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See detailImproving the bioinformatics analysis of HTS clonality data in virus-induced leukemia
Hahaut, Vincent ULiege; Rosewick, Nicolas; Artesi, Maria ULiege et al

Poster (2018, February 02)

Proviral integration into the host genome is one of the main hallmarks of infection by oncogenic retroviruses. This event creates a life-long signature, each infected cell being characterized by a ... [more ▼]

Proviral integration into the host genome is one of the main hallmarks of infection by oncogenic retroviruses. This event creates a life-long signature, each infected cell being characterized by a specific integration site (IS). Monitoring of the clonal architecture over time (clone: population of cells sharing an identical IS) has significantly contributed to a better understanding of HIV persistence, gene therapy vector mediated treatment and deltaretrovirus-induced leukemia. Our lab recently developed an optimized high-throughput sequencing (HTS) based clonality method. It enables the identification of proviral integration sites genome-wide while simultaneously quantifying the abundance of the corresponding clones. The method is superior to any of the previously available protocols, mainly in terms of sensitivity, cost-effectiveness and hands-on time, making it suitable for routine clinical observation of infected individuals. Using this method, we recently showed that longitudinal monitoring of the dominant leukemic clone in patients infected by Human T-cell Leukemia Virus-1 (HTLV-1) better predicts therapeutic response (Artesi et al, Leukemia, 2017). We applied the method to biological samples isolated from HTLV-1 infected patients and Bovine Leukemia Virus (BLV) infected animals (bovine and sheep). This resulted in the generation of an unprecedented volume of raw sequence data. In this study we developed a novel clonality analysis pipeline that better exploits the potential of the method, improving previously published protocols. [less ▲]

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See detailThe Landscape And Evolution Of Somatic Mutations In Bovine Leukemia Virus Induced Tumors
Durkin, Keith ULiege; Artesi, Maria ULiege; Hahaut, Vincent ULiege et al

Conference (2017, September 21)

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an ... [more ▼]

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an aggressive leukemia/lymphoma in about ~5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary somatic events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a tumor. At the current time little is known about the landscape of somatic changes in BLV induced tumors and the timing of their occurrence. To address this we have carried out whole genome sequencing of BLV induced tumors from two cattle, and from five sheep with matched normal tissue. This revealed frequent aneuploidy, with orthologous regions of the genome involved in both species and elevated mitochondria DNA copy numbers in tumors. Recurrent structural variants (SVs) were seen affecting the tumor suppressors CDKN2A and ARID1A, both on OAR2. On average ~1400 somatic SNVs were observed in each ovine tumor, with high/moderate impact variants in known cancer drivers genes such as KMT2A, ATRX, RPL22 and KRAS. The five sheep were also sampled at regular time points, prior to leukemia onset, allowing us to examine tumor clone evolution. High throughput sequencing of proviral integration sites showed that the tumor clone represents only a small fraction of the infected cells for the majority of the disease, only expanding rapidly in the terminal stages. Low coverage sequencing of samples prior to tumor development indicates that aneuploidy of OAR9 is a feature of the majority of BLV infected clones. Preliminary nested PCR also showed that many SVs were present prior to tumor development. High throughput approaches are being developed to track both SVs and SNV in the preleukemic stages of the disease. [less ▲]

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See detailIdentification and management of recessive genetic defects in Belgian Blue beef cattle
Druet, Tom ULiege; Sartelet, Arnaud ULiege; Hubin, Xavier et al

Conference (2017, August)

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See detailSomatic Structural And Numerical Aberrations In Bovine Leukemia Virus Induced Tumors
Durkin, Keith ULiege; Artesi, Maria ULiege; Hahaut, Vincent ULiege et al

Poster (2017, July)

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an ... [more ▼]

