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Abstract XY C57BL/6J (B6) mice harboring a Mus musculus domesticus-type Y chromosome (YPOS), known as B6.YPOS mice, commonly undergo gonadal sex reversal and develop as phenotypic females. In a minority of cases, B6.YPOS males are identified and a proportion of these are fertile. This phenotypic variability on a congenic B6 background has puzzled geneticists for decades. Recently, a B6.YPOS colony was shown to carry a non-B6-derived region of chromosome 11 that protected against B6.YPOS sex reversal. Here. we show that a B6.YPOS colony bred and archived at the MRC Harwell Institute lacks the chromosome 11 modifier but instead harbors an ∼37 Mb region containing non-B6-derived segments on chromosome 13. This region, which we call Mod13, protects against B6.YPOS sex reversal in a proportion of heterozygous animals through its positive and negative effects on gene expression during primary sex determination. We discuss Mod13’s influence on the testis determination process and its possible origin in light of sequence similarities to that region in other mouse genomes. Our data reveal that the B6.YPOS sex reversal phenomenon is genetically complex and the explanation of observed phenotypic variability is likely dependent on the breeding history of any local colony.

Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.

Partial deletions on the long arm of chromosome 13 lead to a number of different phenotypes depending on the size and position of the deleted region. The present study investigated 2 patients with 13q terminal (13qter) deletion syndrome, which manifested as anal atresia with rectoperineal fistula, complex type congenital heart disease, esophageal hiatus hernia with gastroesophageal reflux, facial anomalies and developmental and mental retardation. Array comparative genomic hybridization identified 2 regions of deletion on chromosome 13q31-qter; 20.38 Mb in 13q31.3-qter and 12.99 Mb in 13q33.1-qter in patients 1 and 2, respectively. Comparisons between the results observed in the present study and those obtained from patients in previous studies indicate that the gene encoding ephrin B2 (EFNB2) located in the 13q33.3-q34 region, and the gene coding for endothelin receptor type B, in the 13q22.1-31.3 region, may be suitable candidate genes for the observed urogenital/anorectal anomalies. In addition, the microRNA-17-92a-1 cluster host gene and the glypican 6 gene in the 13q31.3 region, as well as EFNB2 and the collagen type IV a1 chain (COL4A1) and COL4A2 genes in the 13q33.1-q34 region may together contribute to cardiovascular disease development. It is therefore possible that these genes may be involved in the pathogenesis of complex type congenital heart disease in patients with 13q deletion syndrome.

Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.

Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome. The DNA in a human cell is divided between forty-six structures called chromosomes. Before a cell divides, it copies every chromosome so that each daughter cell will have the same DNA as the parent cell. These chromosomes align in the center of the cell and then the matching chromosomes are separated and pulled to opposite ends. However, in some cases the separation process does not work properly, which can produce cells that either have too many, or too few, chromosomes. Abnormal numbers of chromosomes within cells—called aneuploidy—is a leading cause of miscarriage and birth defects in humans. Aneuploidy is also a common feature of cancer cells. It is common for the chromosomes in cancer cells to be distributed unequally when the cell divides. This phenomenon is known as chromosomal instability, but the link between aneuploidy and chromosomal instability in cancer cells is not fully understood. Here, Nicholson et al. used live-cell imaging techniques to analyze healthy human cells and cancer cells that had either the normal forty-six chromosomes, or a defined extra chromosome. Nicholson et al. found that when the cells divided, the chromosomes in the cells that had an extra copy of chromosome 7 or 13 were more prone to distributing chromosomes unequally, compared to cells with a normal number of chromosomes. Nicholson et al. also observed that the cells with an extra chromosome 13 were unable to properly divide into two. These cells had increased levels of a protein called Spartin—which is important for the last stage in cell division—and this was responsible for the failure to produce two daughter cells. These findings show that aneuploidy can cause chromosomal instability in human cells. Furthermore, Nicholson et al. have identified a defect in cell division that is specifically caused by the presence of an extra chromosome 13 in human cells. A future challenge will be to determine how, and to what extent, different chromosomes can affect chromosome stability. This could be useful in the development of therapies against cancer cells with aneuploidy.

We present the analysis of defective pathways in multiple myeloma (MM) using two recently developed sampling algorithms of the biological pathways: The Fisher’s ratio sampler, and the holdout sampler. We performed the retrospective analyses of different gene expression datasets concerning different aspects of the disease, such as the existing difference between bone marrow stromal cells in MM and healthy controls (HC), the gene expression profiling of CD34+ cells in MM and HC, the difference between hyperdiploid and non-hyperdiploid myelomas, and the prediction of the chromosome 13 deletion, to provide a deeper insight into the molecular mechanisms involved in the disease. Our analysis has shown the importance of different altered pathways related to glycosylation, infectious disease, immune system response, different aspects of metabolism, DNA repair, protein recycling and regulation of the transcription of genes involved in the differentiation of myeloid cells. The main difference in genetic pathways between hyperdiploid and non-hyperdiploid myelomas are related to infectious disease, immune system response and protein recycling. Our work provides new insights on the genetic pathways involved in this complex disease and proposes novel targets for future therapies.

