Current Genomics - Volume 9, Issue 7, 2008

Tomato (Solanum lycopersicum L., Solanaceae) is an excellent model plant for genomic research of solanaceous plants, as well as for studying the development, ripening, and metabolism of fruit. In 2003, the International Solanaceae Project (SOL, www.sgn.cornell.edu) was initiated by members from more than 30 countries, and the tomato genome- sequencing project is currently underway. Genome sequence of tomato obtained by this project will provide a firm foundation for forthcoming genomic studies such as the comparative analysis of genes conserved among the Solanaceae species and the elucidation of the functions of unknown tomato genes. To exploit the wealth of the genome sequence information, there is an urgent need for novel resources and analytical tools for tomato functional genomics. Here, we present an overview of the development of genetic and genomic resources of tomato in the last decade, with a special focus on the activities of Japan SOL and the National Bio-Resource Project in the development of functional genomic resources of a model cultivar, Micro-Tom.

Alcohol dependence is a worldwide public health problem, and involves both environmental and genetic vulnerability factors. The heritability of alcohol dependence is rather high, ranging between 50% and 60%, although alcohol dependence is a polygenic, complex disorder. Genome-wide scans on large cohorts of multiplex families, including the collaborative study on genetics of alcoholism (COGA), emphasized the role of many chromosome regions and some candidate genes. The genes encoding the alcoholmetabolizing enzymes, or those involved in brain reward pathways, have been involved. Since dopamine is the main neurotransmitter in the reward circuit, genes involved in the dopaminergic pathway represent candidates of interest. Furthermore, gamma-amino-butyric acid (GABA) neurotransmitter mediates the acute actions of alcohol and is involved in withdrawal symptomatology. Numerous studies showed an association between variants within GABA receptors genes and the risk of alcohol dependence. In accordance with the complexity of the “alcohol dependence” phenotype, another field of research, related to the concept of endophenotypes, received more recent attention. The role of vulnerability genes in alcohol dependence is therefore re-assessed focusing on different phenotypes and endophenotypes. The latter include brain oscillations, EEG alpha and beta variants and alpha power, and amplitude of P300 amplitude elicited from a visual oddball task. Recent enhancement on global characterizations of the genome by high-throughput approach for genotyping of polymorphisms and studies of transcriptomics and proteomics in alcohol dependence is also reviewed.

Molecular cytogenetics is a promising field of biomedical research that has recently revolutionized our thinking on genome structure and behavior. This is in part due to discoveries of human genomic variations and their contribution to biodiversity and disease. Since these studies were primarily targeted at variation of the genome structure, it appears apposite to cover them by molecular cytogenomics. Human brain diseases, which encompass pathogenic conditions from severe neurodegenerative diseases and major psychiatric disorders to brain tumors, are a heavy burden for the patients and their relatives. It has been suggested that most of them, if not all, are of genetic nature and several recent studies have supported the hypothesis assuming them to be associated with genomic instabilities (i.e. single-gene mutations, gross and subtle chromosome imbalances, aneuploidy). The present review is focused on the intriguing relationship between genomic instability and human brain diseases. Looking through the data, we were able to conclude that both interindividual and intercellular genomic variations could be pathogenic representing, therefore, a possible mechanism for human brain malfunctioning. Nevertheless, there are still numerous gaps in our knowledge concerning the link between genomic variations and brain diseases, which, hopefully, will be filled by forthcoming studies. In this light, the present review considers perspectives of this dynamically developing field of neurogenetics and genomics.

Microarray-based clinical tests have become powerful tools in the diagnosis and treatment of diseases. In contrast to traditional DNA-based tests that largely focus on single genes associated with rare conditions, microarray-based tests are ideal for the study of diseases with underlying complex genetic causes. Several microarray based tests have been translated into clinical practice such as MammaPrint and AmpliChip CYP450. Additional cancer-related microarray-based tests are either in the process of FDA review or under active development, including Tissue of Tumor Origin and Ampli- Chip p53. All diagnostic microarray testing is ordered by physicians and tested by a Clinical Laboratories Improvement Amendment-certified (CLIA) reference laboratory. Recently, companies offering consumer based microarray testing have emerged. Individuals can order tests online and service providers deliver the results directly to the clients via a passwordprotected secure website. Navigenics, 23andMe and deCODE Genetics represent pioneering companies in this field. Although the progress of these microarray-based tests is extremely encouraging with the potential to revolutionize the recognition and treatment of common diseases, these tests are still in their infancy and face technical, clinical and marketing challenges. In this article, we review microarray-based tests which are currently approved or under review by the FDA, as well as the consumer-based testing. We also provide a summary of the challenges and strategic solutions in the development and clinical use of the microarray-based tests. Finally, we present a brief outlook for the future of microarray-based clinical applications.

