Showing papers in "Annual Review of Genetics in 2002"

Estimating F-statistics.

Abstract: ▪ Abstract A moment estimator of θ, the coancestry coefficient for alleles within a population, was described by Weir & Cockerham in 1984 (100) and is still widely cited. The estimate is used by population geneticists to characterize population structure, by ecologists to estimate migration rates, by animal breeders to describe genetic variation, and by forensic scientists to quantify the strength of matching DNA profiles. This review extends the work of Weir & Cockerham by allowing different levels of coancestry for different populations, and by allowing non-zero coancestries between pairs of populations. All estimates are relative to the average value of θ between pairs of populations. Moment estimates for within- and between-population θ values are likely to have large sampling variances, although these may be reduced by combining information over loci. Variances also decrease with the numbers of alleles at a locus, and with the numbers of populations sampled. This review also extends the work of Weir ...

Toward maintaining the genome: DNA damage and replication checkpoints.

Abstract: DNA checkpoints play a significant role in cancer pathology, perhaps most notably in maintaining genome stability. This review summarizes the genetic and molecular mechanisms of checkpoint activation in response to DNA damage. The major checkpoint proteins common to all eukaryotes are identified and discussed, together with how the checkpoint proteins interact to induce arrest within each cell cycle phase. Also discussed are the molecular signals that activate checkpoint responses, including single-strand DNA, double-strand breaks, and aberrant replication forks. We address the connection between checkpoint proteins and damage repair mechanisms, how cells recover from an arrest response, and additional roles that checkpoint proteins play in DNA metabolism. Finally, the connection between checkpoint gene mutation and genomic instability is considered.

Genetic engineering using homologous recombination.

Abstract: ■ Abstract In the past few years, in vivo technologies have emerged that, due to their efficiency and simplicity, may one day replace standard genetic engineering techniques. Constructs can be made on plasmids or directly on the Escherichia colichromosome from PCR products or synthetic oligonucleotides by homologous recombination. This is possible because bacteriophage-encoded recombination functions efficiently recombine sequences with homologies as short as 35 to 50 base pairs. This technology, termed recombineering, is providing new ways to modify genes and segments of the chromosome. This review describes not only recombineering and its applications, but also summarizes homologous recombination in E. coli and early uses of homologous recombination to modify the bacterial chromosome. Finally, based on the premise that phage-mediated recombination functions act at replication forks, specific molecular models are proposed.

Xist RNA and the Mechanism of X Chromosome Inactivation

Abstract: ▪ Abstract Dosage compensation in mammals is achieved by the transcriptional inactivation of one X chromosome in female cells. From the time X chromosome inactivation was initially described, it was clear that several mechanisms must be precisely integrated to achieve correct regulation of this complex process. X-inactivation appears to be triggered upon differentiation, suggesting its regulation by developmental cues. Whereas any number of X chromosomes greater than one is silenced, only one X chromosome remains active. Silencing on the inactive X chromosome coincides with the acquisition of a multitude of chromatin modifications, resulting in the formation of extraordinarily stable facultative heterochromatin that is faithfully propagated through subsequent cell divisions. The integration of all these processes requires a region of the X chromosome known as the X-inactivation center, which contains the Xist gene and its cis-regulatory elements. Xist encodes an RNA molecule that plays critical roles in t...

Allosteric Cascade of Spliceosome Activation

Abstract: Introns are removed from precursor messenger RNAs in the cell nucleus by a large ribonucleoprotein complex called the spliceosome. The spliceosome contains five subcomplexes called snRNPs, each with one RNA and several protein components. Interactions of the snRNPs with each other and the intron are highly dynamic, changing in an ordered progression throughout the splicing process. This allosteric cascade of interactions is programmed into the RNA and protein components of the spliceosome, and is driven by a family of DExD/H-box RNA-dependent ATPases. The dependence of cascade progression on multiple intron-recognition events likely serves to enforce the accuracy of splicing. Here, the progression of the allosteric cascade from the first recognition event to the first catalytic step of splicing is reviewed.

The Genetics of RNA Silencing

Abstract: ■ Abstract Although initially recognized as a handy tool to reduce gene expression, RNA silencing, triggered by double-stranded RNA molecules, is now recognized as a mechanism for cellular protection and cleansing: It defends the genome against molecular parasites such as viruses and transposons, while removing abundant but aberrant nonfunctional messenger RNAs. The underlying mechanisms in distinct gene silencing phenomena in different genetic systems, such as cosuppression in plants and RNAi in animals, are very similar. There are common RNA intermediates, and similar genes are required in RNA silencing pathways in protozoa, plants, fungi, and animals, thus indicating an ancient pathway. This chapter gives an overview of both biochemical and genetic approaches leading to the current understanding of the molecular mechanism of RNA silencing and its probable biological function.

