Three Common Variants of LEP, NPY1R and GPR54 Show No Association with Age at Menarche

International audienc

Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting β cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age

Genetic information transfer promotes cooperation in bacteria

Many bacterial species are social, producing costly secreted “public good” molecules that enhance the growth of neighboring cells. The genes coding for these cooperative traits are often propagated via mobile genetic elements and can be virulence factors from a biomedical perspective. Here, we present an experimental framework that links genetic information exchange and the selection of cooperative traits. Using simulations and experiments based on a synthetic bacterial system to control public good secretion and plasmid conjugation, we demonstrate that horizontal gene transfer can favor cooperation. In a well-mixed environment, horizontal transfer brings a direct infectious advantage to any gene, regardless of its cooperation properties. However, in a structured population transfer selects specifically for cooperation by increasing the assortment among cooperative alleles. Conjugation allows cooperative alleles to overcome rarity thresholds and invade bacterial populations structured purely by stochastic dilution effects. Our results provide an explanation for the prevalence of cooperative genes on mobile elements, and suggest a previously unidentified benefit of horizontal gene transfer for bacteria

Engineering gene overlaps to sustain genetic constructs in vivo

International audienceEvolution is often an obstacle to the engineering of stable biological systems due to the selection of mutations inactivating costly gene circuits. Gene overlaps induce important constraints on sequences and their evolution. We show that these constraints can be harnessed to increase the stability of costly genes by purging loss-of-function mutations. We combine computational and synthetic biology approaches to rationally design an overlapping reading frame expressing an essential gene within an existing gene to protect. Our algorithm succeeded in creating overlapping reading frames in 80% of E. coli genes. Experimentally, scoring mutations in both genes of such overlapping construct, we found that a significant fraction of mutations impacting the gene to protect have a deleterious effect on the essential gene. Such an overlap thus protects a costly gene from removal by natural selection by associating the benefit of this removal with a larger or even lethal cost. In our synthetic constructs, the overlap converts many of the possible mutants into evolutionary dead-ends, reducing the evolutionary potential of the system and thus increasing its stability over time

Indirect Fitness Benefits Enable the Spread of Host Genes Promoting Costly Transfer of Beneficial Plasmids

<div><p>Bacterial genes that confer crucial phenotypes, such as antibiotic resistance, can spread horizontally by residing on mobile genetic elements (MGEs). Although many mobile genes provide strong benefits to their hosts, the fitness consequences of the process of transfer itself are less clear. In previous studies, transfer has been interpreted as a parasitic trait of the MGEs because of its costs to the host but also as a trait benefiting host populations through the sharing of a common gene pool. Here, we show that costly donation is an altruistic act when it spreads beneficial MGEs favoured when it increases the inclusive fitness of donor ability alleles. We show mathematically that donor ability can be selected when relatedness at the locus modulating transfer is sufficiently high between donor and recipients, ensuring high frequency of transfer between cells sharing donor alleles. We further experimentally demonstrate that either population structure or discrimination in transfer can increase relatedness to a level selecting for chromosomal transfer alleles. Both mechanisms are likely to occur in natural environments. The simple process of strong dilution can create sufficient population structure to select for donor ability. Another mechanism observed in natural isolates, discrimination in transfer, can emerge through coselection of transfer and discrimination alleles. Our work shows that horizontal gene transfer in bacteria can be promoted by bacterial hosts themselves and not only by MGEs. In the longer term, the success of cells bearing beneficial MGEs combined with biased transfer leads to an association between high donor ability, discrimination, and mobile beneficial genes. However, in conditions that do not select for altruism, host bacteria promoting transfer are outcompeted by hosts with lower transfer rate, an aspect that could be relevant in the fight against the spread of antibiotic resistance.</p></div

Association Analysis Indicates That a Variant GATA-Binding Site in the <i>PIK3CB</i> Promoter Is a Cis-Acting Expression Quantitative Trait Locus for This Gene and Attenuates Insulin Resistance in Obese Children

