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Environ 5 % des cancers bronchiques non à petites cellules (CBNPC) sont porteurs du réarrangement ALKaccessible aux thérapies ciblées de type inhibiteur de tyrosine kinase ALK (ITK ALK). À l’heure actuelle, plusieurs produits sont disponibles en première ligne thérapeutique (crizotinib, céritinib, alectinib) après avoir démontré leur supériorité par rapport à la chimiothérapie en termes de survie sans progression. Malheureusement, le développement des divers mécanismes de résistance aux ITK ALK amène à la progression tumorale. En cas d’oligoprogression, un traitement local peut être envisagé avec la poursuite du même ITK ALK. En cas de progression multifocale, le changement de ligne thérapeutique s’impose. La rebiopsie/biopsie liquide doit être discutée à la progression pour mieux comprendre les mécanismes de résistance et adapter au mieux le traitement de chaque patient. Des stratégies thérapeutiques doivent être définies pour la gestion des mutations ALK pour aider le clinicien dans la pratique courante étant donnée la multiplication des choix thérapeutiques. Cette revue a pour objectif de proposer une synthèse des données récentes de la littérature concernant les stratégies thérapeutiques actuelles et les possibilités futures chez les patients ayant un CBNPC ALK positif de stade IV.

The aim of this study was to evaluate the effect of 2 climatic environments (temperate [TEMP] vs. tropical humid [TROP]) on production and thermoregulation traits in growing pigs. A backcross design involving Large White (LW; heat sensitive) and Creole (CR; heat tolerant) pigs was studied. The same 10 F1LW × CR boars were mated with related LW sows in each environment. A total of 1,298 backcross pigs (n= 634 pigs from 11 batches for the TEMP environment and n= 664 pigs from 12 batches for the TROP environment) were phenotyped on BW (every 15 d from wk 11 to 23 of age), voluntary feed intake (ADFI, from wk 11 to 23), backfat thickness (BFT; at wk 19 and 23), skin temperature (ST; at wk 19 and 23), and rectal temperature (RT; at wk 19, 21, and 23). The feed conversion ratio was computed for the whole test period (11 to 23 wk). The calculation of the temperature–humidity index showed an average difference of 2.4°C between the TEMP and TROP environments. The ADG and ADFI were higher in the TEMP environment than in the TROP environment (834 vs. 754 g/d and 2.20 vs. 1.80 kg/d, respectively; P< 0.001). Body temperatures were higher in the TROP environment than in the TEMP environment (35.9 vs. 34.8°C for ST and 39.5 vs. 39.3°C for RT, respectively; P< 0.001). Most of the studied traits (i.e., BW, BFT, ADG, ADFI, and RT) were affected by sire family × environment interactions (P< 0.05), resulting in “robust” and “sensitive” families. Our results show a family dependency in the relationships between heat resistance and robustness, suggesting the possibility of finding genotypes with high production and low heat sensitivity. Further research is needed to confirm the genetic × environment interaction and to detect QTL related to heat tolerance.