Recombination in evolutionary genomics.

Abstract: ▪ Abstract Recombination can be a dominant force in shaping genomes and associated phenotypes. To better understand the impact of recombination on genomic evolution, we need to be able to identify recombination in aligned sequences. We review bioinformatic approaches for detecting recombination and measuring recombination rates. We also examine the impact of recombination on the reconstruction of evolutionary histories and the estimation of population genetic parameters. Finally, we review the role of recombination in the evolutionary history of bacteria, viruses, and human mitochondria. We conclude by highlighting a number of areas for future development of tools to help quantify the role of recombination in genomic evolution.

Genetic mating systems and reproductive natural histories of fishes: lessons for ecology and evolution.

Abstract: Fish species have diverse breeding behaviors that make them valuable for testing theories on genetic mating systems and reproductive tactics. Here we review genetic appraisals of paternity and maternity in wild fish populations. Behavioral phenomena quantified by genetic markers in various species include patterns of multiple mating by both sexes; frequent cuckoldry by males and rare cuckoldry by females in nest-tending species; additional routes to surrogate parentage via nest piracy and egg-thievery; egg mimicry by nest-tending males; brood parasitism by helper males in cooperative breeders; clutch mixing in oral brooders; kinship in schooling fry of broadcast spawners; sperm storage by dams in female-pregnant species; and sex-role reversal, polyandry, and strong sexual selection on females in some male-pregnant species. Additional phenomena addressed by genetic parentage analyses in fishes include clustered mutations, filial cannibalism, and local population size. All results are discussed in the context of relevant behavioral and evolutionary theory.

Genetics of Motility and Chemotaxis of a Fascinating Group of Bacteria: The Spirochetes

Abstract: Spirochetes are a medically important and ecologically significant group of motile bacteria with a distinct morphology. Outermost is a membrane sheath, and within this sheath is the protoplasmic cell cylinder and subterminally attached periplasmic flagella. Here we address specific and unique aspects of their motility and chemotaxis. For spirochetes, translational motility requires asymmetrical rotation of the two internally located flagellar bundles. Consequently, they have swimming modalities that are more complex than the well-studied paradigms. In addition, coordinated flagellar rotation likely involves an efficient and novel signaling mechanism. This signal would be transmitted over the length of the cell, which in some cases is over 100-fold greater than the cell diameter. Finally, many spirochetes, including Treponema, Borrelia, and Leptospira, are highly invasive pathogens. Motility is likely to play a major role in the disease process. This review summarizes the progress in the genetics of motility and chemotaxis of spirochetes, and points to new directions for future experimentation.

DNA Topology-Mediated Control of Global Gene Expression in Escherichia coli

Abstract: Because the level of DNA superhelicity varies with the cellular energy charge, it can change rapidly in response to a wide variety of altered nutritional and environmental conditions. This is a global alteration, affecting the entire chromosome and the expression levels of all operons whose promoters are sensitive to superhelicity. In this way, the global pattern of gene expression may be dynamically tuned to changing needs of the cell under a wide variety of circumstances. In this article, we propose a model in which chromosomal superhelicity serves as a global regulator of gene expression in Escherichia coli, tuning expression patterns across multiple operons, regulons, and stimulons to suit the growth state of the cell. This model is illustrated by the DNA supercoiling-dependent mechanisms that coordinate basal expression levels of operons of the ilv regulon both with one another and with cellular growth conditions.

Transvection effects in Drosophila.

Abstract: ▪ Abstract An unusual feature of the Diptera is that homologous chromosomes are intimately synapsed in somatic cells. At a number of loci in Drosophila, this pairing can significantly influence gene expression. Such influences were first detected within the bithorax complex (BX-C) by E.B. Lewis, who coined the term transvection to describe them. Most cases of transvection involve the action of enhancers in trans. At several loci deletion of the promoter greatly increases this action in trans, suggesting that enhancers are normally tethered in cis by the promoter region. Transvection can also occur by the action of silencers in trans or by the spreading of position effect variegation from rearrangements having heterochromatic breakpoints to paired unrearranged chromosomes. Although not demonstrated, other cases of transvection may involve the production of joint RNAs by trans-splicing. Several cases of transvection require Zeste, a DNA-binding protein that is thought to facilitate homolog interactions by s...

Genetics of Cryptococcus neoformans.