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an aggressive leukemia/lymphoma in about ~5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a tumor. At the current time little is known about the landscape of somatic changes in BLV induced tumors. To examine gross numerical and structural variants (SVs) we assayed 12 bovine tumors on the BovineSNP50 Illumina BeadChip as well as 22 ovine tumors on the OvineSNP50 Illumina BeadChip. We also carried out whole genome sequencing (~30X) on 4 ovine tumors with matched normal tissue. Initial examination of the tumors revealed frequent aneuploidy, with orthologous regions of the genome involved in both species. Focal SVs identified included an amplification (>4 copies) of the terminus of BTA16 in three tumors (contains PTPRC & miR-181), while the tumor suppressor CDKN2A on OAR2 was deleted in multiple ovine tumors. For the 4 sequenced tumors multiple time points over the course of infection were available allowing us to determine when these SVs arose via nested PCR. Interestingly we observed that the SVs involving well know cancer driver genes generally appear many months prior to tumor development. These preliminary results indicate that tumors induced by HTLV-1 and BLV display somatic structural changes that impinge on overlapping sets of genes and point to the emergence of SVs affecting cancer driver genes in the preleukemic clone, well before the clone undergoes rapid expansion. [less ▲]

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See detailCis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis
Rosewick, Nicolas; Durkin, Keith ULiege; Artesi, Maria ULiege et al

in Nature Communications (2017), 8

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See detailInvestigating non-coding viral transcripts in Bovine Leukemia Virus induced leukemia
Hahaut, Vincent ULiege; Artesi, Maria ULiege; Durkin, Keith ULiege et al

Poster (2017, March 08)

Bovine Leukemia Virus (BLV) is a deltaretrovirus closely related to the Human T-cell leukemia virus-1 (HTLV-1). The natural host of BLV is cattle and much like the case of HTLV-1 in humans, about ~5% of ... [more ▼]

Bovine Leukemia Virus (BLV) is a deltaretrovirus closely related to the Human T-cell leukemia virus-1 (HTLV-1). The natural host of BLV is cattle and much like the case of HTLV-1 in humans, about ~5% of infected individuals develop leukemia/lymphoma following a long period of asymptomatic infection (~7 years in cattle, several decades in human). Experimental infection of sheep with BLV results in a reduced latency period (2 years on average), making for an attractive cancer model. A further advantage of the BLV system is that it is possible to infect sheep via injection of a cloned provirus, facilitating the mutation of specific parts of the viral genome to examine the function of viral products in vivo. Like HTLV-1, the BLV mRNAs/proteins are transcribed from the viral 5’ long terminal repeat (LTR), a region rich in regulatory elements. It was previously believed that the BLV provirus was transcriptionally silent in tumors, however we identified a cluster of five abundantly expressed non-canonical RNA polymerase III dependent microRNAs (miRNAs) encoded by BLV (Rosewick et al., PNAS 2013). In addition, using RNA sequencing we recently discovered viral antisense transcripts originating in the 3' Long Terminal Repeat (LTR) of the BLV provirus (Durkin et al., Retrovirology 2016) . While 5'LTR dependent transcription is absent in malignant cells, both the viral miRNAs and the antisense transcripts are expressed in all BLV induced leukemic and pre-leukemic samples examined to date, pointing to a vital role in the life cycle of the virus and a critical function in cellular transformation. [less ▲]

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See detailStructural And Numerical Somatic Changes In BLV Induced Tumors
Durkin, Keith ULiege; Artesi, Maria ULiege; Hahaut, Vincent ULiege et al

Poster (2017, March)

Background Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1) BLV ... [more ▼]