The effects of 21 yr of selection were estimated for sow and piglet performance during the suckling period in a French Large White (LW) pig population using frozen semen. Two experimental groups (EXP = L77 and L98) were produced by inseminating LW sows with either stored frozen semen from 17 LW boars born in 1977 (EXP = L77) or with fresh semen from 23 LW boars born in 1998 (EXP = L98). Seventy-four L77 and 89 L98 randomly chosen females were mated to 15 L77 and 15 L98, respectively, randomly chosen boars for 6 successive parities. They produced 2,796 L77 progeny (G77) and 3,529 L98 progeny (G98) piglets including stillbirths. To disentangle direct and maternal effects on piglet growth, a 2 × 2 factorial design was set by cross-fostering half-litters across genetic groups the day after farrowing, resulting in mixed G77/G98 litters nursed by either L77 or L98 sows. Piglet traits investigated included individual weight at birth (IWB), at 21 d of age (IW21d), and at weaning at 4 wk of age (IWW) and ADG from birth to 21 d of age (ADG21d) and from birth to weaning (ADGBW) as well as probability of stillbirth, probability of mortality on the first day after farrowing and from d 2 to weaning. Sow traits analyzed included weight before farrowing and at weaning, feed intake, milk production, colostrum, and milk composition. The variability of performance across genetic groups and litters was also investigated. The data were analyzed using generalized (piglet mortality) or linear mixed models (other traits). Results showed an increase in IWB (+240 ± 72 g in 21 yr for IWB adjusted for total number born), and a negative maternal genetic trend was observed on piglet growth during the suckling period (e.g., +33 ± 13 g/d in 21 yr for ADG21d, that is, 14% of the mean), whereas direct genetic effects remained unchanged. Piglets from L98 litters also had a 40% larger probability of being stillborn and a 28% larger probability of dying on d 1 and had a more heterogeneous IWB (358 vs. 336 g; P< 0.001) and growth during the suckling period (60 vs. 56 g/d; P< 0.001). Sows from L77 and L98 experimental groups did not differ in weight, feed intake, colostrum, and milk composition. These results give evidence of negative correlated effects of selection for piglet traits related to robustness. These adverse effects are at least partly of maternal origin.

Genetic trends for male and female sexual development and components of litter size and weight at birth (LB) as well as traits related to sow lifetime productivity were estimated in a French Large White (LW) pig population using frozen semen. Two experimental groups (EXP = L77 and L98) were produced by inseminating LW sows with either stored frozen semen from 17 LW boars born in 1977 (EXP = L77) or with semen from 23 LW boars born in 1998 (EXP = L98). In each group, about 100 males were measured for testicular development and bulbo-urethral gland development, and 90 gilts were checked for puberty, among which about 50 gilts were measured for their first ovulation rate at puberty (ORP). The females were then mated to 15 randomly chosen males for each group for 6 successive parities and measured for total number born (TNB), number born alive (NBA), litter weight at birth (LWB), and interval from weaning to first estrus as well as ovulation rate at fertilization (ORF = ovulation rate of gestating sows) on a subset of litters. The data were analyzed using mixed linear models including the fixed effects of EXP, of finishing (sexual development traits) or farrowing group, and parity (LB traits); the random effects of birth litter (sexual development traits) or sow (LB traits); and, when relevant, age or BW as covariates. The homogeneity of residual variances across EXP was also tested. For each trait, the genetic trend was estimated as twice the difference between L98 and L77. Limited differences were observed for sexual development traits, except for ORF, which increased by 0.17 ± 0.06/yr. The residual SD of NBA (2.7 vs. 2.0; P= 0.004) and LWB (3.1 vs. 2.5; P= 0.03) were larger in L98 sows than in L77 sows. Positive trends were observed for all litter traits (0.22 ± 0.07 ova, 0.12 ± 0.04 piglet, 0.09 ± 0.04 piglet, and 0.23 ± 0.06 kg/yr for ORF, TNB, NBA, and LWB, respectively) but at the expense of a degradation of prenatal and farrowing survival. A negative trend was also observed for length of productive life (−8.9 ± 3.9 d/yr). These results suggest that gains in productivity were associated with a loss of robustness.

