-activated protein kinase (MAPK) signal transduction cascades that share multiple signaling components. In this review we first describe potential mechanisms by which specificity could be achieved by signaling pathways that share components. Second, we summarize key features and components of the yeast MAPK pathways that control the mating pheromone response, filamentous growth, and the response to high osmolarity. Finally, we review biochemical analyses in yeast of mutations that cause cross-talk between these three MAPK pathways and their implications for the mechanistic bases for signaling specificity. Although much remains to be learned, curre...

Journal ArticleDOI
TL;DR: This review examines functional implications of the long-range organization of the genome in interphase nuclei, general concepts of interphase nuclear order, the role of the nuclear envelope and lamins, and the importance of spatial organization for DNA replication and heritable gene expression.
Abstract: ▪ Abstract Eukaryotic genomes are distributed on linear chromosomes that are grouped together in the nucleus, an organelle separated from the cytoplasm by a characteristic double membrane studded with large proteinaceous pores. The chromatin within chromosomes has an as yet poorly characterized higher-order structure, but in addition to this, chromosomes and specific subchromosomal domains are nonrandomly positioned in nuclei. This review examines functional implications of the long-range organization of the genome in interphase nuclei. A rigorous test of the physiological importance of nuclear architecture is achieved by introducing mutations that compromise both structure and function. Focussing on such genetic approaches, we address general concepts of interphase nuclear order, the role of the nuclear envelope (NE) and lamins, and finally the importance of spatial organization for DNA replication and heritable gene expression.

Journal ArticleDOI
TL;DR: The investigation of these processes has revealed a new type of proteolytic activity, regulated intramembrane proteolysis, and a reversible switch in activity occurring in the HtrA family of serine proteases.
Abstract: Proteases can play key roles in regulation by controlling the levels of critical components of, for example, signal transduction pathways. Proteolytic processing can remove regulatory proteins when they are not needed, while transforming others from the dormant into the biologically active state. The latter mechanism often involves a subsequent change of cellular localization such as the movement from the membrane to the nucleus. The investigation of these processes has revealed a new type of proteolytic activity, regulated intramembrane proteolysis, and a reversible switch in activity occurring in the HtrA family of serine proteases. The bacterial RseA and the human amyloid precursor processing pathways are used as models to review these novel principles that are evolutionarily conserved and have wide biological implications.

Journal ArticleDOI
TL;DR: This review surveys the current molecular understanding of how pollination proceeds, and asks to what extent is each step important for mate discrimination.
Abstract: For pollination to succeed, pollen must carry sperm through a variety of different floral tissues to access the ovules within the pistil. The pistil provides everything the pollen requires for success in this endeavor including distinct guidance cues and essential nutrients that allow the pollen tube to traverse enormous distances along a complex path to the unfertilized ovule. Although the pistil is a great facilitator of pollen function, it can also be viewed as an elaborate barrier that shields ovules from access from inappropriate pollen, such as pollen from other species. Each discrete step taken by pollen tubes en route to the ovules is a potential barrier point to ovule access and waste by inappropriate mates. In this review, we survey the current molecular understanding of how pollination proceeds, and ask to what extent is each step important for mate discrimination. As this field progresses, this synthesis of functional biology and evolutionary studies will provide insight into the molecular basis of the species barriers that maintain the enormous diversity seen in flowering plants.

Journal ArticleDOI
TL;DR: This review focuses on the biosynthesis of pigments in the unicellular alga Chlamydomonas reinhardtii and their physiological and regulatory functions in the context of information gathered from studies of other photosynthetic organisms.
Abstract: ▪ Abstract This review focuses on the biosynthesis of pigments in the unicellular alga Chlamydomonas reinhardtii and their physiological and regulatory functions in the context of information gathered from studies of other photosynthetic organisms. C. reinhardtii is serving as an important model organism for studies of photosynthesis and the pigments associated with the photosynthetic apparatus. Despite extensive information pertaining to the biosynthetic pathways critical for making chlorophylls and carotenoids, we are just beginning to understand the control of these pathways, the coordination between pigment and apoprotein synthesis, and the interactions between the activities of these pathways and those for other important cellular metabolites branching from these pathways. Other exciting areas relating to pigment function are also emerging: the role of intermediates of pigment biosynthesis as messengers that coordinate metabolism in the chloroplast with nuclear gene activity, and the identification o...

