Constraining local structure can speed up folding by promoting structural polarization of the folding pathway

The pathway which proteins take to fold can be influenced from the earliest events of structure formation. In this light, it was both predicted and confirmed that increasing the stiffness of a beta hairpin turn decreased the size of the transition state ensemble (TSE), while increasing the folding rate. Thus, there appears to be a relationship between conformationally restricting the TSE and increasing the folding rate, at least for beta hairpin turns. In this study, we hypothesize that the enormous sampling necessary to fold even two-state folding proteins in silico could be reduced if local structure constraints were used to restrict structural heterogeneity by polarizing folding pathways or forcing folding into preferred routes. Using a Gō model, we fold Chymotrypsin Inhibitor 2 (CI-2) and the src SH3 domain after constraining local sequence windows to their native structure by rigid body dynamics (RBD). Trajectories were monitored for any changes to the folding pathway and differences in the kinetics compared with unconstrained simulations. Constraining local structure decreases folding time two-fold for 41% of src SH3 windows and 45% of CI-2 windows. For both proteins, folding times are never significantly increased after constraining any window. Structural polarization of the folding pathway appears to explain these rate increases. Folding rate enhancements are consistent with the goal to reduce sampling time necessary to reach native structures during folding simulations. As anticipated, not all constrained windows showed an equal decrease in folding time. We conclude by analyzing these differences and explain why RBD may be the preferred way to constrain structure.     

具有约束条件的变分不等式的可行的增广拉格朗日方法

采用增广拉格朗日方法求解了具有约束条件的变分不等式问题,并证明了这一方法的全局收敛性．运用增广拉格朗日方法和非精确的半光滑牛顿法求解了具有约束条件的变分不等式的一类子问题．我们给出了四个数值算例以说明这一方法的可行性．     

A conceptual framework for the evolution of ecological specialisation

Ecology Letters (2011) 14: 841-851 ABSTRACT: Ecological specialisation concerns all species and underlies many major ecological and evolutionary patterns. Yet its status as a unifying concept is not always appreciated because of its similarity to concepts of the niche, the many levels of biological phenomena to which it applies, and the complexity of the mechanisms influencing it. The evolution of specialisation requires the coupling of constraints on adaptive evolution with covariation of genotype and environmental performance. This covariation itself depends upon organismal properties such as dispersal behaviour and life history and complexity in the environment stemming from factors such as species interactions and spatio-temporal heterogeneity in resources. Here, we develop a view on specialisation that integrates across the range of biological phenomena with the goal of developing a more predictive conceptual framework that specifically accounts for the importance of biotic complexity and coevolutionary events.     

Maternal effort and joey growth in koalas (Phascolarctos cinereus)

The extent to which sex-biased maternal investment characterizes mammals is controversial, with less information available for evaluating patterns of maternal effort in marsupials than in placentals. Koalas Phascolarctos cinereus are size-dimorphic animals with a lengthy period of dependency and they reside in mating systems that might favour sex-biased maternal investment. We examined 18 years of data recorded from koalas living at the San Diego Zoo in order to examine how joey development and maternal condition might be connected. Koalas are pregnant for only 1 month, but joey emergence from the pouch does not occur until 32 weeks of age. Neither maternal condition nor age affected sex ratio at joey emergence, and both sexes had the same survivorship prospects. Koala dams transport and nurse joeys for close to 1 year, at which time the two sexes are size dimorphic. Given the poor-quality diet of koalas, combined with maternal transport of infants who are at least 25% of maternal mass, we suggest that infant rearing poses high energetic costs on koala females. We suggest that ecological and energetic constraints have moulded koala maternal strategies such that females maximize allocation of resources to offspring, regardless of sex, in order to increase prospects for joey survivorship.     

Developmental differences in visceral morphology of megophryine pelobatid tadpoles in relation to their body form and mode of life

Tadpoles face severe packing constraints on viscera within the pleuro-peritoneal cavity because of their extremely short torsos—a feature they share with adult anurans—and the concomitant need for relatively slender torsos for efficient locomotion. We examined the effects of differences in body form and habits on the size, shape and development of viscera in three kinds of sympatric, stream-associated pelobatid tadpoles. Leptobrachium montanumlarvae are generalized, wide, deep-bodied tadpoles. Larval Leptolalax gracilis are very slender and live in the crevices between rocks on the bottom of riffles. Larval Megophrys nasuta are intermediate between the other two in body form, and live with L. montanum in a variety of microhabitats but feed at the surface film. In all three species, liver, gall bladder, arid kidneys begin development early and grow isometrically throughout larval life. The gut and pancreas have a growth spurt shortly after hatching, then grow at a constant rate until near metamorphosis when both shrink drastically. The spleen grows at a slower rate than the body throughout the larval period. Lungs do not appear in L. gracilis until the tadpole approaches metamorphosis, which accords with its benthic habits, whereas they grow throughout the larval period in L. montanum and M. nasuta. In M. nasuta, however, the lungs are unusually wide anteriorly; this shifts buoyancy forward and facilitates the head-up feeding posture characteristic of that species. Gonads appear early in L. montanum and L. gracilis, but not until near metamorphosis in M. nasuta. We suggest that accelerated gonadal development in tadpoles characterizes species that metamorphose close to their size at first reproduction. Leptobrachium montanum, with the bulkiest body and most generalized habits, has relatively and absolutely the largest gut, liver (x of combined gut and liver volume = 24%, of total volume), and kidneys. Leptolalax gracilis, the most slender tadpole, has relatively the smallest combined gut and liver volume (x = 10% of total volume). Other premetamorphic differences among the species were observed in gut coiling, liver, pancreas and kidney shape and left/right asymmetry of urogenital organs. The major interspecific differences we observed in the size, shape, and developmental patterns of viscera in tadpoles are clearly related to interspecific differences in torso shape, microhabitat distribution and mode of feeding.     