Abstract: Cryptococcus neoformans is a pathogenic fungus that primarily afflicts immunocompromised patients, infecting the central nervous system to cause meningoencephalitis that is uniformly fatal if untreated. C. neoformans is a basidiomycetous fungus with a defined sexual cycle that has been linked to differentiation and virulence. Recent advances in classical and molecular genetic approaches have allowed molecular descriptions of the pathways that control cell type and virulence. An ongoing genome sequencing project promises to reveal much about the evolution of this human fungal pathogen into three distinct varieties or species. C. neoformans shares features with both model ascomycetous yeasts (Saccharomyces cerevisiae, Schizosaccharomyces pombe) and basidiomycetous pathogens and mushrooms (Ustilago maydis, Coprinus cinereus, Schizophyllum commune), yet ongoing studies reveal unique features associated with virulence and the arrangement of the mating type locus. These advances have catapulted C. neoformans to center stage as a model of both fungal pathogenesis and the interesting approaches to life that the kingdom of fungi has adopted.

Studying Gene Function in Eukaryotes by Conditional Gene Inactivation

Abstract: The prospect of specifically controlling gene activities in vivo has become a defining hallmark of many model organisms of biological research. Where once the aim was to gain control over gene activities using endogenous control elements, new technologies have emerged that owe their remarkable specificity to heterologous components derived from evolutionarily distant species. This review highlights inducible transcriptional systems and site-specific recombination. Their quantitative and qualitative characteristics are discussed, with examples of how recent developments have expanded the spectrum of cells and organisms that are now accessible to genetic dissection of unprecedented precision. Transgenesis has already converted the mouse into a prime model for mammalian genetics. Combined with the new approaches of conditional activation or inactivation of genes, this model has opened up new horizons for the analysis of gene function in mammals.

Development and function of the angiosperm female gametophyte

Abstract: The plant life cycle alternates between a diploid sporophyte generation and a haploid gametophyte generation. The angiosperm female gametophyte is critical to the reproductive process. It is the structure within which egg cell production and fertilization take place. In addition, the female gametophyte plays a role in pollen tube guidance, the induction of seed development, and the maternal control of seed development. Genetic analysis in Arabidopsis has uncovered mutations that affect female gametophyte development and function. Mutants defective in almost all stages of development have been identified, and analysis of these mutants is beginning to reveal features of the female gametophyte developmental program. Other mutations that affect female gametophyte function have uncovered regulatory genes required for the induction of endosperm development. From these studies, we are beginning to understand the regulatory networks involved in female gametophyte development and function. Further investigation of the female gametophyte will require complementary approaches including expression-based approaches to obtain a complete profile of the genes functioning within this critical structure.

Genetics of sensory mechanotransduction.

Abstract: ▪ Abstract The molecular mechanisms for the transduction of light and chemical signals in animals are fairly well understood. In contrast, the processes by which the senses of touch, balance, hearing, and proprioception are transduced are still largely unknown. Biochemical approaches to identify transduction components are difficult to use with mechanosensory systems, but genetic approaches are proving more successful. Genetic research in several organisms has demonstrated the importance of cytoskeletal, extracellular, and membrane components for sensory mechanotransduction. In particular, researchers have identified channel proteins in the DEG/ENaC and TRP families that are necessary for signaling in a variety of mechanosensory cells. Proof that these proteins are components of the transduction channel, however, is incomplete.

Genetics of influenza viruses.

Abstract: ▪ Abstract Influenza A viruses contain genomes composed of eight separate segments of negative-sense RNA. Circulating human strains are notorious for their tendency to accumulate mutations from one year to the next and cause recurrent epidemics. However, the segmented nature of the genome also allows for the exchange of entire genes between different viral strains. The ability to manipulate influenza gene segments in various combinations in the laboratory has contributed to its being one of the best characterized viruses, and studies on influenza have provided key contributions toward the understanding of various aspects of virology in general. However, the genetic plasticity of influenza viruses also has serious potential implications regarding vaccine design, pathogenicity, and the capacity for novel viruses to emerge from natural reservoirs and cause global pandemics.

Origins of Spontaneous Mutations: Specificity and Directionality of Base-Substitution, Frameshift, and Sequence-Substitution Mutageneses

Abstract: ▪ Abstract Spontaneous mutations are derived from various sources, including errors made during replication of undamaged template DNA, mutagenic nucleotide substrates, and endogenous DNA lesions. These sources vary in their frequencies and resultant mutations, and are differently affected by the DNA sequence, DNA transactions, and cellular metabolism. Organisms possess a variety of cellular functions to suppress spontaneous mutagenesis, and the specificity and effectiveness of each function strongly affect the pattern of spontaneous mutations. Base substitutions and single-base frameshifts, two major classes of spontaneous mutations, occur non-randomly throughout the genome. Within target DNA sequences there are hotspots for particular types of spontaneous mutations; outside of the hotspots, spontaneous mutations occur more randomly and much less frequently. Hotspot mutations are attributable more to endogenous DNA lesions than to replication errors. Recently, a novel class of mutagenic pathway that depen...

Chromosome Rearrangements and Transposable Elements

Abstract: ▪ Abstract There has been limited corroboration to date for McClintock's vision of gene regulation by transposable elements (TEs), although her proposition on the origin of species by TE-induced co...

