The Evolution of Mammalian Gene Families

Gene families are groups of homologous genes that are likely to have highly similar functions. Differences in family size due to lineage-specific gene duplication and gene loss may provide clues to the evolutionary forces that have shaped mammalian genomes. Here we analyze the gene families contained within the whole genomes of human, chimpanzee, mouse, rat, and dog. In total we find that more than half of the 9,990 families present in the mammalian common ancestor have either expanded or contracted along at least one lineage. Additionally, we find that a large number of families are completely lost from one or more mammalian genomes, and a similar number of gene families have arisen subsequent to the mammalian common ancestor. Along the lineage leading to modern humans we infer the gain of 689 genes and the loss of 86 genes since the split from chimpanzees, including changes likely driven by adaptive natural selection. Our results imply that humans and chimpanzees differ by at least 6% (1,418 of 22,000 genes) in their complement of genes, which stands in stark contrast to the oft-cited 1.5% difference between orthologous nucleotide sequences. This genomic “revolving door” of gene gain and loss represents a large number of genetic differences separating humans from our closest relatives

Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response

Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1

We have previously shown that platelets express 2 receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via alpha(IIb)beta(3). Adhesion occurs more slowly than with adenosine diphosphate (ADP) and requires phosphatidylinositol 3 (PI3)-kinase and protein kinase C activity but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca(++) ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation, or the activation of PI3-kinase and Src. From this we conclude that (1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca(++); (2) this is accomplished in part by activating Rap1; and (3) these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domai