The aim of the study was to evaluate the consequences of a divergent selection for residual feed intake (RFI) during growth in a temperate environment (TEMP) on sow performance in a tropical environment (TROP). Sows came from a selection experiment conducted at INRA in which 2 lines were selected for larger (RFI+) or smaller (RFI─) feed intake than predicted from performance. In the first analysis, a subsample of data obtained in TROP conditions (49 lactations) was compared to those obtained in TEMP on their sibs mated with the same boars (54 lactations). In the second analysis, data obtained in the TROP environment (82 lactations) were analyzed for testing the effect of season (warm vs. hot) and line on sow performance. Except for the lactation length, the interaction between line and climatic environment was not significant for the others traits (P> 0.05). The ADFI expressed per kilogram of litter BW gain tended to be higher in the RFI+line bred in the TROP environment (P =0.080), together with piglet BW at weaning, which tended to be lower (P =0.080). The ADFI was lower in TROP than in TEMP (4.56 vs.5.86 kg/d; P =0.003), with negative consequence on litter BW gain and maternal BW loss. The RFI–sows tended to eat less feed than RFI+sows during lactation (4.55 vs. 5.86 kg/d; P =0.099). Litter BW at weaning was higher in the RFI─line. The RFI─sows ate significantly less feed to produce 1 kg of litter than the RFI+sows and tended to lose a larger amount of BW during lactation than the RFI+sows (2.40 vs.3.02 kg/kg and -0.66 vs. -0.39 kg/d, respectively, P <0.10). Whatever the line, ADFI was reduced by about 21% in the hot season (P <0.05). Litter BW gain was depressed (P <0.05) in the hot season (1.72 vs. 2.08 kg/d in the warm season; P= 0.023). Lactation maternal BW loss tended to increase in the hot season (1.10 vs.0.71 kg/d in the warm season; P =0.016), but back fat loss remained constant (P =0.295). In the TROP environment, the amount of feed required to produce 1 kg of litter was not influenced by the line in the warm season (2.53 kg/kg on average; P =0.99), but it tended to be lower in the RFI─line when compared to the RFI+line in the hot season (2.06 vs.3.45 kg/kg; P =0.050). This higher apparent efficiency in RFI─sows was mainly related to greater maternal body reserve mobilization (i.e., BW and back fat losses). In conclusion, selection for low RFI during growth in a TEMP environment did not impair sow and litter performance in tropical conditions.

Residual feed intake (RFI) has been explored as an alternative selection criterion to feed conversion ratio to capture the fraction of feed intake not explained by expected production and maintenance requirements. Selection experiments have found that low RFI in the growing pig is genetically correlated with reduced fatness and feed intake. Selection for feed conversion ratio also reduces sow appetite and fatness, which, together with increased prolificacy, has been seen as a hindrance for sow lifetime performance. The aims of our study were to derive equations for sow RFI during lactation (SRFI) and to evaluate the effect of selection for RFI during growth on sow traits during lactation. Data were obtained on 2 divergent lines selected for 7 generations for low and high RFI during growth in purebred Large Whites. The RFI was measured on candidates for selection (1,065 pigs), and sow performance data were available for 480 sows having from 1 to 3 parities (1,071 parities). Traits measured were sow daily feed intake (SDFI); sow BW and body composition before farrowing and at weaning (28.4 ± 1.7d); number of piglets born total, born alive, and surviving at weaning; and litter weight, average piglet BW, and within-litter SD of piglet BW at birth, 21 d of age (when creep feeding was available), and weaning. Sow RFI was defined as the difference between observed SDFI and SDFI predicted for sow maintenance and production. Daily production requirements were quantified by litter size and daily litter BW gain as well as daily changes in sow body reserves. The SRFI represented 24% of the phenotypic variability of SDFI. Heritability estimates for RFI and SRFI were both 0.14. The genetic correlation between RFI and SRFI was 0.29 ± 0.23. Genetic correlations of RFI with sow traits were low to moderate, consistent with responses to selection; selection for low RFI during growth reduced SDFI and increased number of piglets and litter growth, but also increased mobilization of body reserves. No effect on rebreeding performance was found. Metabolic changes previously observed during growth in response to selection might explain part of the better efficiency of the low-RFI sows, decreasing basal metabolism and favoring rapid allocation of resources to lactation. We propose to consider SRFI as an alternative to SDFI to select for efficient sows with reduced input demands during lactation.

