Current Genomics - Volume 8, Issue 6, 2007

The availability of high-throughput genomic data has motivated the development of numerous algorithms to infer gene regulatory networks. The validity of an inference procedure must be evaluated relative to its ability to infer a model network close to the ground-truth network from which the data have been generated. The input to an inference algorithm is a sample set of data and its output is a network. Since input, output, and algorithm are mathematical structures, the validity of an inference algorithm is a mathematical issue. This paper formulates validation in terms of a semi-metric distance between two networks, or the distance between two structures of the same kind deduced from the networks, such as their steady-state distributions or regulatory graphs. The paper sets up the validation framework, provides examples of distance functions, and applies them to some discrete Markov network models. It also considers approximate validation methods based on data for which the generating network is not known, the kind of situation one faces when using real data.

Zebrafish (Danio rerio) is a bona fide vertebrate model system for understanding human diseases. It allows the transparent visualization of the effects of ionizing radiation and the convenient testing of potential radioprotectors with morpholino-modified oligonucleotides (MO) knockdown. Furthermore, various reverse and forward genetic methods are feasible to decipher novel genetic modifiers of radioprotection. Examined in the review are the radioprotective effects of the proposed radiomodifiers Nanoparticle DF-1 (C-Sixty, Inc., Houston, TX) and Amifostine (WR-2721, Ethyol), the DNA repair proteins Ku80 and ATM, as well as the transplanted hematopoietic stem cells in irradiated zebrafish. The presence of any of these sufficiently rescued the radiation-induced damages in zebrafish, while its absence resulted in mutagenic phenotypes as well as an elevation of time- and dose-dependent radiation-induced apoptosis. Radiosensitizers Flavopiridol and AG1478, both of which block progression into the radioresistant S phase of the cell cycle, have also been examined in zebrafish. Zebrafish has indeed become a favorite model system to test for radiation modifiers that can potentially be used for radiotherapeutic purposes in humans.

Nucleotide insertions and deletions (indels) are responsible for gaps in the sequence alignments. Indel is one of the major sources of evolutionary change at the molecular level. We have examined the patterns of insertions and deletions in the 19 mammalian genomes, and found that deletion events are more common than insertions in the mammalian genomes. Both the number of insertions and deletions decrease rapidly when the gap length increases and single nucleotide indel is the most frequent in all indel events. The frequencies of both insertions and deletions can be described well by power law.

Gastric adenocarcinoma occurs via a sequence of molecular events known as the Correa's Cascade which often progresses over many years. Gastritis, typically caused by infection with the bacterium H. pylori, is the first step of the cascade that results in gastric cancer; however, not all cases of gastritis progress along this carcinogenic route. Despite recent antibiotic intervention of H. pylori infections, gastric adenocarcinoma remains the second most common cause of cancer deaths worldwide. Intestinal metaplasia is the next step along the carcinogenic sequence after gastritis and is considered to be a precursor lesion for gastric cancer; however, not all patients with intestinal metaplasia develop adenocarcinoma and little is known about the molecular and genetic events that trigger the progression of intestinal metaplasia into adenocarcinoma. This review aims to highlight the progress to date in the genetic events involved in intestinal-type gastric adenocarcinoma and its precursor lesion, intestinal metaplasia. The use of technologies such as whole genome microarray analysis, immunohistochemical analysis and DNA methylation analysis has allowed an insight into some of the events which occur in intestinal metaplasia and may be involved in carcinogenesis. There is still much that is yet to be discovered surrounding the development of this lesion and how, in many cases, it develops into a state of malignancy.

The currently estimated number of genes in the human genome is much smaller than previously predicted. As an explanation for this disparity, most individual genes have multiple transcriptional units that represent a variety of biologically important gene products. GNAS exemplifies a gene of such complexity. One of its products is the α-subunit of the stimulatory heterotrimeric G protein (Gsα), a ubiquitous signaling protein essential for numerous different cellular responses. Loss-of-function and gain-of-function mutations within Gsα-coding GNAS exons are found in various human disorders, including Albright's hereditary osteodystrophy, pseudohypoparathyroidism, fibrous dysplasia of bone, and some tumors of different origin. While Gsα expression in most tissues is biallelic, paternal Gsα expression is silenced in a small number of tissues, playing an important role in the development of phenotypes associated with GNAS mutations. Additional products derived exclusively from the paternal GNAS allele include XLαs, a protein partially identical to Gsα, and two non-coding RNA molecules, the A/B transcript and the antisense transcript. The maternal GNAS allele leads to NESP55, a chromogranin-like neuroendocrine secretory protein. In vivo animal models have demonstrated the importance of each of the exclusively imprinted GNAS products in normal mammalian physiology. However, although one or more of these products are also disrupted by most naturally occurring GNAS mutations, their roles in disease pathogenesis remain unknown. To further our understanding of the significance of this gene in physiology and pathophysiology, it will be important to elucidate the cellular roles and the mechanisms regulating the expression of each GNAS product.