Annual Review of Genetics - Volume 42, 2008

Beginning in the 1930s, evolution became an experimental subject. New techniques, especially in Drosophila, made possible quantitative analysis of natural populations. In addition to a large number of studies on many species, there were four major controversies that dominated much of the discussion and experimentation. Some of the arguments were quite heated. These controversies were: Wright vs Fisher on Wright's shifting-balance theory; dominance vs overdominance as an explanation of heterosis; the classical vs balance hypothesis for genetic variability; the neutral theory of molecular evolution. Curiously, most of these issues were not really resolved. Rather they were abandoned in favor of more tractable studies made possible by the new molecular methods.

Yeast cells sense the amount and quality of external nutrients through multiple interconnected signaling networks, which allow them to adjust their metabolism, transcriptional profile and developmental program to adapt readily and appropriately to changing nutritional states. We present our current understanding of the nutritional sensing networks yeast cells rely on for perceiving the nutritional landscape, with particular emphasis on those sensitive to carbon and nitrogen sources. We describe the means by which these networks inform the cell's decision among the different developmental programs available to them—growth, quiescence, filamentous development, or meiosis/sporulation. We conclude that the highly interconnected signaling networks provide the cell with a highly nuanced view of the environment and that the cell can interpret that information through a sophisticated calculus to achieve optimum responses to any nutritional condition.

Diatoms are single-celled algae that produce intricately structured cell walls made of nanopatterned silica (SiO2). The cell wall structure is a species-specific characteristic demonstrating that diatom silica morphogenesis is genetically encoded. Understanding the molecular mechanisms by which a single cell executes the morphogenetic program for the formation of an inorganic material (biomineralization) is not only a fascinating biological problem, but also of great interest for nanomaterials science and technology. Recently, analysis of the organic components associated with diatom silica, the development of techniques for molecular genetic manipulation of diatoms, and two diatom genome sequencing projects are providing insight into the composition and mechanism of the remarkable biosilica-forming machinery.

Myxococcus xanthus creates complex and dynamic multicellular patterns as it swarms. The cells have two polar gliding engines: pulling type IV pili at their leading pole and pushing slime secretory nozzles at their lagging pole. Evidence is presented that slime secretion is vital for cell survival and that the peptidoglycan/cytoskeleton serves as a template to keep both engines oriented in the same direction. Swarming requires that each cell periodically reverse its gliding direction. For the leading pole to become the trailing pole, old engines are inactivated at both ends while new engines are being created at both ends. Reversal is initiated by a small G-protein reversal switch; a pulse of frzE∼P from a reversal clock triggers MglA to bind GTP. Mgl·GTP then recognizes the engines that are currently in use and inactivates both of them. Meanwhile, new engines appear as instructed by the template, and the cell starts to glide in the opposite direction.

Genome-wide association analysis is emerging as a powerful tool to define novel genes and molecular pathways involved in susceptibility to human complex disorders. However, in spite of recent successes, this approach is not without its limitations, the most notable of which is inconsistent phenotype penetrance due to varied environmental exposures. Mouse models do, however, circumvent some of these drawbacks by allowing for a much higher degree of control over genetic variation and environmental exposure, and although their application to human complex genetics is not always straightforward, they do serve as a powerful means of complementing observations in human populations. Mouse quantitative trait locus mapping has proven a successful, yet technically demanding method for defining trait susceptibility. In this review, we focus upon recent advances that are both reducing the technical burden traditionally associated with quantitative trait locus mapping, and enhancing the applicability of these approaches to human disease.

Retroviruses are highly successful intracellular parasites, and as such they are found in nearly all branches of life. Some are relatively benign, but many are highly pathogenic and can cause either acute or chronic diseases. Therefore, there is tremendous selective pressure on the host to prevent retroviral replication, and for this reason cells have evolved a variety of restriction factors that act to inhibit or block the viruses. This review is a survey of the best-characterized restriction factors capable of inhibiting retroviral replication and aims to highlight the diversity of strategies used for this task.

