Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.     

Exploring the energy landscapes of molecular recognition by a genetic algorithm: Analysis of the requirements for robust docking of HIV-1 protease and FKBP-12 complexes

Energy landscapes of molecular recognition are explored by performing “semi-rigid” docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-12), and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration. © 1996 Wiley-Liss, Inc.     

Identification of protein-protein interaction sites from docking energy landscapes

Protein recognition is one of the most challenging and intriguing problems in structural biology. Despite all the available structural, sequence and biophysical information about protein-protein complexes, the physico-chemical patterns, if any, that make a protein surface likely to be involved in protein-protein interactions, remain elusive. Here, we apply protein docking simulations and analysis of the interaction energy landscapes to identify protein-protein interaction sites. The new protocol for global docking based on multi-start global energy optimization of an all-atom model of the ligand, with detailed receptor potentials and atomic solvation parameters optimized in a training set of 24 complexes, explores the conformational space around the whole receptor without restrictions. The ensembles of the rigid-body docking solutions generated by the simulations were subsequently used to project the docking energy landscapes onto the protein surfaces. We found that highly populated low-energy regions consistently corresponded to actual binding sites. The procedure was validated on a test set of 21 known protein-protein complexes not used in the training set. As much as 81% of the predicted high-propensity patch residues were located correctly in the native interfaces. This approach can guide the design of mutations on the surfaces of proteins, provide geometrical details of a possible interaction, and help to annotate protein surfaces in structural proteomics.     

Folding and binding cascades: dynamic landscapes and population shifts

Whereas previously we have successfully utilized the folding funnels concept to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein Eng 12:713-720) and to describe binding (Tsai CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci 8:1181-1190), here we further extend the concept of folding funnels, illustrating its utility in explaining enzyme pathways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynamic, depending on the physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, Proc Natl Acad Sci USA 96:9970-9972). Different binding states change the surrounding environment of proteins. The changed environment is in turn expressed in shifted energy landscapes, with different shapes and distributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three-dimensional structure; they are determined by the distribution of its conformational substates, and in particular, by the redistributions of the populations under different environments. That is, protein function derives from its dynamic energy landscape, caused by changes in its surroundings.     

Differential environmental response of plant functional types in hedgerow habitats

Classifying species into functional groups reacting similar to multiple environmental factors based on shared biological characteristics forms a major challenge faced by present-day ecologists. Based on data of a hedgerow plant community, this study uses a multivariate approach to analyse if trait-based emergent species groups have real functional significance, i.e. if these groups are characterised by specific response profiles to a wide range of environmental factors. First, the influence of explanatory variable groups (abiotic environmental conditions, management variables, structural aspects, historical background and spatial configuration of the hedgerow network) on distribution patterns of individual plant species was analysed with partial logistic regression. Significant relationships were found between the ecological characteristics of a species and the relative importance of variable groups affecting the distribution of that species within a hedgerow network landscape. Next, a trait-based classification of hedgerow plant species was constructed using a hierarchical clustering procedure. Woody species segregated into two distinct groups, with differences predominantly associated with generative traits, herbaceous species in four groups differing mainly in vegetative traits and habitat preferences. Clear differences in response to multiple environmental factors between the emergent species groups demonstrated the functional significance of the constructed classification. Relationships between the trait- and response profile were examined and their ecological relevance discussed. With respect to the woody species groups, zoochorous species were affected more strongly by hedgerow structure and landscape context than anemochorous species. For the herbaceous species clustering, a relatively strong impact was found, amongst others, of historical variables on species with woodland preference in comparison with other species groups.

Zusammenfassung

Die Klassifizierung von Arten in funktionelle Gruppen, die aufgrund von gemeinsamen biologischen Eigenschaften in gleicher Weise auf multiple Umweltfaktoren reagieren, ist eine große Herausforderung, vor der heutige Ökologen stehen. Auf der Grundlage von Daten einer Heckenpflanzen-Lebensgemeinschaft folgt diese Untersuchung einer multivariaten Vorgehensweise, um zu analysieren, ob die auftretenden Artengruppen auf der Basis von Merkmalen eine wirkliche funktionelle Bedeutung haben, d. h. ob diese Gruppen durch spezifische Antwortprofile auf eine große Auswahl von Umweltfaktoren charakterisiert sind. Zuerst wurde der Einfluss von Gruppen erklärender Variablen (abiotische Umweltbedingungen, Managementvariablen, strukturelle Aspekte, geschichtlicher Hintergrund und räumliche Anordnung des Heckennetzes) auf die Verteilungsmuster einzelner Pflanzenarten mit partiellen logistischen Regressionen analysiert. Signifikante Beziehungen wurden zwischen den ökologischen Eigenschaften einer Art und der relativen Wichtigkeit von Variablengruppen gefunden, die die Verbreitung der Art innerhalb der Heckennetzlandschaft beeinflussen. Im Anschluss wurde eine merkmalsbasierte Klassifikation der Heckenpflanzenarten unter der Verwendung einer hierarchischen Gruppierungsprozedur konstruiert. Aufgrund von Unterschieden, die vor allem mit den Fortpflanzungsmerkmalen einhergingen, trennten sich die holzigen Arten in zwei verschiedene Gruppen auf. Krautige Arten trennten sich in vier Gruppen auf, die sich vor allem in den vegetativen Merkmalen und Habitatpräferenzen unterschieden. Klare Unterschiede in den Reaktionen auf multiple Umweltfaktoren zwischen den entstandenen Artengruppen demonstrierten die funktionelle Bedeutung der konstruierten Klassifikation. Die Beziehungen zwischen den Merkmals- und Antwortprofilen wurden untersucht und ihre ökologische Relevanz diskutiert. In Bezug auf die holzigen Artengruppen waren die zoochoren Arten stärker von der Heckenstruktur und dem Landschaftskontext beeinflusst als anemochore Arten. Für die krautigen Artencluster wurde unter anderem ein relativ starker Einfluss von historischen Variablen auf die Arten mit Waldpräferenz im Vergleich zu anderen Artengruppen gefunden.     

