Annual Review of Genetics - Volume 33, 1999

The immune response is regulated not only by cell proliferation and differentiation, but also by programmed cell death, or apoptosis. In response to various stimuli, death factors bind to their respective receptors and activate the apoptotic death program in target cells. A cascade of specific proteases termed caspases mediates the apoptotic process. The activated caspases cleave various cellular components, a process that leads to morphological changes of the cells and nuclei, as well as to degradation of the chromosomal DNA. Loss-of-function mutations in the signaling molecules involved in apoptosis cause hyper-proliferation of cells in mouse and human. In contrast, exaggeration of this death cascade causes the destruction of various tissues.

A decade of research on adaptive mutation has revealed a plethora of mutagenic mechanisms that may be important in evolution. The DNA synthesis associated with recombination could be an important source of spontaneous mutation in cells that are not proliferating. The movement of insertion elements can be responsive to environmental conditions. Insertion elements not only activate and inactivate genes, they also provide sequence homology that allows large-scale genomic rearrangements. Some conjugative plasmids can recombine with their host's chromosome, and may acquire chromosomal genes that could then spread through the population and even to other species. Finally, a subpopulation of transient hypermutators could be a source of multiple variant alleles, providing a mechanism for rapid evolution under adverse conditions.

The past decade has witnessed extraordinary progress in retinal disease gene identification, the analysis of animal and tissue culture models of disease processes, and the integration of this information with clinical observations and with retinal biochemistry and physiology. During this period over twenty retinal disease genes were identified and for many of these genes there are now significant insights into their role in disease. This review presents an overview of the basic and clinical biology of the retina, summarizes recent progress in understanding the molecular mechanisms of inherited retinal diseases, and offers an assessment of the role that genetics will play in the next phase of research in this area.

Lentiviruses are associated with chronic diseases of the hematological and neurological systems in animals and man. In particular, human immunodeficiency virus type 1 (HIV-1) is the etiological agent of the global AIDS epidemic. The genomes of lentiviruses are complex, encoding a number of regulatory and accessory proteins not found in other retroviruses. This complexity is reflected in their replication cycle, which reveals intricate regulatory pathways and unique mechanisms for viral persistence. In this review, we highlight some of these unique features for HIV-1, with particular focus on the transcriptional and posttranscriptional control of gene expression. Although our understanding of the biology of HIV-1 is far from complete, the knowledge gained thus far has already led to novel strategies for both virus intervention and exploiting the lentiviruses for therapeutic applications.

Conservative site-specific recombination functions to create biological diversity in prokaryotes. Simple site-specific recombination systems consist of two recombination sites and a recombinase gene. The plasmid R64 shufflon contains seven recombination sites, which flank and separate four DNA segments. Site-specific recombinations mediated by the product of the rci gene between any two inverted recombination sites result in the inversion of four DNA segments independently or in groups. The shufflon functions as a biological switch to select one of seven C-terminal segments of the PilV proteins, which is a minor component of R64 thin pilus. The shufflon determines the recipient specificity in liquid matings of plasmid R64. Other multiple inversion systems as well as integrons, which are multiple insertion systems, are also described in this review.

The stability of mRNA in prokaryotes depends on multiple factors and it has not yet been possible to describe the process of mRNA degradation in terms of a unique pathway. However, important advances have been made in the past 10 years with the characterization of the cis-acting RNA elements and the trans-acting cellular proteins that control mRNA decay. The trans-acting proteins are mainly four nucleases, two endo- (RNase E and RNase III) and two exonucleases (PNPase and RNase II), and poly(A) polymerase. RNase E and PNPase are found in a multienzyme complex called the degradosome. In addition to the host nucleases, phage T4 encodes a specific endonuclease called RegB. The cis-acting elements that protect mRNA from degradation are stable stem-loops at the 5′ end of the transcript and terminators or REP sequences at their 3′ end. The rate-limiting step in mRNA decay is usually an initial endonucleolytic cleavage that often occurs at the 5′ extremity. This initial step is followed by directional 3′ to 5′ degradation by the two exonucleases. Several examples, reviewed here, indicate that mRNA degradation is an important step at which gene expression can be controlled. This regulation can be either global, as in the case of growth rate–dependent control, or specific, in response to changes in the environmental conditions.