Journal ArticleDOI
TL;DR: Bacterial genetics holds the key to understanding when and to what extent these metabolisms influence modern geochemical cycles, as well as develop a basis for deciphering their origins and how organisms that utilized them may have altered the chemical and physical features of the authors' planet.
Abstract: Bacteria are remarkable in their metabolic diversity due to their ability to harvest energy from myriad oxidation and reduction reactions. In some cases, their metabolisms involve redox transformations of metal(loid)s, which lead to the precipitation, transformation, or dissolution of minerals. Microorganism/mineral interactions not only affect the geochemistry of modern environments, but may also have contributed to shaping the near-surface environment of the early Earth. For example, bacterial anaerobic respiration of ferric iron or the toxic metalloid arsenic is well known to affect water quality in many parts of the world today, whereas the utilization of ferrous iron as an electron donor in anoxygenic photosynthesis may help explain the origin of Banded Iron Formations, a class of ancient sedimentary deposits. Bacterial genetics holds the key to understanding how these metabolisms work. Once the genes and gene products that catalyze geochemically relevant reactions are understood, as well as the conditions that trigger their expression, we may begin to predict when and to what extent these metabolisms influence modern geochemical cycles, as well as develop a basis for deciphering their origins and how organisms that utilized them may have altered the chemical and physical features of our planet.

Journal ArticleDOI
TL;DR: This review summarizes knowledge on how diverse mechanisms that were first dissected at the postembryonic level are now beginning to provide an understanding of plant embryogenesis.
Abstract: Many of the patterning mechanisms in plants were discovered while studying postembryonic processes and resemble mechanisms operating during animal development. The emergent role of the plant hormone auxin, however, seems to represent a plant-specific solution to multicellular patterning. This review summarizes our knowledge on how diverse mechanisms that were first dissected at the postembryonic level are now beginning to provide an understanding of plant embryogenesis.

Journal ArticleDOI
TL;DR: The major host factors involved in the early phase of the viral life cycle are discussed.
Abstract: Host cellular genes can have profound effects on retrovirus replication. Many of these genes encode restriction factors that block virus infection; others encode positive factors that are exploited by the viruses. Recently, a number of such genes have been cloned and characterized, bringing into sharper focus the mechanisms and pathways exploited by these viruses. The major host factors involved in the early phase of the viral life cycle are discussed.

Journal ArticleDOI
TL;DR: Comparisons reveal an evolutionarily conserved trans-reg Regulatory apparatus and a similar organization of sequence-specific cis-regulatory replicator and origin elements, and indicate a regulatory role for chromatin structure and transcriptionally active genes near the origins.
Abstract: Developmentally regulated gene amplification serves to increase the number of templates for transcription, yielding greatly increased protein and/or RNA product for gene(s) at the amplified loci. It is observed with genes that are very actively transcribed and during narrow windows of developmental time where copious amounts of those particular gene products are required. Amplification results from repeated firing of origins at a few genomic loci, while the rest of the genome either does not replicate, or replicates to a lesser extent. As such, amplification is a striking exception to the once-and-only-once rule of DNA replication and may be informative as to that mechanism. Drosophila amplifies eggshell (chorion) genes in the follicle cells of the ovary to allow for rapid eggshell synthesis. Sciara amplifies multiple genes in larval salivary gland cells that encode proteins secreted in the saliva for the pupal case. Finally, Tetrahymena amplifies its rRNA genes several thousand-fold in the creation of the transcriptionally active macronucleus. Due to the ease of molecular and genetic analysis with these systems, the study of origin regulation has advanced rapidly. Comparisons reveal an evolutionarily conserved trans-regulatory apparatus and a similar organization of sequence-specific cis-regulatory replicator and origin elements. The studies indicate a regulatory role for chromatin structure and transcriptionally active genes near the origins.

Journal ArticleDOI
TL;DR: Although prions can be detrimental, they may also be beneficial to their hosts, and, like other infectious elements, show species barriers to transmission.
Abstract: ▪ Abstract Just as nucleic acids can carry out enzymatic reactions, proteins can be genes. These heritable infectious proteins (prions) follow unique genetic rules that enable their identification: reversible curing, inducible “spontaneous generation,” and phenotype surprises. Most prions are based on self-propagating amyloids, depend heavily on chaperones, show strain phenomena and, like other infectious elements, show species barriers to transmission. A recently identified prion is based on obligatory self-activation of an enzyme in trans. Although prions can be detrimental, they may also be beneficial to their hosts.

Journal ArticleDOI
TL;DR: The genetic screens that can be used to identify pathogen virulence factors are summarized and a comparative overview of existing or emerging genetically tractable host models is presented.
Abstract: ▪ Abstract To decipher the complexity of host-pathogen interactions the widest possible range of model hosts and of analytical methods is required. As some virulence mechanisms and certain host responses have been conserved throughout evolution, even simple organisms can be used as model hosts to help our understanding of infectious diseases. The availability of molecular genetic tools and a cooperative community of researchers are pivotal to the emergence of model systems. In this review, we first summarize the genetic screens that can be used to identify pathogen virulence factors, then we present a comparative overview of existing or emerging genetically tractable host models.