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

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

International audienc

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

International audienc

Variation of ribosomal DNA and inheritance of polymorphisms in 6 Petunia hybrida hort lines

Ribosomal DNA polymorphisms were studied in 6 lines of Petunia hybrida using EcoRI, BamHI, HindIII, Kpnl, SacI or Xhol. Each line carries several unit types, and 13 types were found in lines, which was not expected. We characterized the unit types and we determined the number of loci. Two kinds of unit types carrying no or several HindIII sites were revealed. The longest EcoRI and BamHI fragments in St43 correspond to a 11.4 kb unit type. Moreover, a 2.6 kb EcoRI fragment cannot be mapped in the 11.4 kb unit. It was found to be equivalent to the 2.45 kb EcoRI fragment carrying the 25 S rRNA coding sequence. Consequently, it was mapped in another unit 11.7 kb long. In TIh1 the corresponding EcoRI and BamHI fragments enabled us to construct 8.8, 9.2 and 10.8 kb segments. These fragments are therefore considered to be part of the 11.4 kb unit length. Other lines display combinations of these length units. The inheritance of polymorphic fragments of lines (St43 and TIh1) for 50 individuals of the 2 possible backcrosses [(St43 x TIh1) x St43] and [(St43 x TIh1) x TIh1] indicated at least 2 loci. The presence in Sk176 of 6.2, 5.7 and 5.4 EcoRI fragments suggested 3 loci. The haploid plants obtained from the hybrid (St43 x TIh1) display 1 individual carrying the 3 unit types present in the hybrid which proves the presence of 3 rDNA loci in TIh1. Moreover, the segregation in the backcrosses corresponds to only 2 loci in St43. It carries a nulli-allele. Evidence for such hypotheses were obtained by in situ hybridization with a biotinylated probe. The TIh1 and TIh7 dihaploid lines display more unit types and, consequently, more polymorphisms than other lines.Variation de l'ADN ribosomique et hérédité du polymorphisme dans 6 lignées de Petunia hybrida Hort. Dans 6 lignées de Petunia hybrida dont l'ADN a été hydrolysé par EcoRI, BamHI, HindIII, KpnI, SacI ou XhoI, l'ADN ribosomique est apparu très polymorphe. Chaque lignée porte plusieurs types d'unités ; ainsi 13 types différents sont révélés dans les lignées, ce qui est surprenant. Nous avons caractérisé les différents types et déterminé le nombre de loci. Deux types d'unités avec et sans sites HindIII sont révélés. Pour la lignée St43 les fragments EcoRI et BamHI permettent de construire une unité de 11,4 kb. En outre un fragment EcoRI de 2,6 kb ne peut être placé dans l'unité de 11,4 kb. II est en effet équivalent au fragment de 2,4 kb portant la séquence codante du gène 25 S. Il est donc placé dans une unité de 11,7 kb. Dans la lignée TIh1 les fragments correspondants ne permettent de construire que des unités de 8,8 kb, 9,2 kb, et 10,8 kb, donc considérées comme une partie d'unités de 11,4 kb. Les autres lignées montrent une combinaison des fragments précédents. L'hérédité du polymorphisme dans 50 descendants du couple de lignées (St43 et TIh1) et les 2 rétrocroisements possibles [(St43 x TIh1) x St43] et [(St43 x TIh1) x TIh1] indique au moins 2 loci. La présence dans Sk176 des fragments EcoRI 6,2, 5,7 et 5,4 suggère 3 loci. Parmi les plantes haploïdes obtenues de l'hybride F1 (St43 x TIh1), un descendant porte les 3 types d'unité présents dans l'hybride, ce qui ne peut s'expliquer que s'ils sont répartis sur 3 loci. De plus la ségrégation dans les rétrocroisements correspond à 2 loci pour St43, il porte donc un nuiliallèle. La confirmation des hypothèses est apportée par hybridation in situ avec une sonde ribosomique biotinylée. Les 2 lignées dihaploïdes TIh1 et TIh7 montrent le plus d'unités et par conséquent le polymorphisme le plus élevé

