Genome-Wide Effects of Long-Term Divergent Selection

To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaig

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age ∼13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m−2/150 mg m−2 day−1, 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1–7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin–temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m−2 cisplatin and 150 mg m−2 × 5 temozolomide in heavily treated, and 200 mg m−2 × 5 temozolomide in less-heavily pretreated children

Using Classical Population Genetics Tools with Heterochroneous Data: Time Matters!

BACKGROUND:New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. METHODOLOGY/PRINCIPAL FINDINGS:We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony ( approximately 10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism theta, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22-130 thousand years ago (KYA)). CONCLUSIONS/SIGNIFICANCE:Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale

The noble gas "subduction barrier" revisited

International audienceIt has been proposed that an important subduction of atmospheric noble gases in the mantle occurred during Earth's history, on the basis of the measurements of light xenon isotopes in CO2 well gases. Moreover, the fact that the 38Ar/36Ar ratio is atmospheric in all oceanic basalts, even for uncontaminated samples (e.g. with high 20Ne/22Ne), may also suggest that a massive subduction of atmospheric argon occurred, if the primitive Earth had a solar-like 38Ar/36Ar. This also implies that the atmosphere suffered a massive gas loss accompanied by mass fractionation (e.g. hydrodynamic escape) after mantle degassing or that a late veneer with an atmospheric composition occurred. Such a hypothesis is explored for rare gases, by developing a model in which degassing and air subduction started ~4.4Ga ago. In the model, both radiogenic and non-radiogenic isotopic ratios are used to constrain the subduction flux and the degassing parameters. It is shown that subduction and massive contamination of the entire mantle is possible but implies that the 40Ar/36Ar and the 129Xe/130Xe ratios were higher in the past than today, which is not observed in Archean samples. It also implies that the sediments and the altered oceanic crust do not lose their noble gases during subduction or that the contaminated mantle wedge is mixed by the convective mantle.Moreover, such a model has to apply to the OIB source since it shows the same isotopic signature of argon and xenon. A scenario where the isotopic composition of the argon and xenon were acquired before or during accretion is therefore preferred to the subduction hypothesis (e.g. irradiation by solar wind for argon)

Air like 38Ar/36Ar in the mantle: implications for the nature of the parent bodies of the Earth

International audienceThe `'stable'' 20Ne/22Ne ratios in mantle-derived samples clearly differ from the atmospheric ratio. 20Ne/22Ne in oceanic basalts show obviously a solar origin (>12). Nevertheless, the mantle ratio (e.g. not contaminated by air) is not precisely determined. No mantle-derived samples have precise 20Ne/22Ne ratios above 13.0±0.2 (1σ). Two models are generally discussed to explain this solar origin. One is to dissolve solar wind gases in a previously degassed magma ocean. The other is that the mantle value is similar to the so-called Neon B (12.5 ± 0.2; (1σ)), which corresponds to mixing between the `'normal'' solar wind and solar energetic particles (SEP). This ratio is notably observed in gas rich meteorites, which are breccias irradiated in an early phase of the planetary accretion. The knowledge of the isotopic composition of rare gases in the mantle has important implications for the model of volatile acquisition on Earth. Some mantle-derived samples show 38Ar/36Ar ratios different from the atmosphere ratio and trend to the solar-wind isotopic composition. These results were challenged and an air like argon composition in the mantle has been suggested. As 40Ar signal is up to one million times higher than the 38Ar, we can suspect an influence of the 40Ar signal on the 38Ar base line (tail effect) during mass spectrometer analyses, giving low 38Ar/36Ar. Moreover, step heating appears to fractionate argon isotopes. We have performed a complete study of He, Ne and Ar in MORB and OIB in order to constrain the argon isotopic composition of the mantle. Using samples that have suffered only little air contamination and degassing, analyzed by crushing with a new analytical procedure, we show that the mantle 38Ar/36Ar is not different from the atmospheric ratio even for 20Ne/22Ne higher than 12.5. Starting from isotopic compositions close to the solar wind for both Ne and Ar, one may suppose than atmospheric argon was recycled within the mantle without neon during subduction. However, the 129Xe anomalies observed in mantle-derived sample suggest that the subduction of argon is probably not the source of the atmospheric 38Ar/36Ar in the mantle. The simplest explanation is that the parent bodies of the Earth were irradiated by a solar wind during the planetary accretion (T Tauri ?), giving these specific neon and argon isotopic compositions to the Earth (gas rich meteorite show air-like argon associated to neon B)

Coupling crushing and laser ablation in submarine glasses provide new constraints on noble gases composition of Earth's mantle

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He, Ne and Ar systematic on the scale of vesicle: Implication for noble gases behavior in the mantle

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