The genotype-phenotype relationship and evolutionary genetics in the light of the Metabolic Control Analysis.

Metabolic control analysis has long been used as a systemic model of the genotype-phenotype (GP) relationship. By considering kinetic parameters and enzyme concentrations as reflecting the genotype level and metabolic fluxes or pools as phenotypes related to fitness, MCA has given a biological basis to the relationship between these two levels. The non-linear and concave relationship between enzymes and fluxes can account for common genetic effects that reductionist approaches have been powerless to explain, such as the dominance of active alleles over less active alleles, the various types of epistasis and heterosis, and reveals the structural links between these genetic effects. The summation property of the flux control coefficients accounts for the L-shaped distribution of Quantitative Trait Locus (QTL) effects, irrespective of other possible causes. Metabolic models of response to selection results in evolutionary scenarios that are markedly different from those derived from the classical infinitesimal model of quantitative genetics. In particular, evolution towards selective neutrality appears to be a consequence of the diminishing return of the flux-enzyme relationship. In this paper, we survey the historical and recent achievements of MCA in genetics, quantitative genetics and evolution, focusing on epistasis and the evolution of flux in relation to enzyme concentrations.

Does transanal local resection increase morbidity for subsequent total mesorectal excision for early rectal cancer?

AIM: Local excision is recommended for early rectal cancer (pT1). Complementary total mesorectal excision (cTME) is warranted when bad pathological features are present. The impact of a prior local resection on the outcome remains unclear. The aim of this study was to assess if prior local excision increases the morbidity of a subsequent cTME compared with primary TME. METHODS: From 2001 to 2016 all patients who underwent TME after local excision for rectal adenocarcinoma were studied. All were matched (1:1) with patients who underwent primary TME, without neoadjuvant radiochemotherapy. The matching factors included age, sex, body mass index, American Society of Anesthesiologists score and type of surgery. Short-term morbidity and pathological examination of the resected specimen were compared. RESULTS: Forty-one patients were included (14 women, 34%, mean age 65 ± 11 years), comprising classic transanal excision (66%) and transanal endoscopic microsurgery (34%), and were matched to 41 patients who had primary TME. cTME was significantly longer (315 min ± 87 vs 275 min ± 58, P = 0.03). The overall morbidity was 48.8% in the local excision group vs 31.7% in the control group (P = 0.18). Surgical morbidity was 31.7% vs 26.8% (P = 0.8). Anastomotic related morbidity was similar (local excision 17% vs TME 14.6%, P = 0.84) and the mean length of stay was similar (14 days) in both groups. There was a tendency to a worse quality of mesorectal excision in the cTME group (17% vs 5%, P = 0.15). CONCLUSION: Local excision prior to TME for early rectal cancer tends to increase overall morbidity and may worsen the quality of the mesorectal plane but should be considered as a surgical approach in select cases.

Study on the repair of the radioinduced lesions involved in the formation of chromosomal aberrations in G0 human lymphocytes after exposure to gamma-rays and fast neutrons.

Cytosine arabinoside (ara-C), an inhibitor of DNA synthesis and repair, has been used to study the mechanisms of formation of chromosomal aberrations after exposure to low- and high-LET radiation. When G0 human lymphocytes were exposed either to gamma-rays or to d(50 MeV)-Be neutrons and immediately treated with ara-C for increasing periods of time, the frequency of aberrations (dicentrics) increased sharply. For gamma-rays, the enhancement increased with the duration of the treatment up to 5 h, whereas for neutrons, an ara-C treatment lasting for 5 h was no more effective than treatment for 3 h. These results were confirmed by the second experiment in which ara-C was administered for 3 h with an increasing time delay following irradiation. Since no increase in the dicentric frequency was observed when ara-C was administered 5 h after gamma-irradiation, it is suggested that the induced breaks rejoined within that time. For neutrons, the data were conflicting since the repair was completed within 3 h after a dose of 0.5 Gy, and in approximately 5 h after a dose of 2.0 Gy. From both experiments, it appears that gamma-rays and fast neutrons produce similar types of lesions, as ara-C increased the frequencies of aberrations induced by both types of radiation. However, the ara-C treatment resulted in a smaller increase in aberrations following neutron irradiation. According to the enzymatic nature of break formation and the mode of action of ara-C on the polymerase activity, it is suggested that, in addition to double-strand breaks, single-strand breaks could be the lesions involved in the repair processes inhibited by ara-C. Single-strand breaks formed directly or by secondary reactions would, therefore, be one of the major lesions responsible for the aberrations produced by gamma and neutron radiations.

[The repair of DNA damage induced in human lymphocytes by gamma rays and fast neurons]. / Etude de la réparation des dommages de l'ADN induits dans les lymphocytes humains par les rayons gamma et les neutrons rapides.

When Go human lymphocytes are exposed either to gamma-rays or to d(50)-Be neutrons and then immediately incubated in presence of cytosine arabinoside, the frequency of chromosomal aberrations which is normally observed after radiation exposure only is sharply increased. This enhancement of the aberrations, particularly the dicentrics, is, however, less marked when cytosine arabinoside is administered at longer intervals of time after irradiation. For gamma-rays, the treatment with cytosine arabinoside has no effect on the dicentrics yield when given 5 h after irradiation, indicating that the repair is completed within the 5 h after irradiation and that the lesions are not anymore available to produce exchange aberrations. For d(50)-Be neutrons, the time of repair takes approximately 5 h after a dose of 2.0 Gy, whereas it appears to be shorter (3 h) after a dose of 0.5 Gy.