MHC genomics and disease: Looking back to go forward

Ancestral haplotypes are conserved but extremely polymorphic kilobase sequences, which have been faithfully inherited over at least hundreds of generations in spite of migration and admixture. They carry susceptibility and resistance to diverse diseases, including deficiencies of CYP21 hydroxylase (47.1) and complement components (18.1), as well as numerous autoimmune diseases (8.1). The haplotypes are detected by segregation within ethnic groups rather than by SNPs and GWAS. Susceptibility to some other diseases is carried by specific alleles shared by multiple ancestral haplotypes, e.g., ankylosing spondylitis and narcolepsy. The difference between these two types of association may explain the disappointment with many GWAS. Here we propose a pathway for combining the two different approaches. SNP typing is most useful after the conserved ancestral haplotypes have been defined by other methods

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

Understanding the genesis of the block haplotype structure of the genome is a major challenge. With the completion of the sequencing of the Human Genome and the initiation of the HapMap project the concept that the chromosomes of the mammalian genome are a mosaic, or patchwork, of conserved extended block haplotype sequences is now accepted by the mainstream genomics research community. Ancestral Haplotypes (AHs) can be viewed as a recombined string of smaller Polymorphic Frozen Blocks (PFBs). How have such variant extended DNA sequence tracts emerged in evolution? Here the relevant literature on the problem is reviewed from various fields of molecular and cell biology particularly molecular immunology and comparative and functional genomics. Based on our synthesis we then advance a testable molecular and cellular model. A critical part of the analysis concerns the origin of the strand biased mutation signatures in the transcribed regions of the human and higher primate genome, A-to-G versus T-to-C (ratio ~1.5 fold) and C-to-T versus G-to-A (≥1.5 fold). A comparison and evaluation of the current state of the fields of immunoglobulin Somatic Hypermutation (SHM) and Transcription-Coupled DNA Repair focused on how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g., the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g., retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level, e.g., recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription process (also likely to be error-prone) that we have called "reverse transcription-mediated long DNA conversion." Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "transcription factories."

Genomic evolution and polymorphism: Segmental duplications and haplotypes at 108 regions on 21 chromosomes

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes.We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA).This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility.The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation

Eco-evolutionary dynamics on deformable fitness landscapes

Conventional approaches to modelling ecological dynamics often do not include evolutionary changes in the genetic makeup of component species and, conversely, conventional approaches to modelling evolutionary changes in the genetic makeup of a population often do not include ecological dynamics. But recently there has been considerable interest in understanding the interaction of evolutionary and ecological dynamics as coupled processes. However, in the context of complex multi-species ecosytems, especially where ecological and evolutionary timescales are similar, it is difficult to identify general organising principles that help us understand the structure and behaviour of complex ecosystems. Here we introduce a simple abstraction of coevolutionary interactions in a multi-species ecosystem. We model non-trophic ecological interactions based on a continuous but low-dimensional trait/niche space, where the location of each species in trait space affects the overlap of its resource utilisation with that of other species. The local depletion of available resources creates, in effect, a deformable fitness landscape that governs how the evolution of one species affects the selective pressures on other species. This enables us to study the coevolution of ecological interactions in an intuitive and easily visualisable manner. We observe that this model can exhibit either of the two behavioural modes discussed in the literature; namely, evolutionary stasis or Red Queen dynamics, i.e., continued evolutionary change. We find that which of these modes is observed depends on the lag or latency between the movement of a species in trait space and its effect on available resources. Specifically, if ecological change is nearly instantaneous compared to evolutionary change, stasis results; but conversely, if evolutionary timescales are closer to ecological timescales, such that resource depletion is not instantaneous on evolutionary timescales, then Red Queen dynamics result. We also observe that in the stasis mode, the overall utilisation of resources by the ecosystem is relatively efficient, with diverse species utilising different niches, whereas in the Red Queen mode the organisation of the ecosystem is such that species tend to clump together competing for overlapping resources. These models thereby suggest some basic conditions that influence the organisation of inter-species interactions and the balance of individual and collective adaptation in ecosystems, and likewise they also suggest factors that might be useful in engineering artificial coevolution

Multiple drivers of decline in the global status of freshwater crayfish (Decapoda: Astacidea)

International audienceRates of biodiversity loss are higher in freshwater ecosystems than in most terrestrial or marine ecosystems, making freshwater conservation a priority. However, prioritization methods are impeded by insufficient knowledge on the distribution and conservation status of freshwater taxa, particularly invertebrates. We evaluated the extinction risk of the world's 590 freshwater crayfish species using the IUCN Categories and Criteria and found 32% of all species are threatened with extinction. The level of extinction risk differed between families, with proportionally more threatened species in the Parastacidae and Astacidae than in the Cambaridae. Four described species were Extinct and 21% were assessed as Data Deficient. There was geographical variation in the dominant threats affecting the main centres of crayfish diversity. The majority of threatened US and Mexican species face threats associated with urban development, pollution, damming and water management. Conversely, the majority of Australian threatened species are affected by climate change, harvesting, agriculture and invasive species. Only a small proportion of crayfish are found within the boundaries of protected areas, suggesting that alternative means of long-term protection will be required. Our study highlights many of the significant challenges yet to come for freshwater biodiversity unless conservation planning shifts from a reactive to proactive approach

Corporate social responsibility: The good, the bad and the ugly

In this article I critically analyze contemporary discourses of corporate social responsibility and related discourses of sustainability and corporate citizenship. I argue that despite their emancipatory rhetoric, discourses of corporate citizenship, social responsibility and sustainability are defined by narrow business interests and serve to curtail interests of external stakeholders. I provide an alternate perspective, one that views discourses of corporate citizenship, corporate social responsibility, and sustainability as ideological movements that are intended to legitimize and consolidate the power of large corporations. I also problematize the popular notion of organizational 'stakeholders'. I argue that stakeholder theory of the firm represents a form of stakeholder colonialism that serves to regulate the behavior of stakeholders. I conclude by discussing implications for critical management studies

Atheism Considered as a Christian Sect

AbstractAtheists in general need share no particular political or metaphysical views, but atheists of the most modern, Western, militant sort, escaping from a merely nihilistic mind-set, are usually humanists of an especially triumphalist kind. In this paper I offer a critical analysis and partial history of their claims, suggesting that they are members of a distinctively Christian heretical sect, formed in reaction to equally heretical forms of monotheistic idolatry.</jats:p

The evolution of language: a comparative review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful &quot;just so stories&quot; about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the ‘‘descended larynx’ ’ of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language