Current Genomics - Volume 6, Issue 4, 2005

The idea that all humans naturally belong to one of a few biological types or races that evolved in isolation was unchallenged for centuries, but large-scale modern studies failed to associate racial labels with recognizable genetic clusters. Recently, the conclusions of those studies have been questioned by authors who argue that racial classification has objective scientific bases and is indispensable in epidemiology and genetics. However, no classification is useful if the classification units are vague or controversial, and no consensus was ever reached on the number and definition of the human races. The available studies show that there is geographic structure in human genome diversity, and that it is possible to infer with reasonable accuracy the continent of origin from an individual's multilocus genotype. However, clear-cut genetic boundaries between human groups, which would be necessary to recognise these groups as relatively isolated mating units which zoologists would call races, have not been identified so far. On the contrary, allele frequencies and synthetic descriptors of genetic variation appear distributed in gradients over much of the planet, which points to gene flow, rather than to isolation, as the main evolutionary force shaping human genome diversity. A better understanding of patterns of human diversity and of the underlying evolutionary processes is important for its own sake, but is also indispensable for the development of diagnostic and therapeutic tools designed for the individual genotype, rather than for illdefined race-specific genotypes.

The maintenance and assembly of chromatin is critical for the health of all cells. Cells, whether dividing or quiescent, that propagate damaged DNA or maintain chromosomes that are not properly assembled and/or packaged will ultimately succumb to genomic instability and cell death. Chromatin, the building block of the chromosome, is composed of repeated units of 147 basepairs of DNA wrapped around two copies of each of the four core histones, H2A, H2B, H3 and H4. Histones within chromatin serve as templates for a host of posttranslational modifications that facilitate virtually all events that require chromatin or chromosomes. Many studies have focused on the molecular mechanisms mediating and regulating the assembly process. These studies have utilized model systems ranging from yeast to humans. The regulatory processes are tightly linked to the cell cycle and require precise interactions between kinase cascades and the ubiquitintargeting pathway. It appears likely that not only are the series of factors required to assemble chromatin conserved across evolutionary boundaries, but so are the regulatory mechanisms that control these processes. The implications of these findings to research make it clear that lower eukaryotic model systems provide a powerful opportunity to learn valuable lessons about complicated higher eukaryotic molecular pathways. The lessons learned from yeast studies will provide valuable insight into understanding the disease processes that occur in humans as a result of impaired chromatin assembly.

Parkinson disease is one of the most common human neurodegenerative diseases. Its importance has led to a large number of studies focused on the development of cellular and animal models for the disease. We first discuss the potentials and limitations of the available mammalian models for PD. The results obtained so far in some alternative models, such as yeasts or invertebrates (Drosophila, Caenorhabditis), that may be used to develop rapid genetic or pharmacological screenings, are also summarized. Finally, we briefly discuss the results derived from novel approaches, such as the analysis of expression profiles using microarrays and proteomic analyses of cellular and animal models of Parkinson disease. Integration of the data derived from all those approaches emerges as a significant problem to be solved in the next few years.

A large number of tumor suppressor genes have been identified in Drosophila. Mutations in these genes cause effects in a wide range of tissues resulting in hyperplastic and, in the case of a few specific genes, neoplastic growth. The study of these tumors can provide molecular and cellular information that may shed some light on the possible mechanisms of tumorigenesis and invasiveness of human tumor cells. Recently, several studies have shown links between homologs of Drosophila tumor suppressor genes and human cancer. These recent advances are reviewed.

The neuronal ceroid lipofuscinoses (NCL) are the most common childhood neurodegenerative disorders with a worldwide incidence of up to 1 in 12, 500 live births. Various subtypes have been described on a clinical and genetic level, with mutations in one of at least eight genes, termed CLN1-8, forming the molecular basis of the disease. Since mutations in distinct genes result in similar pathologies, suggesting a common biological pathway, it is important to not only elucidate the function of the proteins they encode but also to examine the possible consequences of protein dysfunction in cellular processes. Development of animal models of NCL disease and advancements in genomic and proteomic technologies provide valuable tools in the search for the underlying basis of disease. Application of DNA microarray analysis has revealed alterations in the expression of genes involved in a number of cellular processes including inflammation, neuronal function, oxidative stress, energy metabolism and proteolytic processing. Comparison of DNA microarray data from various NCL animal models has revealed not only alterations in a number of common pathological pathways characteristic of neurodegenerative disorders, but also some unique changes that may provide an insight into the function of the mutated proteins that underlie these diseases. Here, we review and discuss how such studies have furthered our current understanding of protein function and related pathological processes.

Newly developed full-length cDNA library technologies have enabled us to generate an unprecedented scale of cDNA resources with respect to both the forms of the physical cDNA clones and cDNA sequence information. Detailed annotations were attached to each of the cDNAs both computationally and manually and several integrated databases on the cDNA information were launched in a publicly accessible manner. Now, taking advantage of the physical cDNA clone resources, which are thought to cover most of the entire protein-coding genes in humans and mice non-redundantly, efficient high-throughput approaches, collectively called functional genomics approaches, are underway for characterizing biological functions of the encoded proteins from various points of view. In addition, it has become clear that the fulllength cDNA resources are also useful for determining the precise genomic positions of the transcriptional start sites. The positional information of the TSSs allowed us to identify and analyze the adjacent promoter regions as putative transcriptional regulatory regions. Moreover, several very recently developed methods, combining full-length cDNA technologies with SAGE technologies, have enabled further high-throughput identification of the TSSs. Based on further expansion of the full-length cDNA data, attempts have been started towards a comprehensive understanding of what genomic elements, including genic regions and non-genic regions such as promoters, would bring about what biological consequences in what cellular contexts. Rapid compilation of genomic sequence data as well as multifaceted use of the full-length cDNA resources will shortly lay a firm foundation for a global understanding of the complex molecular biological systems which convert the information in the genomic DNA into a living cell.