A conserved mRNA degradation system, referred to as mRNA surveillance, exists in eukaryotic cells to degrade aberrant mRNAs. A defining aspect of aberrant transcripts is that the spatial relationship between the termination codon and specific downstream sequence information has been altered. A key, yet unknown, feature of the mRNA surveillance system is how this spatial relationship is assessed in individual transcripts. Two views have emerged to describe how discrimination between proper and improper termination might occur. In the first view, a surveillance complex assembles onto the mRNA after translation termination, and scans the mRNA in a 3′ to 5′ direction for a limited distance. If specific downstream sequence information is encountered during this scanning, then the surveillance complex targets the transcript for rapid decay. An alternate view suggests that the downstream sequence information influences how translation termination occurs. This view encompasses several ideas including: (a) The architecture of the mRNP can alter the rate of key steps in translation termination; (b) the discrimination between a proper and improper termination occurs via an internal, Upf1-dependent, timing mechanism; and (c) proper termination results in the restructuring of the mRNP to a form that promotes mRNA stability. This proposed model for mRNA surveillance is similar to other systems of kinetic proofreading that monitor the accuracy of other biogenic processes such as translation and spliceosome assembly.

The synthesis of ribosomes is one of the major metabolic pathways in all cells. In addition to around 75 individual ribosomal proteins and 4 ribosomal RNAs, synthesis of a functional eukaryotic ribosome requires a remarkable number of trans-acting factors. Here, we will discuss the recent, and often surprising, advances in our understanding of ribosome synthesis in the yeast Saccharomyces cerevisiae. These will underscore the unexpected complexity of eukaryotic ribosome synthesis.

French genetics had unusual beginnings. There are clear indications that the French biological establishment resisted Mendelian genetics strenuously from about 1910 to 1940. From about 1930 to 1950 several unconventional research programs with a strongly physiological orientation paved the way for the full entrance of French biology into genetics after World War II. This review examines some salient features of this history to clarify the strengths, weaknesses, and distinctive features of French genetics until about 1965. We suggest that after that date French genetics slowly merged into the international mainstream as genetics has become a largely molecular discipline.

Recent results from ancestral (minimally derived) protists testify to the tremendous diversity of the mitochondrial genome in various eukaryotic lineages, but also reinforce the view that mitochondria, descendants of an endosymbiotic α-Proteobacterium, arose only once in evolution. The serial endosymbiosis theory, currently the most popular hypothesis to explain the origin of mitochondria, postulates the capture of an α-proteobacterial endosymbiont by a nucleus-containing eukaryotic host resembling extant amitochondriate protists. New sequence data have challenged this scenario, instead raising the possibility that the origin of the mitochondrion was coincident with, and contributed substantially to, the origin of the nuclear genome of the eukaryotic cell. Defining more precisely the α-proteobacterial ancestry of the mitochondrial genome, and the contribution of the endosymbiotic event to the nuclear genome, will be essential for a full understanding of the origin and evolution of the eukaryotic cell as a whole.

Molecular genetic analysis of chemotaxis and thermotaxis in Caenorhabditis elegans has revealed the molecular bases of olfaction, taste, and thermosensation, which, in turn, has demonstrated that sensory signaling in C. elegans is very similar to that in vertebrates. A cyclic nucleotide-gated channel (TAX-2/TAX-4) that is highly homologous to the olfactory and photoreceptor channels in vertebrates is required for taste and thermosensation, in addition to olfaction. A cation channel (OSM-9) that is closely related to a capsaicin receptor channel is required for olfactory adaptation in one olfactory neuron and olfactory sensation in the other olfactory neuron. A novel Gα protein (ODR-3) is essential for olfactory responses in all olfactory neurons and aversive responses in a polymodal sensory neuron. A G protein–coupled seven-transmembrane receptor (ODR-10) is the first olfactory receptor whose ligand was elucidated. Using chemotaxis and thermotaxis as behavioral paradigms, neural plasticity including learning and memory can be studied genetically in C. elegans.

Formation of the bacterial division septum is catalyzed by a number of essential proteins that assemble into a ring structure at the future division site. Assembly of proteins into the cytokinetic ring appears to occur in a hierarchial order that is initiated by the FtsZ protein, a structural and functional analog of eukaryotic tubulins.

Placement of the division site at its correct location in Escherichia coli requires a division inhibitor (MinC), that is responsible for preventing septation at unwanted sites near the cell poles, and a topological specificity protein (MinE), that forms a ring at midcell and protects the midcell site from the division inhibitor. However, the mechanism responsible for identifying the position of the midcell site or the polar sites used for spore septum formation is still unclear.