A QTL analysis of female reproductive data from a 3-generation experimental cross between Meishan and Large White pig breeds is presented. Six F1boars and 23 F1sows, progeny of 6 Large White boars and 6 Meishan sows, produced 502 F2gilts whose reproductive tract was collected after slaughter at 30 d of gestation. Five traits [i.e., the total weight of the reproductive tract, of the empty uterine horns, of the ovaries (WOV), and of the embryos], as well as the length of uterine horns (LUH), were measured and analyzed with and without adjustment for litter size. Animals were genotyped for a total of 137 markers covering the entire porcine genome. Analyses were carried out based on interval mapping methods, using a line-cross regression and a half-full sib maximum likelihood test. A total of 18 genome-wide significant (P< 0.05) QTL were detected on 9 different chromosomes (i.e., SSC 1, 5, 6, 7, 9, 12, 13, 18, and X). Five genome-wide significant QTL were detected for LUH, 4 for weight of the empty uterine horns and WOV, 2 for total weight of the reproductive tract, and 1 for weight of the embryos. Twenty-two additional suggestive QTL were also detected. The largest effects were obtained for LUH and WOV on SSC13 (9.2 and 7.0% of trait phenotypic variance, respectively). Meishan alleles had both positive (e.g., on SSC7) and negative effects (e.g., on SSC13) on the traits investigated. Moreover, the QTL were generally not fixed in founder breeds, and opposite effects were in some cases obtained in different families. Although reproductive tract characteristics had only a moderate correlation with reproductive performances, most of the major QTL detected in this study were previously reported as affecting female reproduction, generally with reduced significance levels. This study thus shows that focusing on traits with high heritability might help to detect loci involved in low heritability major traits for breeding.

Residual feed intake (RFI) is defined as the difference between the observed feed intake and that expected based on requirements for maintenance and production. A divergent selection was conducted during 4 generations in Large White male pigs to produce low and high RFI lines. The present study aims at determining the influence of this selection on biochemical and histological traits of skeletal muscle, and relating these changes to correlated effects on growth, carcass composition, and meat quality traits. At 8 d preslaughter, biopsies from the LM were taken in the fed state on 14 females from each RFI line fed ad libitum. Animals were slaughtered at 107.8 ± 8.0 kg of BW without any previous fasting. Samples of LM, semimembranosus (SM), biceps femoris (BFM), and rhomboideus muscles were taken at both 30 min and 24 h postmortem. Myofiber typing was only assessed in LM. Low RFI pigs (“efficient”) had leaner carcasses with greater muscle content (P< 0.001), less backfat thickness (P< 0.001), and less intramuscular fat content in all 4 muscles (P< 0.01 to P= 0.04). Their greater muscle content was associated with hypertrophy of all fast-twitch fibers. Glycogen content in all glycolytic muscles (i.e., LM, SM and BFM), was greater in low than high RFI pigs. The greater accumulation of glycogen in LM of low RFI pigs was specifically located in the fast-twitch glycolytic IIBW fibers, which correspond to fibers containing IIb, IIb + IIx, or IIx myosin heavy chains. The difference in muscle glycogen content between RFI line pigs was more significant in the living animals (P= 0.0003) than at 30 min postmortem (P= 0.08). This was associated with a decreased ultimate pH (P= 0.001), and greater lightness of color (P= 0.002) and drip loss (P= 0.04) in LM of low than high RFI line pigs, suggesting that selection for reduced RFI may impair some meat quality traits, such as water-holding capacity. Pigs from the low RFI line exhibited a greater (P= 0.02) percentage of IIBW fibers in LM and tended (P< 0.10) to have less lipid β-oxidative capacity in LM, SM, and BFM. In contrast, no difference (P> 0.10) between lines was found for citrate synthase and lactate dehydrogenase activities, mitochondrial activity, and expression of genes coding for uncoupling proteins 2 and 3. Differences between RFI pigs in plasma leptin, cortisol, and thyroid hormone concentrations are presented and discussed. In conclusion, selection for low RFI influenced muscle properties in a way favoring muscle mass, but likely impairing meat quality.