Insect heritable symbionts have proven to be ubiquitous, based on molecular screening of various insect lineages. Recently, molecular and experimental approaches have yielded an immensely richer understanding of their diverse biological roles, resulting in a burgeoning research literature. Increasingly, commonalities and intermediates are being discovered between categories of symbionts once considered distinct: obligate mutualists that provision nutrients, facultative mutualists that provide protection against enemies or stress, and symbionts such as Wolbachia that manipulate reproductive systems. Among the most far-reaching impacts of widespread heritable symbiosis is that it may promote speciation by increasing reproductive and ecological isolation of host populations, and it effectively provides a means for transfer of genetic information among host lineages. In addition, insect symbionts provide some of the extremes of cellular genomes, including the smallest and the fastest evolving, raising new questions about the limits of evolution of life.

The rhomboids are a well-conserved family of intramembrane serine proteases, which are unrelated to the classical soluble serine proteases. Their active site is buried within the plane of the membrane, and they cleave substrates in or near transmembrane domains. Although recently discovered, it is becoming clear that rhomboids control many important cellular functions. This review briefly describes recent biochemical and structural work that begins to explain how proteolysis occurs in a hydrophobic environment, but then focuses more extensively on the emerging biological functions of rhomboids. Although the function of most rhomboids is not yet known, they have already been implicated in growth factor signaling, mitochondrial function, host cell invasion by apicomplexan parasites, and protein translocation across membranes in bacteria. By exploiting cellular membrane trafficking machinery, rhomboids have evolved novel strategies to regulate proteolysis.

Many bacterial cellular processes interact intimately with the chromosome. Such interplay is the major driving force of genome structure or organization. Interactions take place at different scales—local for gene expression, global for replication—and lead to the differentiation of the chromosome into organizational units such as operons, replichores, or macrodomains. These processes are intermingled in the cell and create complex higher-level organizational features that are adaptive because they favor the interplay between the processes. The surprising result of selection for genome organization is that gene repertoires change much more quickly than chromosomal structure. Comparative genomics and experimental genomic manipulations are untangling the different cellular and evolutionary mechanisms causing such resilience to change. Since organization results from cellular processes, a better understanding of chromosome organization will help unravel the underlying cellular processes and their diversity.

Multicellularity appeared early and repeatedly in life's history; its instantiations presumably required the confluence of environmental, ecological, and genetic factors. Comparisons of several independently evolved pairs of multicellular and unicellular relatives indicate that transitions to multicellularity are typically associated with increases in the numbers of genes involved in cell differentiation, cell-cell communication, and adhesion. Further examination of the DNA record suggests that these increases in gene complexity are the product of evolutionary innovation, tinkering, and expansion of genetic material. Arguably, the most decisive multicellular transition was the emergence of animals. Decades of developmental work have demarcated the genetic toolkit for animal multicellularity, a select set of a few hundred genes from a few dozen gene families involved in adhesion, communication, and differentiation. Examination of the DNA records of the earliest-branching animal phyla and their closest protist relatives has begun to shed light on the origins and assembly of this toolkit. Emerging data favor a model of gradual assembly, with components originating and diversifying at different time points prior to or shortly after the origin of animals.

While traditionally microbiologists have examined bacterial behavior averaged over large populations, increasingly we are becoming aware that bacterial populations can be composed of phenotypically diverse individuals generated by a variety of mechanisms. Though the results of different mechanisms, the phenomena of bistability, persistence, variation in chemotactic response, and phase and antigenic variation are all strategies to develop population-level diversity. The understanding of individuality in bacteria requires an appreciation of their environmental and ecological context, and thus evolutionary theory regarding adaptations to time-variable environments is becoming more applicable to these problems. In particular, the application of game and information theory to bacterial individuality has addressed some interesting problems of bacterial behavior. In this review we discuss the mechanisms of generating population-level variability, and the application of evolutionary theory to problems of individuality in bacteria.

Tn5 was one of the first transposons to be identified (10). As a result of Tn5's early discovery and its simple macromolecular requirements for transposition, the Tn5 system has been a very productive tool for studying the molecular mechanism of DNA transposition. These studies are of broad value because they offer insights into DNA transposition in general, because DNA transposition is a useful model with which to understand other types of protein-DNA interactions such as retroviral DNA integration and the DNA cleavage events involved in immunoglobulin gene formation, and because Tn5-derived tools are useful adjuncts in genetic experimentation.