Regulation of the division process and its coordination with other cell cycle events, such as chromosome replication, are poorly understood. However, a protein has been identified in Caulobacter (CtrA) that regulates both the initiation of chromosome regulation and the transcription of ftsZ, and that may play an important role in the coordination process.

Due to the increase of human migrations, the appearance of emerging and reemerging endemies, growing antibiotic resistance, and climatic changes, infectious diseases most probably constitute the major challenge for medicine in the next century. The advent of molecular methods of pathogen characterization has considerably improved our knowledge of the epidemiology of these diseases. However, the use of concepts of evolutionary genetics for interpreting “molecular epidemiology” data remains limited, although the application of such methods would broaden considerably the scope of this field of research, and allow epidemiologic and taxonomic approaches to be ascertained on a much firmer basis. In turn, pathogens, hosts, and vectors provide fascinating models for basic research. The artificial character of the border between “basic” and “applied” research is especially apparent with regard to the “integrated genetic epidemiology of infectious diseases” concept. The goal of this chapter is to evaluate the respective impact, on the transmission and pathogenicity of infectious diseases, of the host's, the pathogen's, and the vector's (for vector-borne diseases) genetic diversity, and the interactions between these three parameters (coevolution phenomena).

Retrotransposons are mobile genetic elements that transpose through reverse transcription of an RNA intermediate. Retrotransposons are ubiquitous in plants and play a major role in plant gene and genome evolution. In many cases, retrotransposons comprise over 50% of nuclear DNA content, a situation that can arise in just a few million years. Plant retrotransposons are structurally and functionally similar to the retrotransposons and retroviruses that are found in other eukaryotic organisms. However, there are important differences in the genomic organization of retrotransposons in plants compared to some other eukaryotes, including their often-high copy numbers, their extensively heterogeneous populations, and their chromosomal dispersion patterns. Recent studies are providing valuable insights into the mechanisms involved in regulating the expression and transposition of retrotransposons. This review describes the structure, genomic organization, expression, regulation, and evolution of retrotransposons, and discusses both their contributions to plant genome evolution and their use as genetic tools in plant biology.

DNA mismatch repair (MMR) is one of multiple replication, repair, and recombination processes that are required to maintain genomic stability in prokaryotes and eukaryotes. In the wake of the discoveries that hereditary nonpolyposis colorectal cancer (HNPCC) and other human cancers are associated with mutations in MMR genes, intensive efforts are under way to elucidate the biochemical functions of mammalian MutS and MutL homologs, and the consequences of defects in these genes. Genetic studies in cultured mammalian cells and mice are proving to be instrumental in defining the relationship between the functions of MMR in mutation and tumor avoidance. Furthermore, these approaches have raised awareness that MMR homologs contribute to DNA damage surveillance, transcription-coupled repair, and recombinogenic and meiotic processes.

HK022 is a temperate coliphage related to phage λ. Its chromosome has been completely sequenced, and several aspects of its life cycle have been intensively studied. In the overall arrangement, expression, and function of most of its genes, HK022 broadly resembles λ and other members of the λ family. Upon closer view, significant differences emerge. The differences reveal alternative strategies used by related phages to cope with similar problems and illuminate previously unknown regulatory and structural motifs. HK022 prophages protect lysogens from superinfection by producing a sequence-specific RNA binding protein that prematurely terminates nascent transcripts of infecting phage. It uses a novel RNA-based mechanism to antiterminate its own early transcription. The HK022 protein shell is strengthened by a complex pattern of covalent subunit interlinking to form a unitary structure that resembles chainmail armor. Its integrase and repressor proteins are similar to those of λ, but the differences provide insights into the evolution of biological specificity and the elements needed for construction of a stable genetic switch.

Meiotic chromosomes have been studied for many years, in part because of the fundamental life processes they represent, but also because meiosis involves the formation of homolog pairs, a feature which greatly facilitates the study of chromosome behavior. The complex events involved in homolog juxtaposition necessitate prolongation of prophase, thus permitting resolution of events that are temporally compressed in the mitotic cycle. Furthermore, once homologs are paired, the chromosomes are connected by a specific structure: the synaptonemal complex. Finally, interaction of homologs includes recombination at the DNA level, which is intimately linked to structural features of the chromosomes. In consequence, recombination-related events report on diverse aspects of chromosome morphogenesis, notably relationships between sisters, development of axial structure, and variations in chromatin status. The current article reviews recent information on these topics in an historical context. This juxtaposition has suggested new relationships between structure and function. Additional issues were addressed in a previous chapter (551).