Genetic trends for growth, feed efficiency, composition, and morphometry of carcasses were estimated in a French Large White (LW) pig population using frozen semen. Two groups of pigs were produced by inseminating LW sows with either stored, frozen semen from 17 LW boars born in 1977 or with semen from 23 LW boars born in 1998. In each group, 15 males and 90 females were randomly chosen and mated to produce approximately 1,000 pigs/group. These pigs were performance tested with individual ADFI and serial BW and backfat thickness measurements, slaughtered at 105 kg of BW, and measured for carcass traits. The data were analyzed using mixed linear animal models, including the fixed effect of the experimental group (offspring of 1977 or 1998 boars), the random effect of the additive genetic value of each animal, and, when significant, the fixed effects of sex, fattening batch, and slaughterhouse, the linear regression on BW, and the random effect of the common environment of birth litter. For each trait, the genetic trend was estimated as twice the difference between the 2 experimental groups. Results showed moderately favorable trends for on-test ADG (3.7 ± 1.3 g/d per year) and feed conversion ratio (−0.014 ± 0.005 kg/kg per year) in spite of a tendency toward an increase in ADFI (7.6 ± 4.7 g/yr). A strong reduction in carcass fatness (−0.35 ± 0.07 mm/yr for carcass average backfat thickness) and a large improvement in carcass leanness (0.31 ± 0.10 mm2/yr and 0.41 ± 0.08%/yr for loin eye area and carcass muscle content, respectively) were observed. Carcass shape measurements (back and leg length, back width, muscle thickness of hind limbs) were not affected by selection. Serial measurements of BW and backfat thickness showed that the major part of the genetic gains occurred during late growth and that the reduction in the backfat layer was more pronounced in the rear than in the front part of the carcass. The use of frozen semen appears to be a powerful practice to thoroughly investigate changes attributable to selection.

Data were collected over the first 4 generations of a divergent selection experiment for residual feed intake of Large White pigs having ad libitum access to feed. This data set was used to obtain estimates of heritability for residual feed intake and genetic correlations (ra) between this trait and growth, carcass, and meat quality traits. Individual feed intake of group-housed animals was measured by single-space electronic feeders. Upward and downward selection lines were maintained contemporarily, with 6 boars and 35 to 40 sows per line and generation. Numbers of records were 793 for residual feed intake (RFI1) of boar candidates for selection issued from first-parity (P1) litters and tested over a fixed BW range (35 to 95 kg) and 657 for residual feed intake (RFI2) and growth, carcass, and meat quality traits of castrated males and females issued from second-parity (P2) litters and tested from 28 to 107 kg of BW. Variance and covariance components were estimated using REML methodology applied to a series of multitrait animal models, which always included the criterion for selection as 1 of the traits. Estimates of heritability for RFI1 and RFI2 were 0.14 ± 0.03 and 0.24 ± 0.03, respectively, whereas the estimate of rabetween the 2 traits was 0.91 ± 0.08. Estimates of raindicated that selection for low residual feed intake has the potential to improve feed conversion ratio and reduce daily feed intake, with minimal correlated effect for ADG of P2 animals. Estimates of rabetween RFI2 and body composition traits of P2 animals were positive for traits related to the amount of fat depots (ra= 0.44 ± 0.16 for carcass backfat thickness) and negative for carcass lean meat content (ra= −0.55 ± 0.14). There was a tendency for a negative genetic correlation between RFI2 and carcass dressing percent (ra= −0.36 ± 0.21). Moreover, selection for low residual feed intake is expected, through lower ultimate pH and lighter color, to decrease pork quality (ra= 0.77 ± 0.14 between RFI2 and a meat quality index intended to predict the ratio of the weight of ham after curing and cooking to the weight of defatted and boneless fresh ham).