Tuberous Sclerosis Complex is a multisystem disorder exhibiting a wide range of manifestations characterized by tumour-like lesions called hamartomas in the brain, skin, eyes, heart, lungs and kidneys. Tuberous Sclerosis Complex is genetically determined with an autosomal dominant inheritance and is caused by inactivating mutations in either the TSC1 or TSC2 genes. TSC1/2 genes play a fundamental role in the regulation of phosphoinositide 3-kinase (PI3K) signalling pathway, inhibiting the mammalian target of rapamycin (mTOR) through activation of the GTPase activity of Rheb. Mutations in TSC1/2 genes impair the inhibitory function of the hamartin/tuberin complex, leading to phosphorylation of the downstream effectors of mTOR, p70 S6 kinase (S6K), ribosomal protein S6 and the elongation factor binding protein 4E-BP1, resulting in uncontrolled cell growth and tumourigenesis. Despite recent promising genetic, diagnostic, and therapeutic advances in Tuberous Sclerosis Complex, continuing research in all aspects of this complex disease will be pivotal to decrease its associated morbidity and mortality. In this review we will discuss and analyse all the important findings in the molecular pathogenesis of Tuberous Sclerosis Complex, focusing on genetics and the molecular mechanisms that define this multisystemic disorder.

Human toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) to raise innate immune responses. The human TLR family was discovered because of its sequence similarity to fruit fly (Drosophila) Toll, which is involved in an anti-fungal response. In this review, we focus on the origin of the vertebrate TLR family highlighted through functional and phylogenetic analyses of TLRs in non-mammalian vertebrates. Recent extensive genome projects revealed that teleosts contain almost all subsets of TLRs that correspond to human TLRs (TLR1, 2, 3, 4, 5, 7, 8, and 9), whereas the urochordate Ciona intestinalis contains only a few TLR genes. Therefore, mammals likely obtained almost all TLR family members at the beginning of vertebrate evolution. This premise is further supported by several functional analyses of non-mammalian TLRs. We have summarized several teleost TLRs with unique properties distinct from mammalian TLRs to outline their specific roles. According to Takifugu rubripes genome project, the puffer fish possesses fish-specific TLR21 and 22. Surprisingly, phylogenetic analyses indicate that TLR21 and 22 emerged during an early period of vertebrate evolution in parallel with other TLRs and that the mammalian ancestor lost TLR21 and 22 during evolution. Our laboratory recently revealed that TLR22 recognizes double-strand RNA and induces interferon production through the TICAM-1 adaptor, as in TLR3, but unlike TLR3, TLR22 localizes to the cell surface. Therefore, differential expression of TLR3 and TLR22, rather than simple redundancy of RNA sensors, may explain the effective protection of fish from RNA virus infection in the water. In this review, we summarize the similarities and differences of the TLR family in various vertebrates and introduce these unique TLRs for a possible application to the field of clinical practices for cancer or virus infection.

The identification of quantitative trait loci, QTL, in arthritis animal models is a straight forward process. However, to identify the underlying genes is a great challenge. One strategy frequently used, is to combine QTL analysis with genomic/proteomic screens. This has resulted in a number of publications where carefully performed genomic analyses present likely candidate genes for their respective QTL's. However, seldom the findings are reconnected to the QTL controlled phenotypes. In this review, we use our own data as an illustrative example that “very likely candidate genes” identified by genomic/proteomics is not necessarily the same as true QTL underlying genes.

Transgenerational epigenetic inheritance, while poorly understood, is of great interest because it might help explain the increase in the incidence of diseases with an environmental contribution in humans, such as cancer, diabetes, and heart disease. Here, we review five Drosophila examples of transgenerational epigenetic inheritance and propose a unified mechanism that involves Polycomb Response Element/Trithorax Response Element (PRE/TRE) occupancy by either Polycomb Group (PcG) protein complexes or Trithorax group (TrxG) complexes. Among their other activities, PcG complexes cause histone 3 lysine 27 tri-methylation associated with repressed chromatin, whereas Trithorax group (TrxG) complexes induce histone 3 lysine 4 tri-methylation associated with actively transcribed chromatin. In this model, Hsp90 is an environmentally sensitive chromatin remodeling regulator that causes a switch in the chromatin from a permissive state to a non-permissive state for transcription. Consistent with this model, Hsp90 has recently been shown to be a chaperone for Tah1p (TPR-containing protein associated with Hsp90) and Pih1p (protein interacting with Hsp90), which connect to the chromatin remodelling factor Rvb1p (RuvB-like protein 1)/Rvb2p in yeast [1]. Also, Hsp90 is required for optimal activity of the histone H3 lysine-4 methyltransferase SMYD3 in mammals [2, 3]. Since PcG and TrxG complexes are involved in the post-translational modifications of histones, and since such modifications have been shown to be required to maintain imprinted marks, this unified mechanism might also help to explain transgenerational epigenetic inheritance in humans.