Meiotic Recombination and Chromosome Segregation in Drosophila Females

Abstract: ▪ Abstract In this review, we describe the pathway for generating meiotic crossovers in Drosophila melanogaster females and how these events ensure the segregation of homologous chromosomes. As appears to be common to meiosis in most organisms, recombination is initiated with a double-strand break (DSB). The interesting differences between organisms appear to be associated with what chromosomal events are required for DSBs to form. In Drosophila females, the synaptonemal complex is required for most DSB formation. The repair of these breaks requires several DSB repair genes, some of which are meiosis-specific, and defects at this stage can have effects downstream on oocyte development. This has been suggested to result from a checkpoint-like signaling between the oocyte nucleus and gene products regulating oogenesis. Crossovers result from genetically controlled modifications to the DSB repair pathway. Finally, segregation of chromosomes joined by a chiasma requires a bipolar spindle. At least two kinesin...

Genetic approaches to molecular and cellular cognition: a focus on LTP and learning and memory.

Abstract: ▪ Abstract Long-term potentiation (LTP) is the predominant experimental model for the synaptic plasticity mechanisms thought to underlie learning and memory. This review is focused on the contributions of genetics to the understanding of the role of LTP in learning and memory. These studies have used a combination of genetics, molecular biology, neurophysiology, and psychology to demonstrate that molecular mechanisms of synaptic plasticity are critical for learning and memory. Because of the large scope of this literature, we focus primarily on genetic studies of hippocampal-dependent learning. Altogether, these findings not only demonstrate a role for plasticity in learning, they also lay down the foundations for the new field of molecular and cellular cognition.

Understanding the function of actin-binding proteins through genetic analysis of Drosophila oogenesis.

Abstract: Much of our knowledge of the actin cytoskeleton has been derived from biochemical and cell biological approaches, through which actin-binding proteins have been identified and their in vitro interactions with actin have been characterized. The study of actin-binding proteins (ABPs) in genetic model systems has become increasingly important for validating and extending our understanding of how these proteins function. New ABPs have been identified through genetic screens, and genetic results have informed the interpretation of in vitro experiments. In this review, we describe the molecular and ultrastructural characteristics of the actin cytoskeleton in the Drosophila ovary, and discuss recent genetic analyses of actin-binding proteins that are required for oogenesis.

The Feline Genome Project.

Abstract: The compilation of a dense gene map and eventually a whole genome sequence (WGS) of the domestic cat holds considerable value for human genome annotation, for veterinary medicine, and for insight into the evolution of genome organization among mammals. Human association and veterinary studies of the cat, its domestic breeds, and its charismatic wild relatives of the family Felidae have rendered the species a powerful model for human hereditary diseases, for infectious disease agents, for adaptive evolutionary divergence, for conservation genetics, and for forensic applications. Here we review the advantages, rationale, and present strategy of a feline genome project, and we describe the disease models, comparative genomics, and biological applications posed by the full resolution of the cat's genome.

Primordial genetics: phenotype of the ribocyte.

Abstract: The idea that the ancestors of modern cells were RNA cells (ribocytes) can be investigated by asking whether all essential cellular functions might be performed by RNAs. This requires isolating suitable molecules by selection-amplification when the predicted molecules are presently extinct. In fact, RNAs with many properties required during a period in which RNA was the major macromolecular agent in cells (an RNA world) have been selected in modern experiments. There is, accordingly, reason to inquire how such a ribocyte might appear, based on the properties of the RNAs that composed it. Combining the intrinsic qualities of RNA with the fundamental characteristics of selection from randomized sequence pools, one predicts ribocytes with a cell cycle measured (roughly) in weeks. Such cells likely had a rapidly varying genome, composed of many small genetic and catalytic elements made of tens of ribonucleotides. There are substantial arguments that, at the mid-RNA era, a subset of these nucleotides are reproducibly available and resemble the modern four. Such cells are predicted to evolve rapidly. Instead of modifying preexisting genes, ribocytes frequently draw new functions from an internal pool containing zeptomoles (<1 attomole) of predominantly inactive random sequences.

Directions in Evolutionary Biology

Abstract: ▪ Abstract In order to understand both the past and future directions of research in evolutionary biology we need to begin by understanding in what way these programs of research differ from the model of most scientific work. The study of evolutionary processes and, in particular, the genetics of the evolutionary process must confront special difficulties in both the conceptual and the methodological aspects of research. On the conceptual side, unlike for molecular, cellular, and developmental biology, there is no basic mechanism that evolutionists are attempting to elucidate. There is no single cause of the evolutionary change in the properties of members of a species. Natural selection may be involved but so are random events, patterns of migration and interbreeding, mutational events, and horizontal transfer of genes across species boundaries. The change in each character of each species is a consequence of a particular mixture of these causal pathways.