Background Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1) BLV induces an aggressive leukemia/lymphoma in about ~5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a neoplasm. Recent work in HTLV-1 induced adult T cell leukemia/lymphoma (ATL) identified a large number of somatic changes associated with malignancy. At the current time little is known about the landscape of somatic changes in BLV induced tumors. Methods To examine gross numerical and structural aberrations in BLV induced tumors we assayed 12 bovine tumors on the BovineSNP50 Illumina BeadChip as well as 22 ovine tumors on the OvineSNP50 Illumina BeadChip. The resultant data was examined with penCNV in combination with visual inspection of the Log R ratios and B allele frequencies. Results The tumors from both species showed frequent aneuploidy with the whole or a large part of chromosomes BTA5, BTA10, BTA14 and BTA24 duplicated in >50% of the bovine tumors. In the ovine tumors chromosomes OAR5, OAR7, OAR9 and OAR16 were frequently duplicated. It is interesting to note that BTA14 is orthologous to OAR9 and both are orthologous to HSA8q, a part of the human genome frequently duplicated in ATLs and other leukemias. In addition a number of focal structural variants were observed. In cattle the terminus of BTA16, which includes the CD45 gene and miR-181 was amplified (>4 copies) in three tumors. In sheep, mirroring observations in ATL, the CDKN2A gene was deleted in multiple tumors. Conclusion These preliminary results indicate that tumors induced by HTLV-1 and BLV display somatic structural changes that impinge on overlapping sets of genes. Secondarily, it appears that in the case of BLV despite the much shorter incubation periods in sheep, the resultant tumors in both the natural and the experimental host display evidence of substantial genome instability. [less ▲]

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See detailMonitoring molecular response in adult T-cell leukemia by high-throughput sequencing analysis of HTLV-1 clonality.
Artesi, Maria ULiege; Marcais, A.; Durkin, Keith ULiege et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2017), 31(11), 2532-2535

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See detailCCDC88B is required for pathogenesis of inflammatory bowel disease.
Fodil, Nassima; Moradin, Neda; Leung, Vicki et al

in Nature Communications (2017), 8(1), 932

Inflammatory bowel disease (IBD) involves interaction between host genetic factors and environmental triggers. CCDC88B maps within one IBD risk locus on human chromosome 11q13. Here we show that CCDC88B ... [more ▼]

Inflammatory bowel disease (IBD) involves interaction between host genetic factors and environmental triggers. CCDC88B maps within one IBD risk locus on human chromosome 11q13. Here we show that CCDC88B protein increases in the colon during intestinal injury, concomitant with an influx of CCDC88B+lymphoid and myeloid cells. Loss of Ccdc88b protects against DSS-induced colitis, with fewer pathological lesions and reduced intestinal inflammation in Ccdc88b-deficient mice. In a T cell transfer model of colitis, Ccdc88b mutant CD4+ T cells do not induce colitis in immunocompromised hosts. Expression of human CCDC88B RNA and protein is higher in IBD patient colons than in control colon tissue. In human CD14+ myeloid cells, CCDC88B is regulated by cis-acting variants. In a cohort of patients with Crohn's disease, CCDC88B expression correlates positively with disease risk. These findings suggest that CCDC88B has a critical function in colon inflammation and the pathogenesis of IBD.Hook-related protein family member CCDC88b is encoded by a locus that has been associated with inflammatory bowel disease. Here the authors show that Ccdc88b inactivation in T cells prevents colitis in a transfer model, and detect high colonic levels of CCDC88b in patients with Crohn disease or ulcerative colitis, identifying that expression correlates with disease risk. [less ▲]

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See detailImproved high throughput DNA-seq based mapping of HTLV-1 integration sites: a tool to define response to treatment, ATL prognosis and guide therapeutic strategies
Marçais, Ambroise; Artesi, Maria ULiege; Durkin, Keith ULiege et al

Conference (2017)

Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive CD4+ T-cell malignancy caused by HTLV-1 infection and associated with extremely poor prognosis. In France, treatment strategies mainly ... [more ▼]

Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive CD4+ T-cell malignancy caused by HTLV-1 infection and associated with extremely poor prognosis. In France, treatment strategies mainly include chemotherapy, antiviral therapy and allogeneic stem cell transplantation, based on clinical subtype and therapeutic responses. Response to treatment is evaluated based on consensus criteria defined in 2009 (Tsukasaki K, Hermine O et al, JCO 2009). Although immuno-phenotyping, TCRγ rearrangement and HTLV-1 proviral load (PVL) quantification are often assayed, complete clinical remission (CR) is currently defined by morphological and cytological criteria i.e. complete blood cell counts (CBC) and the presence of abnormal lymphocytes. Given the extremely poor prognosis and high rates of early relapse, a revision of the response criteria is required, calling for improved tools that integrate specific aspects of the pathophysiology of ATL to better estimate response to treatment. Methods We retrospectively analyzed longitudinal PBMC samples from 6 ATL patients diagnosed with a leukemic subtype (5 acute and 1 chronic-aggressive) which all achieved CR upon therapy, yet relapsed after a median time of 15,9 months (range 2,4-70,7). CR was assessed by morphological and cytological criteria. An improved high throughput sequencing (HTS) based method was utilized to map and quantify the abundance of HTLV-1 genomic integration sites (IS), overcoming some of the limitations of previously published protocols. The dynamic range was increased by assaying both the 5’LTR and 3’LTRs, allowing better determination of clone abundance and revealing 5’ deletions. An enrichment step limited PCR duplicates. The addition of off-the-shelf Illumina primers simplified library multiplexing and reduced the costs to the point where the protocol could be applied to a clinical setting. Results HTS- mapping of HTLV-1 IS at diagnosis revealed in all cases a unique IS that constituted 92-99% of proviral genomes, with PVLs of 33-510%. All patients were treated and achieved CR which was characterized by normalized CBC, <5% abnormal lymphocytes and the absence of measurable tumors for >4 weeks. For 3/6 patients, the clone frequency distribution of HTLV-1 infected cells at CR was composed of multiple low abundance clones, of which the unique presumed malignant IS contributed to less than 2% of proviral genomes. In contrast, clonality analysis of the remaining 3/6 patients revealed that the relative abundance of the malignant clone detected at diagnosis remained dominant at CR (36-83% of PVL), despite clinical response criteria typical of CR and a 3-20-fold decrease in PVLs. These patients relapsed after 2.4, 2.9 and 3.4 months respectively with a dominant malignant clone >95% while patients with a polyclonal architecture showed significantly longer CR (28, 59 and 71 months). Conclusions Our observations highlight the great heterogeneity within an identical CR group, underlining the need for revisiting response criteria for ATL. Our results call for the use of this improved HTS-based method to measure HTLV-1 clonality as a tool to better estimate response to treatment, predict relapse and guide therapeutic choices in the course of treatment. [less ▲]

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See detailNGS- based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.
Charlier, Carole ULiege; Li, Wanbo; Harland, Chad ULiege et al

in Genome Research (2016), 26:1-9

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See detailBayesFM: a software program to fine-map multiple causative variants in GWAS identified risk loci.
Fang, Ming; Georges, Michel ULiege

in BioRxiv (2016)

We herein describe a new method to fine-map GWAS-identified risk loci based on the Bayesian Least Absolute Shrinkage Selection Operator (LASSO) combined with a Monte Carlo Markov Chain (MCMC) approach ... [more ▼]

We herein describe a new method to fine-map GWAS-identified risk loci based on the Bayesian Least Absolute Shrinkage Selection Operator (LASSO) combined with a Monte Carlo Markov Chain (MCMC) approach, and corresponding software package (BayesFM). We characterize the performances of BayesFM using simulated data, showing that it outperforms standard forward selection both in terms of sensitivity and specificity. We apply the method to the NOD2 locus, a well-established risk locus for Crohn's disease, in which we identify 13 putative independent signals. [less ▲]

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See detailSequence-based association analysis identifies coding and non-coding variants in HFM1, MLH3, MSH4, MSH5, RNF212 and RNF212B with large effects on male and female recombination rate in cattle
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

Poster (2016, June 15)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires to 94,516 offspring, and 579,996 CO events in oocytes transmitted by 11,461 cows to 25,332 offspring. When measured in identical family structures, the average number of CO in males (23.3) was found to be larger than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females. The genetic correlation was equal to 0.66, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed seven genome-wide significant QTL. Variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed in order to perform a sequence-based association analysis. For four QTLs, we identified missense mutations in genes known to be involved in meiotic recombination among the most significantly associated variants. Most of the identified mutations had significant effects in both genders with three of them accounting each for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Thus, a large fraction of the genetic variance is associated with missense mutations in genes known to be involved in meiotic recombination. Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females, and the genetic correlation is close to 0, whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes. [less ▲]