Characterization and evolution of major histocompatibility complex class II genes in the aye-aye, Daubentonia madagascariensis

Major histocompatibility complex genes (Mhc-DQB and Mhc-DRB) were sequenced in seven aye-ayes (Daubentonia madagascariecsis), which is an endemic and endangered species in Madagascar. An aye-aye from a north-eastern population showed genetic relatedness to individuals of a north-western population and had a somewhat different repertoire from another north-eastern individual. These observations suggest that the extent of genetic variation in Mhc genes is not excessively small in the aye-aye in spite of recent rapid destruction of their habitat by human activities. In light of Mhc gene evolution, trans-species and allelic polymorphisms can be estimated to have been retained for more than 50 Ma (million years) based on the time scale of lemur evolution.     

Post-natal ontogeny of the mandible and ventral cranium in <Emphasis Type="Italic">Marmota</Emphasis> species (Rodentia,Sciuridae): allometry and phylogeny

Post-natal ontogenetic variation of the marmot mandible and ventral cranium is investigated in two species of the subgenus Petromarmota (M. caligata, M. flaviventris) and four species of the subgenus Marmota (M. caudata, M. himalayana, M. marmota, M. monax). Relationships between size and shape are analysed using geometric morphometric techniques. Sexual dimorphism is negligible, allometry explains the main changes in shape during growth, and males and females manifest similar allometric trajectories. Anatomical regions affected by size-related shape variation are similar in different species, but allometric trajectories are divergent. The largest modifications of the mandible and ventral cranium occur in regions directly involved in the mechanics of mastication. Relative to other anatomical regions, the size of areas of muscle insertion increases, while the size of sense organs, nerves and teeth generally decreases. Epigenetic factors, developmental constraints and size variation were found to be the major contributors in producing the observed allometric patterns. A phylogenetic signal was not evident in the comparison of allometric trajectories, but traits that allow discrimination of the Palaearctic marmots from the Nearctic species of Petromarmota are present early in development and are conserved during post-natal ontogeny.     

A population-based LD map of the human chromosome 6p

The recent publication of the complete sequence of human chromosome 6 provides a platform from which to investigate genomic sequence variation. We report here a detailed linkage disequilibrium (LD) pattern map across the entire human chromosome 6p by using a set of 1152 single nucleotide polymorphisms (SNPs) in a population of 198 Singaporean Chinese, with 326 SNPs focused in the major histocompatibility complex (MHC) region. Our analysis shows some unexpectedly high segments of strong LD in a 10-Mb region that includes the extremely polymorphic and gene-rich MHC loci and many non-MHC genes. These include the telomeric peri-MHC region that harbors olfactory receptors, histones and zinc finger clusters, and the centromeric peri-MHC region that contains several unknown open reading frames. The data also help refine a human–mouse synteny break in the region between 28.6 and 29.4 Mb. The population-based LD map presented here will provide an essential resource for understanding the genomic sequence variation of chromosome 6p and LD mapping of disease genes of complex genetic traits. Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users. H. Yu and J.-M. Chia should be regarded as joint first authors.     

Unprecedented intraspecific diversity of the MHC class I region of a teleost medaka, Oryzias latipes

The major histocompatibility complex (MHC) is present at a single chromosomal locus of all jawed vertebrate analyzed so far, from sharks to mammals, except for teleosts whose orthologs of the mammalian MHC-encoded genes are dispersed at several chromosomal loci. Even in teleosts, several class IA genes and those genes directly involved in class I antigen presentation preserve their linkage, defining the teleost MHC class I region. We determined the complete nucleotide sequence of the MHC class I region of the inbred HNI strain of medaka, Oryzias latipes (northern Japan population-derived), from four overlapping bacterial artificial chromosome (BAC) clones spanning 540,982 bp, and compared it with the published sequence of the corresponding region of the inbred Hd-rR strain of medaka (425,935 bp, southern Japan population-derived) as the first extensive study of intraspecies polymorphisms of the ectotherm MHC regions. A segment of about 100 kb in the middle of the compared sequences encompassing two class Ia genes and two immunoproteasome subunit genes, PSMB8 and PSMB10, was so divergent between these two inbred strains that a reliable sequence alignment could not be made. The rest of the compared region (about 320 kb) showed a fair correspondence, and an approximately 96% nucleotide identity was observed upon gap-free segmental alignment. These results indicate that the medaka MHC class I region contains an ∼100-kb polymorphic core, which is most probably evolving adaptively by accumulation of point mutations and extensive genetic rearrangements such as insertions, deletions and duplications. The nucleotide sequence data of HNI MHC class I region reported in this paper have been submitted to the DDBJ/EMBL/GenBank and were assigned the accession number AB183488.     

Mechanisms of constraints: the contributions of selection and genetic variance to the maintenance of cotyledon number in wild radish

The evolutionary mechanisms underlying the maintenance of invariant traits are poorly understood, partly because the lack of variance makes these mechanisms difficult to study. Although the number of cotyledons that plant species produce is highly canalized, populations of plants frequently contain individuals with abnormal cotyledon numbers. In a garden study with 1857 wild radish plants from 75 paternal half-sibling families, 89 (almost 5%) had cotyledon numbers less or greater than two. We found evidence for direct selection on cotyledon number, but no evidence for additive genetic variation for cotyledon number. In spite of the very large sample size, our power to detect variation and selection was hampered by the small number of individuals (10) producing more than two cotyledons. Thus, our results provide support for both a lack of genetic variation and selection as reasons for the current lack of variation in wild radish cotyledon number.