In a wide variety of organisms, synonymous codons are used with different frequencies, a phenomenon known as codon bias. Population genetic studies have shown that synonymous sites are under weak selection and that codon bias is maintained by a balance between selection, mutation, and genetic drift. It appears that the major cause for selection on codon bias is that certain preferred codons are translated more accurately and/or efficiently. However, additional and sometimes maybe even contradictory selective forces appear to affect codon usage as well. In this review, we discuss the current understanding of the ways in which natural selection participates in the creation and maintenance of codon bias. We also raise several open questions: (i) Is natural selection weak independently of the level of codon bias? It is possible that selection for preferred codons is weak only when codon bias approaches equilibrium and may be quite strong on genes with codon bias levels that are much lower and/or above equilibrium. (ii) What determines the identity of the major codons? (iii) How do shifts in codon bias occur? (iv) What is the exact nature of selection on codon bias? We discuss these questions in depth and offer some ideas on how they can be addressed using a combination of computational and experimental analyses.

The genomes of prokaryotes and eukaryotic organelles are usually circular as are most plasmids and viral genomes. In contrast, the nuclear genomes of eukaryotes are organized on linear chromosomes, which require mechanisms to protect and replicate DNA ends. Eukaryotes navigate these problemswith the advent of telomeres, protective nucleoprotein complexes at the ends of linear chromosomes, and telomerase, the enzyme that maintains the DNA in these structures. Mammalian telomeres contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage response and regulates telomere maintenance by telomerase. Recent experiments, discussed here, have revealed how shelterin represses the ATM and ATR kinase signaling pathways and hides chromosome ends from nonhomologous end joining and homology-directed repair.

Accurate segregation of duplicated chromosomes ensures that daughter cells get one and only one copy of each chromosome. Errors in chromosome segregation result in aneuploidy and have severe consequences on human health. Incorrect chromosome number and chromosomal instability are hallmarks of tumor cells. Hence, segregation errors are thought to be a major cause of tumorigenesis. A study of the physical mechanical basis of chromosome segregation is essential to understand the processes that can lead to errors. Tremendous progress has been made in recent years in identifying the proteins necessary for chromosome movement and segregation, but the mechanism and structure of critical force generating components and the molecular basis of centromere stiffness remain poorly understood.

Molecular and genetic approaches in several species have provided new insights into the mechanisms of rest-activity and sleep-wake regulation. Many of these discoveries are believed to support hypotheses about sleep functions, which nevertheless remain elusive. In this review we discuss the specific contribution of both mammalian and invertebrate models to our understanding of the molecular basis of sleep.

Cells split in two at the final step of each division cycle. This division normally bisects through the middle of the cell and generates two equal daughters. However, developmental signals can change the plane of cell cleavage to facilitate asymmetric segregation of fate determinants and control the position and relative sizes of daughter cells. The anaphase spindle instructs the site of cell cleavage in animal cells, hence its position is critical in the regulation of symmetric vs asymmetric cell division. Studies in a variety of models identified evolutionarily conserved mechanisms that control spindle positioning. However, how the spindle determines the cleavage site is poorly understood. Recent results in Caenorhabditis elegans indicate dual functions for a Gα pathway in positioning the spindle and cleavage furrow. We review asymmetric division of the C. elegans zygote, with a focus on microtubule-cortex interactions that position the spindle and cleavage plane.

Rhizobial bacteria colonize legume roots for the purpose of biological nitrogen fixation. A complex series of events, coordinated by host and bacterial signal molecules, underlie the development of this symbiotic interaction. Rhizobia elicit de novo formation of a novel root organ within which they establish a chronic intracellular infection. Legumes permit rhizobia to invade these root tissues while exerting control over the infection process. Once rhizobia gain intracellular access to their host, legumes also strongly influence the process of bacterial differentiation that is required for nitrogen fixation. Even so, symbiotic rhizobia play an active role in promoting their goal of host invasion and chronic persistence by producing a variety of signal molecules that elicit changes in host gene expression. In particular, rhizobia appear to advocate for their access to the host by producing a variety of signal molecules capable of suppressing a general pathogen defense response.