Genomic analysis of non-splenic marginal zone lymphomas (MZL) indicates similarities between nodal and extranodal MZL and supports their derivation from memory B-cells

Three distinct categories of marginal zone lymphomas (MZLs) are currently recognized, principally based on their site of occurrence. They are thought to represent unique entities, but the relationship of one subtype with another is poorly understood. We investigated 17 non-splenic MZLs (seven nodal, 10 extranodal) by gene expression profiling to distinguish between subtypes and determine their cell of origin. Our findings suggest biological inter-relatedness of these entities despite occurrence at different locations and associations with possibly different aetiologies. Furthermore, the expression profiles of non-splenic MZL were similar to memory B cells.

Holocentric chromosomes: convergent evolution, meiotic adaptations, and genomic analysis

In most eukaryotes, the kinetochore protein complex assembles at a single locus termed the centromere to attach chromosomes to spindle microtubules. Holocentric chromosomes have the unusual property of attaching to spindle microtubules along their entire length. Our mechanistic understanding of holocentric chromosome function is derived largely from studies in the nematode Caenorhabditis elegans, but holocentric chromosomes are found over a broad range of animal and plant species. In this review, we describe how holocentricity may be identified through cytological and molecular methods. By surveying the diversity of organisms with holocentric chromosomes, we estimate that the trait has arisen at least 13 independent times (four times in plants and at least nine times in animals). Holocentric chromosomes have inherent problems in meiosis because bivalents can attach to spindles in a random fashion. Interestingly, there are several solutions that have evolved to allow accurate meiotic segregation of holocentric chromosomes. Lastly, we describe how extensive genome sequencing and experiments in nonmodel organisms may allow holocentric chromosomes to shed light on general principles of chromosome segregation.

Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.

Population genomic tests of models of adaptive radiation in Lake Victoria Region cichlid fish

Adaptive radiation is usually thought to be associated with speciation, but the evolution of intraspecific polymorphisms without speciation is also possible. The radiation of cichlid fish in Lake Victoria (LV) is perhaps the most impressive example of a recent rapid adaptive radiation, with 600+ very young species. Key questions about its origin remain poorly characterized, such as the importance of speciation versus polymorphism, whether species persist on evolutionary time scales, and if speciation happens more commonly in small isolated or in large connected populations. We used 320 individuals from 105 putative species from Lakes Victoria, Edward, Kivu, Albert, Nabugabo and Saka, in a radiation-wide amplified fragment length polymorphism (AFLP) genome scan to address some of these questions. We demonstrate pervasive signatures of speciation supporting the classical model of adaptive radiation associated with speciation. A positive relationship between the age of lakes and the average genomic differentiation of their species, and a significant fraction of molecular variance explained by above-species level taxonomy suggest the persistence of species on evolutionary time scales, with radiation through sequential speciation rather than a single starburst. Finally the large gene diversity retained from colonization to individual species in every radiation suggests large effective population sizes and makes speciation in small geographical isolates unlikely.

Comparison of genomic and proteomic data in recurrent airway obstruction affected horses using Ingenuity Pathway Analysis(R)

BACKGROUND: Recurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere. Environmental as well as genetic factors strongly influence the course and prognosis of the disease. Research has been focused on characterization of immunologic factors contributing to inflammatory responses, on genetic linkage analysis, and, more recently, on proteomic analysis of airway secretions from affected horses. The goal of this study was to investigate the interactions between eight candidate genes previously identified in a genetic linkage study and proteins expressed in bronchoalveolar lavage fluid (BALF) collected from healthy and RAO-affected horses. The analysis was carried out with Ingenuity Pathway Analysis(R) bioinformatics software. RESULTS: The gene with the greatest number of indirect interactions with the set of proteins identified is Interleukin 4 Receptor (IL-4R), whose protein has also been detected in BALF. Interleukin 21 receptor and chemokine (C-C motif) ligand 24 also showed a large number of interactions with the group of detected proteins. Protein products of other genes like that of SOCS5, revealed direct interactions with the IL-4R protein. The interacting proteins NOD2, RPS6KA5 and FOXP3 found in several pathways are reported regulators of the NFkappaB pathway. CONCLUSIONS: The pathways generated with IL-4R highlight possible important intracellular signaling cascades implicating, for instance, NFkappaB. Furthermore, the proposed interaction between SOCS5 and IL-4R could explain how different genes can lead to identical clinical RAO phenotypes, as observed in two Swiss Warmblood half sibling families because these proteins interact upstream of an important cascade where they may act as a functional unit.