Variation of ribosomal DNA and inheritance of polymorphisms in 6 Petunia hybrida hort lines

Ribosomal DNA polymorphisms were studied in 6 lines of Petunia hybrida using EcoRI, BamHI, HindIII, KpnI, SacI or XhoI. Each line carries several unit types, and 13 types were found in lines, which was not expected. We characterized the unit types and we determined the number of loci. Two kinds of unit types carrying no or several HindIII sites were revealed. The longest EcoRI and BamHI fragments in St43 correspond to a 11.4 kb unit type. Moreover, a 2.6 kb EcoRI fragment cannot be mapped in the 11.4 kb unit. It was found to be equivalent to the 2.45 kb EcoRI fragment carrying the 25 S rRNA coding sequence. Consequently, it was mapped in another unit 11.7 kb long. In TIh1 the corresponding EcoRI and BamHI fragments enabled us to construct 8.8, 9.2 and 10.8 kb segments. These fragments are therefore considered to be part of the 11.4 kb unit length. Other lines display combinations of these length units. The inheritance of polymorphic fragments of lines (St43 and TIh1) for 50 individuals of the 2 possible backcrosses [(St43 x TIh1) x St43] and [(St43 x TIh1) x TIh1] indicated at least 2 loci. The presence in Sk176 of 6.2, 5.7 and 5.4 EcoRI fragments suggested 3 loci. The haploid plants obtained from the hybrid (St43 x TIh1) display 1 individual carrying the 3 unit types present in the hybrid which proves the presence of 3 rDNA loci in TIh1. Moreover, the segregation in the backcrosses corresponds to only 2 loci in St43. It carries a nulli-allele. Evidence for such hypotheses were obtained by in situ hybridization with a biotinylated probe. The TIh1 and TIh7 dihaploid lines display more unit types and, consequently, more polymorphisms than other lines.Dans 6 lignées de Petunia hybrida dont l’ADN a été hydrolysé par EcoRI, BamHI, HindIII, KpnI, SacI ou XhoI, l’ADN ribosomique est apparu très polymorphe. Chaque lignée porte plusieurs types d’unités ; ainsi 13 types différents sont révélés dans les lignées, ce qui est surprenant. Nous avons caractérisé les différents types et déterminé le nombre de loci. Deux types d’unités avec et sans sites HindIII sont révélés. Pour la lignée St43 les fragments EcoRI et BamHI permettent de construire une unité de 11,4 kb. En outre un fragment EcoRI de 2,6 kb ne peut être placé dans l’unité de 11,4 kb. II est en effet équivalent au fragment de 2,4 kb portant la séquence codante du gène 25 S. Il est donc placé dans une unité de 11,7 kb. Dans la lignée TIh1 les fragments correspondants ne permettent de construire que des unités de 8,8 kb, 9,2 kb, et 10,8 kb, donc considérées comme une partie d’unités de 11,4 kb. Les autres lignées montrent une combinaison des fragments précédents. L’hérédité du polymorphisme dans 50 descendants du couple de lignées (St43 et TIh1) et les 2 rétrocroisements possibles [(St43 x TIh1) x St43] et [(St43 x TIh1) x TIh1] indique au moins 2 loci. La présence dans Sk176 des fragments EcoRI 6,2, 5,7 et 5,4 suggère 3 loci. Parmi les plantes haploïdes obtenues de l’hybride F1 (St43 x TIh1), un descendant porte les 3 types d’unité présents dans l’hybride, ce qui ne peut s’expliquer que s’ils sont répartis sur 3 loci. De plus la ségrégation dans les rétrocroisements correspond à 2 loci pour St43, il porte donc un nuiliallèle. La confirmation des hypothèses est apportée par hybridation in situ avec une sonde ribosomique biotinylée. Les 2 lignées dihaploïdes TIh1 et TIh7 montrent le plus d’unités et par conséquent le polymorphisme le plus élevé