Recessive Osteogenesis Imperfecta Caused by Missense Mutations in SPARC

Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_003118.3","term_id":"365777426","term_text":"NM_003118.3"}}NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.     

The red death meets the abdominal bristle: Polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans

Understanding the genetic basis of susceptibility to pathogens is an important goal of medicine and of evolutionary biology. A key first step toward understanding the genetics and evolution of any phenotypic trait is characterizing the role of mutation. However, the rate at which mutation introduces genetic variance for pathogen susceptibility in any organism is essentially unknown. Here, we quantify the per‐generation input of genetic variance by mutation (VM) for susceptibility of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa (defined as the median time of death, LT50). VM for LT50 is slightly less than VM for a variety of life‐history and morphological traits in this strain of C. elegans, but is well within the range of reported values in a variety of organisms. Mean LT50 did not change significantly over 250 generations of mutation accumulation. Comparison of VM to the standing genetic variance (VG) implies a strength of selection against new mutations of a few tenths of a percent. These results suggest that the substantial standing genetic variation for susceptibility of C. elegans to P. aeruginosa can be explained by polygenic mutation coupled with purifying selection.     

Cross-genome map based dissection of a nitrogen use efficiency ortho-metaQTL in bread wheat unravels concerted cereal genome evolution

Monitoring nitrogen use efficiency (NUE) in plants is becoming essential to maintain yield while reducing fertilizer usage. Optimized NUE application in major crops is essential for long-term sustainability of agriculture production. Here, we report the precise identification of 11 major chromosomal regions controlling NUE in wheat that co-localise with key developmental genes such as Ppd (photoperiod sensitivity), Vrn (vernalization requirement), Rht (reduced height) and can be considered as robust markers from a molecular breeding perspective. Physical mapping, sequencing, annotation and candidate gene validation of an NUE metaQTL on wheat chromosome 3B allowed us to propose that a glutamate synthase (GoGAT) gene that is conserved structurally and functionally at orthologous positions in rice, sorghum and maize genomes may contribute to NUE in wheat and other cereals. We propose an evolutionary model for the NUE locus in cereals from a common ancestral region, involving species specific shuffling events such as gene deletion, inversion, transposition and the invasion of repetitive elements.     

Horizontal gene transfer in nematodes: a catalyst for plant parasitism?

The origin of plant parasitism within the phylum Nematoda is intriguing. The ability to parasitize plants has originated independently at least three times during nematode evolution and, as more molecular data has emerged, it has become clear that multiple instances of horizontal gene transfer (HGT) from bacteria and fungi have played a crucial role in the nematode's adaptation to this new lifestyle. The first reported HGT cases in plant-parasitic nematodes were genes encoding plant cell wall-degrading enzymes. Other putative examples of HGT were subsequently described, including genes that may be involved in the modulation of the plant's defense system, the establishment of a nematode feeding site, and the synthesis or processing of nutrients. Although, in many cases, it is difficult to pinpoint the donor organism, candidate donors are usually soil dwelling and are either plant-pathogenic or plant-associated microorganisms, hence occupying the same ecological niche as the nematodes. The exact mechanisms of transfer are unknown, although close contacts with donor microorganisms, such as symbiotic or trophic interactions, are a possibility. The widespread occurrence of horizontally transferred genes in evolutionarily independent plant-parasitic nematode lineages suggests that HGT may be a prerequisite for successful plant parasitism in nematodes.     

Reconstruction of a beech population bottleneck using archival demographic information and Bayesian analysis of genetic data

Range expansion and contraction has occurred in the history of most species and can seriously impact patterns of genetic diversity. Historical data about range change are rare and generally appropriate for studies at large scales, whereas the individual pollen and seed dispersal events that form the basis of geneflow and colonization generally occur at a local scale. In this study, we investigated range change in Fagus sylvatica on Mont Ventoux, France, using historical data from 1838 to the present and approximate Bayesian computation (ABC) analyses of genetic data. From the historical data, we identified a population minimum in 1845 and located remnant populations at least 200 years old. The ABC analysis selected a demographic scenario with three populations, corresponding to two remnant populations and one area of recent expansion. It also identified expansion from a smaller ancestral population but did not find that this expansion followed a population bottleneck, as suggested by the historical data. Despite a strong support to the selected scenario for our data set, the ABC approach showed a low power to discriminate among scenarios on average and a low ability to accurately estimate effective population sizes and divergence dates, probably due to the temporal scale of the study. This study provides an unusual opportunity to test ABC analysis in a system with a well-documented demographic history and identify discrepancies between the results of historical, classical population genetic and ABC analyses. The results also provide valuable insights into genetic processes at work at a fine spatial and temporal scale in range change and colonization.     

The coupling hypothesis: why genome scans may fail to map local adaptation genes

Genomic scans of multiple populations often reveal marker loci with greatly increased differentiation between populations. Often this differentiation coincides in space with contrasts in ecological factors, forming a genetic-environment association (GEA). GEAs imply a role for local adaptation, and so it is tempting to conclude that the strongly differentiated markers are themselves under ecologically based divergent selection, or are closely linked to loci under such selection. Here, we highlight an alternative and neglected explanation: intrinsic (i.e. environment-independent) pre- or post-zygotic genetic incompatibilities rather than local adaptation can be responsible for increased differentiation. Intrinsic genetic incompatibilities create endogenous barriers to gene flow, also known as tension zones, whose location can shift over time. However, tension zones have a tendency to become trapped by, and therefore to coincide with, exogenous barriers due to ecological selection. This coupling of endogenous and exogenous barriers can occur easily in spatially subdivided populations, even if the loci involved are unlinked. The result is that local adaptation explains where genetic breaks are positioned, but not necessarily their existence, which can be best explained by endogenous incompatibilities. More precisely, we show that (i) the coupling of endogenous and exogenous barriers can easily occur even when ecological selection is weak; (ii) when environmental heterogeneity is fine-grained, GEAs can emerge at incompatibility loci, but only locally, in places where habitats and gene pools are sufficiently intermingled to maintain linkage disequilibria between genetic incompatibilities, local-adaptation genes and neutral loci. Furthermore, the association between the locally adapted and intrinsically incompatible alleles (i.e. the sign of linkage disequilibrium between endogenous and exogenous loci) is arbitrary and can form in either direction. Reviewing results from the literature, we find that many predictions of our model are supported, including endogenous genetic barriers that coincide with environmental boundaries, local GEA in mosaic hybrid zones, and inverted or modified GEAs at distant locations. We argue that endogenous genetic barriers are often more likely than local adaptation to explain the majority of Fst-outlying loci observed in genome scan approaches - even when these are correlated to environmental variables.