Litter characteristics at birth were recorded in 4 genetic types of sows with differing maternal abilities. Eighty-two litters from F1Duroc × Large White sows, 651 litters from Large White sows, 63 litters from Meishan sows, and 173 litters from Laconie sows were considered. Statistical models included random effects of sow, litter, or both; fixed effects of sow genetic type, parity, birth assistance, and piglet sex, as well as gestation length, farrowing duration, piglet birth weight, and litter size as linear covariates. The quadratic components of the last 2 factors were also considered. For statistical analyses, GLM were first considered, assuming a binomial distribution of stillbirth. Hierarchical models were also fitted to the data to take into account correlations among piglets from the same litter. Model selection was performed based on deviance and deviance information criterion. Finally, standard and robust generalized estimating equations (GEE) procedures were applied to quantify the importance of each effect on a piglet's probability of stillbirth. The 5 most important factors involved were, in decreasing order (contribution of each effect to variance reduction): difference between piglet birth weight and the litter mean (2.36%), individual birth weight (2.25%), piglet sex (1.01%), farrowing duration (0.99%), and sow genetic type (0.94%). Probability of stillbirth was greater for lighter piglets, for male piglets, and for piglets from small or very large litters. Probability of stillbirth increased with sow parity number and with farrowing duration. Piglets born from Meishan sows had a lower risk of stillbirth (P< 0.0001) and were little affected by the sources of variation mentioned above compared with the 3 other sow genetic types. Standard and robust GEE approaches gave similar results despite some disequilibrium in the data set structure highlighted with the robust GEE approach.

The aim of this work was to estimate whether genetic dissection of QTL on chromosomes 1, 2, 4, and 7, detected in an F2Meishan × Large White population, can be achieved with a recombinant back-cross progeny test approach. For this purpose, a first generation of backcross (BC1) was produced by using frozen semen of F1Large White × Meishan boars with Large White females. Four BC1boars were selected because of their heterozygosity for at least 1 of the 4 regions. The BC1boars were crossed with Large White sows, and the resulting BC2offspring were measured for several growth and body composition traits. Contrary to the F2animals, BC2animals were also measured for meat quality traits in adductor, gluteus superficialis (GS), longissimus dorsi, and biceps femoris (BF) muscles. Each BC1boar was tested for a total of 39 traits and for the 4 regions with statistical interval mapping analyses. The QTL effects obtained in BC1families showed some differences compared with those described in F1families. However, we confirmed QTL effects for growth in the SW1301–SW2512 markers interval on chromosome 1 and also for body composition in the SW1828–SW2512 markers interval on chromosome 1, in the SW2443–SWR783 markers interval on chromosome 2, and in the SW1369–SW632 markers interval on chromosome 7. In addition, we detected new QTL for growth traits on chromosome 2 and for meat quality traits on chromosomes 1 and 2. Growth of animals from weaning to the end of the test was influenced by the IGF2 gene region on chromosome 2. Concerning meat quality, ultimate pH of adductor, longissimus dorsi, and BF were affected by the interval delimited by UMNP3000 and SW2512 markers on chromosome 1, and a* of GS, L* of BF, and water-holding capacity of GS were affected by QTL located between marker loci SW2443 and SWR783 on chromosome 2. Recombinant progeny testing appeared to be a suitable strategy for the genetic dissection of the QTL investigated.

Pig chromosome 7 (SSC 7) has been shown to be rich in QTL affecting performance and quality traits. Most studies mapped the QTL close to the swine leukocyte antigens (SLA), which has a large effect on adaptability and natural selection. Previous comparative mapping studies suggested that the 15-cM region limited by markers LRA1(mapped at 55 cM) and S0102(mapped at 70 cM) contains hundreds of genes. To decrease the number of candidate genes, we improved the mapping resolution with a genetic chromosome dissection through a backcross recombinant progeny test program between Meishan (MS) and European (EU; i.e., Large White or Landrace) breeds. Three first-generation backcross—(EU × MS) × EU—and two second-generation backcross—([EU × MS] × EU) × EU—sires carrying a recombination in the QTL mapping interval were progeny-tested (i.e., measured for a total of 44 growth, fatness, carcass and meat quality traits). Progeny family size varied from 29 to 119 pigs. Animals were genotyped for markers covering the region of interest. Progeny-test results allowed the QTL interval to be decreased from 15 to 20 cM down to 10 cM, and even less than 6 cM if we assumed that the EU pigs used in this study share only one QTL allele. Except for a putative QTL affecting some carcass composition traits, the SLA is excluded as a candidate region, suggesting that it might be possible to apply a marker-assisted selection strategy for this QTL, while controlling SLA allele diversity. The strong QTL effects remaining in animals with only 12.5% (issued from first-generation backcross boars) and 6.25% (issued from second-generation back-cross boars) Meishan genetic background shows that epistatic interactions are likely to be limited. Finally, the QTL does not have strong effects on meat quality traits.