OBJECTIVE—In search of functional polymorphisms associated with the genetics of insulin resistance, we studied a variant in the promoter of PIK3CB, the gene coding for the catalytic p110β subunit of phosphatidylinositol (PI) 3-kinase, a major effector of insulin action. RESEARCH DESIGN AND METHODS—The rs361072 C/T variant was selected among single nucleotide polymorphisms of the PIK3CB region because we suspected that its common C allele (allelic frequency ∼50% in Europeans) could create a GATA-binding motif and was genotyped in five cohorts of obese (n = 1,876) and two cohorts of nonobese (n = 1,490) European children. To estimate insulin resistance in these children, the homeostasis model assessment for insulin resistance (HOMA-IR) index was measured in strict nutritional conditions. GATA-binding and functional effects of rs361072 were explored in transfected cell lines and in lymphocytes from obese children. RESULTS—The rs361072 C/T variant was associated with HOMA-IR in the obese children cohorts (1.7 × 10−12 &lt; P &lt; 2 × 10−4 for C/C vs. T/T using regression analysis). HOMA-IR averaged 3.3 ± 0.1 in C/C and 4.5 ± 0.2 in T/T obese children (P = 4.5 × 10−6 by ANOVA). C/T patients had intermediate values. As shown by the interaction between BMI and genotype (P = 2.1 × 10−9), the association of rs361072 with HOMA-IR depended on BMI and was only marginal in nonobese children (P = 0.04). At the molecular level, the C allele of rs361072 was found to create a GATA-binding site able to increase transcription of PIK3CB. CONCLUSIONS—We postulate that the C allele of rs361072 is a causal variant capable of attenuating insulin resistance in obese children through increased expression of p110β

Default parameter values used in simulations.

<p>Parameters were generally based on our experimental measurements (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002478#sec015" target="_blank">Materials and Methods</a> for details and exceptions).</p

Selection of donor ability in structured populations.

<p><b>A: Experimental setup.</b> D⁺ (good donor, red) and D⁻ (nondonor, blue) strains are competed. 2.5% of D⁺ and D⁻ cells initially carry C plasmids (bright colours), while 97.5% do not (pale colours). The population <i>m</i> is a single well-mixed population; metapopulation <i>s</i> consists of two subpopulations, <i>s</i>_<i>1</i> and <i>s</i>_<i>2</i>, with initial D⁺/D⁻ ratios of 1/9 and 9/1. After growth and transfer (t₀ to t₁), subpopulations from <i>s</i> are pooled and cells are grown to saturation with or without antibiotic (Cm) selection (t₁ to t₂). The proportions of different cell types are represented schematically and do not correspond to actual numbers. <b>B: Selection of D</b>^<b>+</b> <b>strain.</b> The frequency of the good donor D⁺ is shown for <i>s</i> (black) and <i>m</i> (green) populations, with (plain lines) or without (dashed lines) Cm antibiotic during the selection phase. Good donors are only selected for in the <i>s</i> metapopulation, in the presence of antibiotic. <b>C: Plasmid dynamics.</b> Plasmid frequency in each population is shown for the transfer phase (from t₀ to t₁)_, in each of <i>m</i>, <i>s</i>_<i>1</i>, and <i>s</i>_<i>2</i> populations. Plasmids spread mostly in the s₂ subpopulation, enriched in the better donor, D⁺. <b>D: Transfer bias.</b> The proportion of C plasmids present in D⁺ strain, is shown as a function of time for <i>s</i> and <i>m</i> populations (same colour scheme as in B panel). C plasmids get enriched in the better donor D⁺ strain during the transfer phase, for the structured population <i>s</i>. All results are shown as means ± SEM. (<i>N</i> ≥ 6). Data are available from FigShare at <a href="http://dx.doi.org/10.6084/m9.figshare.3199252" target="_blank">http://dx.doi.org/10.6084/m9.figshare.3199252</a>.</p