Simon-Ando decomposability and fitness landscapes

In this paper, we investigate fitness landscapes (under point mutation and recombination) from the standpoint of whether the induced evolutionary dynamics have a “fast-slow” time scale associated with the differences in relaxation time between local quasi-equilibria and the global equilibrium. This dynamical hevavior has been formally described in the econometrics literature in terms of the spectral properties of the appropriate operator matrices by Simon and Ando (Econometrica 29 (1961) 111), and we use the relations they derive to ask which fitness functions and mutation/recombination operators satisfy these properties. It turns out that quite a wide range of landscapes satisfy the condition (at least trivially) under point mutation given a sufficiently low mutation rate, while the property appears to be difficult to satisfy under genetic recombination. In spite of the fact that Simon-Ando decomposability can be realized over fairly wide range of parameters, it imposes a number of restriction on which landscape partitionings are possible. For these reasons, the Simon-Ando formalism does not appear to be applicable to other forms of decomposition and aggregation of variables that are important in evolutionary systems.     

Fitness landscape of sympatric pupfishes a useful tool for visualizing speciation

Arguably the most useful model of evolution emerged from the mind of Sewall Wright when he invented the fitness landscape (Wright 1932 ). In a recent issue of Molecular Ecology, Martin & Feinstein ( 2014 ) investigate the genetics and demographic history of an adaptive radiation of pupfish on San Salvador Island. Since the founder species colonized the island 10 000 years ago, two descendent species have appeared and in several lakes all three species (a durophage, a scale‐eater, and the generalist ancestral form) coexist. The three species are thought to occupy three distinct fitness peaks. The durophage and generalists' peaks are close, whereas the scale‐eater's peak is predicted to be distant and separated from the other two by a deep valley. Consistent with this view, gene flow between the two species on close fitness peaks is greater than the gene flow between these two species and the third species on a more distant peak. Correspondingly, the inferred fitness landscape predicts progress towards speciation, with more limited separation of species on close peaks, and that speciation is more complete for the scale‐eater. The article provides an illustrative example of the power afforded by analysis of large numbers of SNPs for estimating key parameters underlying evolutionary divergence.     

Managing rock outcrops to improve biodiversity conservation in Australian agricultural landscapes

Summary  Rocky outcrops are prominent geological features in agricultural landscapes worldwide. Reptiles are a major component of these habitats and some species are restricted to, and more abundant on, rocky outcrops than in remnant vegetation. Rock outcrops are important to reptiles because they provide resources that are often limited in the surrounding landscape (e.g. micro-gradients in climatic conditions, basking- and retreat-sites). However, there is a knowledge gap in the literature addressing the conservation value of small, rocky outcrops. Management may be necessary to reverse habitat degradation in these systems. We identify four key areas of management that need to be addressed to improve outcrop habitat values and enhance biodiversity conservation in agricultural landscapes. Specific actions involve: (i) protecting outcrops from processes that cause damage to rock microhabitat, (ii) monitoring and managing changes in vegetation structure to maintain thermally suitable environments, (iii) applying integrated pest animal control and (iv) improving matrix management to enhance inselberg function and landscape connectivity. Further research is required to evaluate the efficacy of different management regimes on outcrop biota. We hope this paper will provide the stimulus for land managers to incorporate rocky outcrops in future biodiversity conservation programmes.     

Infraspecific diversity of Cytisus emeriflorus Reichenb. (Leguminosae), an endemic plant with disjunct distribution: Evidence from isozyme data

ABSTRACT

C. emeriflorus is an endemic species occurring in two disjunct areas some 200 km apart: the Pre-Alps of Lombardia and the Pre-Alps of Friuli. Four populations from the western area and five populations from the eastern area were sampled in order to ascertain the amount and the distribution of variation throughout the range of the species. Phenetic measures of isozyme polymorphism were used. Diversity values showed that the species is polymorphic, despite its restricted distribution and the small population size; phenetic distances revealed that partitioning of diversity was largely within rather than among populations. Moreover, little differentiation was found between the two disjunct areas, although the western populations exhibited a slightly higher diversity compared with the eastern ones. The high level of polymorphism and the overall similarity between populations from the two areas may be ascribed to past contacts, and indicate that, despite the present widespread disjunction, the two areas have not evolved independently long enough for divergence to have occurred. There is no evidence that C. emeriflorus is at present genetically depauperated, although its range of distribution must have been much broader in the past; its present reduced distribution area and the small population size may be mainly due to ecological factors.