The spatiotemporal expression of genes in an organism is determined by regulatory systems that involve a large number of genes connected through a complex network of interactions. As an intuitive understanding of the behavior of these systems is hard to obtain, computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This report reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, ordinary and partial differential equations, stochastic equations, Boolean networks and their generalizations, qualitative differential equations, and rule-based formalisms. In addition, the report discusses how these formalisms have been used in the modeling and simulation of regulatory systems.

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Modeling and simulation of genetic regulatory systems: a literature review.

Alternative pre-mRNA splicing is a central mode of genetic regulation in higher eukaryotes. Variability in splicing patterns is a major source of protein diversity from the genome. In this review, I describe what is currently known of the molecular mechanisms that control changes in splice site choice. I start with the best-characterized systems from the Drosophila sex determination pathway, and then describe the regulators of other systems about whose mechanisms there is some data. How these regulators are combined into complex systems of tissue-specific splicing is discussed. In conclusion, very recent studies are presented that point to new directions for understanding alternative splicing and its mechanisms.

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Mechanisms of Alternative Pre-Messenger RNA Splicing

The protein Id: A negative regulator of helix-loop-helix DNA binding proteins

The collection of components required to carry out the intricate processes involved in generating and maintaining a living, breathing and, sometimes, thinking organism is staggeringly complex. Where do all of the parts come from? Early estimates stated that about 100,000 genes would be required to make up a mammal; however, the actual number is less than one-quarter of that, barely four times the number of genes in budding yeast. It is now clear that the 'missing' information is in large part provided by alternative splicing, the process by which multiple different functional messenger RNAs, and therefore proteins, can be synthesized from a single gene.

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Expansion of the eukaryotic proteome by alternative splicing

http://mcb.berkeley.edu/courses/mcb137/exercises/Tyson%20(2003).pdf

Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell

A logical analysis of the Drosophila gap-gene system.

Sex determination refers to the developmental programme that commits the embryo to either the male or the female pathway. The animal kingdom possesses a wealth of mechanisms via which gender is decided, all of which are represented among the insects. This manuscript focuses on a number of insects for which genetic and molecular data regarding sex determination mechanisms are available. The sex determination genetic cascade of Drosophila melanogaster is first discussed, followed by an analysis of the sex determination genes of other dipteran and non-dipteran insects. Representative examples of sex determination mechanisms that differ in their primary signal are also described. Finally, some evolutionary aspects of these mechanisms are discussed.

/pdf/sex-determining-mechanisms-in-insects-31bw714bsk.pdf

Sex-determining mechanisms in insects

In the past two decades, scientists have elucidated the molecular mechanisms behind Drosophila sex determination and dosage compensation. These two processes are controlled essentially by two different sets of genes, which have in common a master regulatory gene, Sex-lethal (Sxl). Sxl encodes one of the best-characterized members of the family of RNA binding proteins. The analysis of different mechanisms involved in the regulation of the three identified Sxl target genes (Sex-lethal itself, transformer, and male specific lethal-2) has contributed to a better understanding of translation repression, as well as constitutive and alternative splicing. Studies using the Drosophila system have identified the features of the protein that contribute to its target specificity and regulatory functions. In this article, we review the existing data concerning Sxl protein, its biological functions, and the regulation of its target genes.

RNA Binding Protein Sex-Lethal (Sxl) and Control of Drosophila Sex Determination and Dosage Compensation

Segmenting the fly embryo: a logical analysis of the pair-rule cross-regulatory module.

The ratio of X chromosomes to sets of autosomes (X:A) is the primary genetic signal that determines sex and dosage compensation in Drosophila. The gene Sex-lethal (Sxl) receives this signal and is responsible for the execution of the alternative developmental programmes of males and females. We have found that the scute (T4) gene, which is involved in neurogenesis, also plays a role in the activation of Sxl. The following results suggest that scute (T4) may be a numerator element of the X:A signal: scute (T4) mutations show female-specific lethality. There are female-specific lethal synergistic interactions between sis-a, a previously described numerator element, and mutants for T4. The female lethality is suppressed by SxlM1, a constitutive allele which expresses an active Sxl product independently of the X:A ratio. The Hw685 mutation, which overexpresses T4, is lethal to males with a duplication of sis-a. This lethality is suppressed by either Sxlf1, or the T4 point mutation sc10-1. There are female-specific lethal interactions between sc10-1 and daughter-less (da), a gene needed maternally for Sxl to become active. The sc10-1 mutation masculinizes triploid intersexes.

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Lucas Sánchez

Papers

A logical analysis of the Drosophila gap-gene system.

Sex-determining mechanisms in insects

RNA Binding Protein Sex-Lethal (Sxl) and Control of Drosophila Sex Determination and Dosage Compensation

Segmenting the fly embryo: a logical analysis of the pair-rule cross-regulatory module.

The scute (T4) gene acts as a numerator element of the X:a signal that determines the state of activity of sex-lethal in Drosophila.