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See detailIdentification and characterization of novel bovine leukemia virus (BLV) antisense transcripts in leukemic and pre-leukemic clones
Durkin, Keith ULiege; Rosewick, Nicolas; Artesi, Maria ULiege et al

Conference (2016, May 21)

The deltaretrovirus Bovine Leukemia Virus (BLV) is closely related to the Human T-cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, produces a lifelong ... [more ▼]

The deltaretrovirus Bovine Leukemia Virus (BLV) is closely related to the Human T-cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, produces a lifelong infection. Most infected animals remain asymptomatic but following a protracted latency period about ~5% develop an aggressive leukemia/lymphoma, mirroring the disease trajectory of HTLV-1. Like the case in HTLV-1 the 5’LTR BLV provirus is transcriptionally silent in tumors, however the provirus is not entirely quiescent, constitutively express the BLV microRNAs in tumors. Using RNA-seq, we found that in addition to microRNAs, the BLV provirus also constitutively expresses two antisense transcripts in all BLV infected samples examined. The first transcript (AS1) has alternate potential polyadenylation sites generating a short transcript of ~600bp (AS1-S) and a less abundant longer transcript of ~2200bp (AS1-L). Alternative splicing also creates a second transcript of ~400bp (AS2) utilizing the first exon of AS1. Production of AS transcripts from the 3’LTR was supported by reporter assays demonstrating that the BLV LTR has substantial and Tax-independent antisense promoter activity. BLV AS transcripts predominantly localize in the nucleus. Examination of protein coding potential showed AS2 to be non-coding, while the AS1-S/L transcripts coding potential is ambiguous, with a small potential open reading frame (ORF) of 264bp present. The AS1-L transcript overlaps the BLV microRNAs transcribed in the sense direction. Using high throughput sequencing of RNA-ligase-mediated (RLM) 5' RACE products, we show that the perfect complementary between the transcripts leads to RNA-induced silencing complex (RISC) mediated cleavage of AS1-L. Furthermore, experiments using BLV proviruses where the microRNAs were removed or inverted point to additional transcriptional interactions between the two viral RNA species. Knock down of AS1-S/L using locked nucleic acids (LNAs) showed no obvious effect on the cells phenotype. While a detailed elucidation of the BLV antisense transcripts function remains in the future, the constitutive expression in all samples examined, points to a vital role for the transcripts in the life cycle and oncogenic potential of BLV. [less ▲]

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See detailHIGHER MALE THAN FEMALE RECOMBINATION RATE LARGELY CONTROLLED BY MISSENSE VARIANTS IN RNF212, MLH3, HFM1, MSH5 AND MSH4 IN CATTLE
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

Poster (2016, May 11)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires to 94,516 offspring, and 579,996 CO events in oocytes transmitted by 11,461 cows to 25,332 offspring. When measured in identical family structures, the average number of CO in males (23.3) was found to be larger than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females. The genetic correlation was equal to 0.66, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed seven genome-wide significant QTL. Variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed in order to perform a sequence-based association analysis. For four QTLs, we identified missense mutations in genes known to be involved in meiotic recombination among the most significantly associated variants. The P259S variant identified in RNF212 had already been reported, whereas missense mutations in MLH3 (N408S), HFM1 (S1189L), MSH5 (R631Q), MSH4 (C342Y) and a second in RNF212 (A77T) are new. Surprisingly, variants previously identified in REC8 were not associated with a QTL detected on BTA10 whereas variants in RNF212B, a paralog of RNF212, showed much stronger association with the phenotype in this region. This suggests that RNF212B might be involved in the recombination process. Most of the identified mutations had significant effects in both genders with three of them accounting each for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Thus, a large fraction of the genetic variance is associated with missense mutations in genes known to be involved in meiotic recombination. Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females, and the genetic correlation is close to 0, whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes. [less ▲]