The genomic Echinococcus microsatellite EmsB sequences: from a molecular marker to the epidemiological tool

In the field of molecular and epidemiological parasitology, characterization of fast evolving genetic markers appears as an important challenge to consider the diversity and genetic structure of parasites. The study of respective populations can help us to understand their adaptive strategies to survive and perpetuate the species within different host populations, all trying to resist infection. In the past, the relative monomorphic features of Echinococcus multilocularis, the causative agent of alveolar echinococcosis and a severe human parasitic disease, did not stimulate studies dealing with the genetic variability of Echinococcus species or respective populations. A recently developed, characterized and validated original multilocus microsatellite, named EmsB, tandemly repeated in the genome, offered an additional opportunity for this line of investigation. We have compiled in this review new insights brought by this molecular tracker on the transmission activity of Echinococcus among different hosts and at different geographical scales.

Genomic Data Reveal a Complex Making of Humans

In the last few years, two paradigms underlying human evolution have crumbled. Modern humans have not totally replaced previous hominins without any admixture, and the expected signatures of adaptations to new environments are surprisingly lacking at the genomic level. Here we review current evidence about archaic admixture and lack of strong selective sweeps in humans. We underline the need to properly model differential admixture in various populations to correctly reconstruct past demography. We also stress the importance of taking into account the spatial dimension of human evolution, which proceeded by a series of range expansions that could have promoted both the introgression of archaic genes and background selection.

Evolutionary forces shaping genomic islands of population differentiation in humans

Background Levels of differentiation among populations depend both on demographic and selective factors: genetic drift and local adaptation increase population differentiation, which is eroded by gene flow and balancing selection. We describe here the genomic distribution and the properties of genomic regions with unusually high and low levels of population differentiation in humans to assess the influence of selective and neutral processes on human genetic structure. Methods Individual SNPs of the Human Genome Diversity Panel (HGDP) showing significantly high or low levels of population differentiation were detected under a hierarchical-island model (HIM). A Hidden Markov Model allowed us to detect genomic regions or islands of high or low population differentiation. Results Under the HIM, only 1.5% of all SNPs are significant at the 1% level, but their genomic spatial distribution is significantly non-random. We find evidence that local adaptation shaped high-differentiation islands, as they are enriched for non-synonymous SNPs and overlap with previously identified candidate regions for positive selection. Moreover there is a negative relationship between the size of islands and recombination rate, which is stronger for islands overlapping with genes. Gene ontology analysis supports the role of diet as a major selective pressure in those highly differentiated islands. Low-differentiation islands are also enriched for non-synonymous SNPs, and contain an overly high proportion of genes belonging to the 'Oncogenesis' biological process. Conclusions Even though selection seems to be acting in shaping islands of high population differentiation, neutral demographic processes might have promoted the appearance of some genomic islands since i) as much as 20% of islands are in non-genic regions ii) these non-genic islands are on average two times shorter than genic islands, suggesting a more rapid erosion by recombination, and iii) most loci are strongly differentiated between Africans and non-Africans, a result consistent with known human demographic history.

Genomic differences between type strain PG1 and field strains of Mycoplasma mycoides subsp. mycoides small-colony type

The recently accomplished complete genomic sequence analysis of the type strain PG1 of Mycoplasma mycoides subsp. mycoides small-colony type revealed four large repeated segments of 24, 13, 12, and 8 kb that are flanked by insertion sequence (IS) elements. Genetic analysis of type strain PG1 and African, European, and Australian field and vaccine strains revealed that the 24-kb genetic locus is repeated only in PG1 and not in other M. mycoides subsp. mycoides SC strains. In contrast, the 13-kb genetic locus was found duplicated in some strains originating from Africa and Australia but not in strains that were isolated from the European outbreaks. The 12- and 8-kb genetic loci were found in two and three copies, respectively, in all 28 strains analyzed. The flanking IS elements are assumed to lead to these tandem duplications, thus contributing to genomic plasticity. This aspect must be considered when designing novel diagnostic approaches and recombinant vaccines.

Classification and selection of biomarkers in genomic data using LASSO

High-throughput gene expression technologies such as microarrays have been utilized in a variety of scientific applications. Most of the work has been on assessing univariate associations between gene expression with clinical outcome (variable selection) or on developing classification procedures with gene expression data (supervised learning). We consider a hybrid variable selection/classification approach that is based on linear combinations of the gene expression profiles that maximize an accuracy measure summarized using the receiver operating characteristic curve. Under a specific probability model, this leads to consideration of linear discriminant functions. We incorporate an automated variable selection approach using LASSO. An equivalence between LASSO estimation with support vector machines allows for model fitting using standard software. We apply the proposed method to simulated data as well as data from a recently published prostate cancer study.

Visualizing Genomic Data

The advent of experimental techniques capable of probing biomolecules and cells at high levels of resolution has led to a rapid change in the methods used for the analysis of experimental molecular biology data. In this article we give an overview over visualization techniques and methods that can be used to assess various aspects of genomic data.