The hypothalamic–pituitary–adrenal (HPA) axis plays a major role in physiological homeostasis. It is also involved in stress and adaptive response to the environment. In farm animals in general and more specifically in pigs, breeding strategies have highly favored production traits such as lean growth rate, feed efficiency and prolificacy at the cost of robustness. On the hypothesis that the HPA axis could contribute to the trade-off between robustness and production traits, we have designed this experiment to explore individual variation in the biological response to the main stress hormone, cortisol, in pigs. We used adrenocorticotropic hormone (ACTH) injections to trigger production of cortisol in 120 juvenile Large White (LW) pigs from 28 litters, and the kinetics of the response was measured with biological variables and whole blood gene expression at four time points. A multilevel statistical analysis was used to take into account the longitudinal aspect of the data.Cortisol level reached its peak 1 h after ACTH injection. White blood cell composition was modified with a decrease of lymphocytes and monocytes and an increase of granulocytes (FDR< 0.05). Basal level of cortisol was correlated with birth and weaning weights. Microarray analysis identified 65 unique genes whose expression responded to the injection of ACTH (adjusted P-value< 0.05). These genes were classified into four clusters with distinctive kinetics in response to ACTH injection. The first cluster identified genes strongly correlated to cortisol and previously reported as being regulated by glucocorticoids. In particular, DDIT4, DUSP1, FKBP5, IL7R, NFKBIA, PER1, RGS2and RHOBwere shown to be connected to each other by the glucocorticoid receptor NR3C1. Most of the differentially expressed genes that encode transcription factors have not been described yet as being important in transcription networks involved in stress response. Their co-expression indicates possible co-regulation, and they potentially provide new biomarkers of sensitivity to cortisol.

To explore the relationship between gene activity and nuclear position, genomic imprinting leading to parental-specific expression offers a good model. In one cell, it is possible to compare the nuclear environment of the two alleles for a given locus and search for a potential correlation between their nuclear position and expression status. Using 3D RNA-DNA fluorescence in situ hybridization (FISH) in porcine fetal liver cells, we focused on the imprinted region of Insulin-like growth factor 2(IGF2), a paternally expressed gene located on porcine chromosome 2. We investigated the interchromosomal interactions implicating IGF2. Through a 2D FISH screening, imprinted genes from the Imprinted Gene Network (Varrault et al., 2006) were tested for interactions in liver cells. The locus DLK1/MEG3showed the highest rate of colocalization with IGF2. By 3D RNA-DNA FISH combined to confocal microscopy, we demonstrated a preferential implication of the expressed paternal IGF2allele in a transassociation with DLK1/MEG3region (chromosome 7). We showed that this colocalization occurs also in fetal muscle and demonstrated that it occurs preferentially between the expressed IGF2, DLK1, and MEG3alleles. We are extending this analysis through an interdisciplinary approach to develop large functional mappingstudies focused on the mechanisms involved in the transcriptional regulation of genes expressed in muscle during late fetal development of pig. From a transcriptomic analysis carried on fetal muscle of two extreme genetic lines to study maturity, we identified 2000 genes differentially expressed that characterize its establishment (Voillet et al., 2014). We are now constructing, by in silico processes, networks of co-regulated genes with IGF2as starting point. We are also developing a Hi-C approach to construct interaction maps on a genome-wide scale. A set of key genes belonging to these networks and interaction maps will be selected to study by 3D FISH their position in the nuclear space in cells of the two genotypes, and to determine if co-regulated genes implicated in the same biological function co-localize in the nucleus. These data should allow us to determine if these interactions are genotype and expression pattern dependent. This will open interesting questions to study the possible link between nuclear architecture and control of gene expression in muscle in an animal model for which extreme genotypes for maturity at birth are available.