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See detailThe impact of dopaminergic genes on inhibitory processes and cognitive control.
Jaspar, Mathieu ULiege; Muto, Vincenzo ULiege; Meyer, Christelle et al

Poster (2016, March 18)

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See detailImproving the methodology for high throughput mapping of proviral integration sites
Artesi, Maria ULiege; Durkin, Keith ULiege; Rosewick, Nicolas et al

Conference (2016)

Bovine Leukemia Virus (BLV) and Human T-cell leukemia virus-1 (HTLV-1) are closely related delta-retroviruses provoking a polyclonal expansion of infected B- and T-cells respectively, with monoclonal ... [more ▼]

Bovine Leukemia Virus (BLV) and Human T-cell leukemia virus-1 (HTLV-1) are closely related delta-retroviruses provoking a polyclonal expansion of infected B- and T-cells respectively, with monoclonal leukemia/lymphoma developing in about ~5% of infected individuals. To date, the molecular mechanisms leading to cellular transformation remain unclear. Both proviruses are largely transcriptionally silent in tumors and their integration sites in the host genome appear very variable. Mapping proviral insertion sites using high throughput sequencing techniques has provided insights into the evolution of BLV/HTLV-1 infections and the expansion of transformed clones in delta-retrovirus induced leukemia/lymphoma. The methods currently used have a number of limitations such as the utilisation of custom sequencing primers, relatively high sequencing costs, no examination of the 5’LTR host flanking region and a limited dynamic range for determining clone abundance. We have developed an alternative high-throughput sequencing protocol for tracking proviral integration sites and determining clonal abundance in BLV and HTLV-1 infected individuals. We implemented the use of off-the-shelf Illumina primers for the addition of adapters and indexes, which facilitates library multiplexing and avoids the need for custom sequencing primers. Our method reduces the amount of sequencing of PCR duplicates by reducing the number of PCR cycles via an enrichment of BLV- and HTLV-1-carrying DNA fragments. Moreover, in addition to the proviral 3’LTR, our approach also assays the 5’LTR, providing additional information on the frequency of 5’-end deletions in proviruses and increasing the dynamic range of the assay. We have tested the approach on over 100 BLV and HTLV-1 samples, representing both tumors and asymptomatic stages. Our approach allowed for a more accurate determination of clone abundance in tumors and by assaying the provirus 5’ end, identified clones overlooked with previously published methods. Finally, by facilitating greater multiplexing of libraries we have reduced the cost to a level where the technique may be attractive in a clinical setting. [less ▲]

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See detailCoding and noncoding variants in HFM1, MLH3, MSH4, MSH5, RNF212, and RNF212B affect recombination rate in cattle.
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

in Genome Research (2016)

We herein study genetic recombination in three cattle populations from France, New Zealand, and the Netherlands. We identify 2,395,177 crossover (CO) events in 94,516 male gametes, and 579,996 CO events ... [more ▼]

We herein study genetic recombination in three cattle populations from France, New Zealand, and the Netherlands. We identify 2,395,177 crossover (CO) events in 94,516 male gametes, and 579,996 CO events in 25,332 female gametes. The average number of COs was found to be larger in males (23.3) than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females, with a genetic correlation of 0.66 indicating that shared variants are influencing GRR in both sexes. A genome-wide association study identified seven quantitative trait loci (QTL) for GRR. Fine-mapping following sequence-based imputation in 14,401 animals pinpointed likely causative coding (5) and noncoding (1) variants in genes known to be involved in meiotic recombination (HFM1, MSH4, RNF212, MLH3, MSH5) for 5/7 QTL, and noncoding variants (3) in RNF212B for 1/7 QTL. This suggests that this RNF212 paralog might also be involved in recombination. Most of the identified mutations had significant effects in both sexes, with three of them each accounting for approximately 10% of the genetic variance in males. [less ▲]

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