Family and twin studies suggest that genes play a role in male sexual orientation. We conducted a genome-wide association study (GWAS) of male sexual orientation on a primarily European ancestry sample of 1,077 homosexual men and 1,231 heterosexual men using Affymetrix single nucleotide polymorphism (SNP) arrays. We identified several SNPs with p  < 10 −5 , including regions of multiple supporting SNPs on chromosomes 13 (minimum p  = 7.5 × 10 −7 ) and 14 ( p  = 4.7 × 10 −7 ). The genes nearest to these peaks have functions plausibly relevant to the development of sexual orientation. On chromosome 13, SLITRK6 is a neurodevelopmental gene mostly expressed in the diencephalon, which contains a region previously reported as differing in size in men by sexual orientation. On chromosome 14, TSHR genetic variants in intron 1 could conceivably help explain past findings relating familial atypical thyroid function and male homosexuality. Furthermore, skewed X chromosome inactivation has been found in the thyroid condition, Graves’ disease, as well as in mothers of homosexual men. On pericentromeric chromosome 8 within our previously reported linkage peak, we found support ( p  = 4.1 × 10 −3 ) for a SNP association previously reported (rs77013977, p  = 7.1 × 10 −8 ), with the combined analysis yielding p  = 6.7 × 10 −9 , i.e., a genome-wide significant association.

Breast cancer (BCa) is a major global health challenge. The BCa genome often carries extensive somatic copy number alterations (CNAs), including gains/amplifications and losses/deletions. These CNAs significantly affect tumor development, drug response and patient survival. However, how individual CNAs contribute is mostly elusive. We identified loss of chromosome 13q14.2 as a key CNA in BCa, occurring in up to 63% of patients, depending on the subtype, and correlating with poor survival. Through multi-omics and in vitro analyses, we uncover a paradoxical role of 13q14.2 loss, promoting both cell cycle and pro-apoptotic pathways in cancer cells, while also associating with increased NK cell and macrophage populations in the tumor microenvironment. Notably, 13q14.2 loss increases BCa susceptibility to BCL2 inhibitors, both in vitro and in patient-derived xenografts. Thus, 13q14.2 loss could serve as a biomarker for BCa prognosis and treatment, potentially improving outcomes for BCa patients. Graphical abstract

The major mechanism for ring chromosome formation is thought to result from breakage and reunion at the breakpoints on the long and short arms of a chromosome.This fusion event can produce terminal arm inversions,deletions,and duplications that determine the resulting phenotype.[1] Ring chromosome 13 is relatively uncommon,with an estimated incidence of 1/58,000 live births.

Comprehensive analysis of alterations in gene expression along with neoplastic transformation in human cells provides valuable information about the molecular mechanisms underlying transformation. To further address these questions, we performed whole transcriptome analysis to the human mesenchymal stem cell line, UE6E7T-3, which was immortalized with hTERT and human papillomavirus type 16 E6/E7 genes, in association with progress of transformation in these cells. At early stages of culture, UE6E7T-3 cells preferentially lost one copy of chromosome 13, as previously described; in addition, tumor suppressor genes, DNA repair genes, and apoptosis-activating genes were overexpressed. After the loss of chromosome 13, additional aneuploidy and genetic alterations that drove progressive transformation, were observed. At this stage, the cell line expressed oncogenes as well as genes related to anti-apoptotic functions, cell-cycle progression, and chromosome instability (CIN); these pro-tumorigenic changes were concomitant with a decrease in tumor suppressor gene expression. At later stages after prolong culture, the cells exhibited chromosome translocations, acquired anchorage-independent growth and tumorigenicity in nude mice, (sarcoma) and exhibited increased expression of genes encoding growth factor and DNA repair genes, and decreased expression of adhesion genes. In particular, glypican-5 (GPC5), which encodes a cell-surface proteoglycan that might be a biomarker for sarcoma, was expressed at high levels in association with transformation. Patched (Ptc1), the cell surface receptor for hedgehog (Hh) signaling, was also significantly overexpressed and co-localized with GPC5. Knockdown of GPC5 expression decreased cell proliferation, suggesting that it plays a key role in growth in U3-DT cells (transformants derived from UE6E7T-3 cells) through the Hh signaling pathway. Thus, the UE6E7T-3 cell culture model is a useful tool for assessing the functional contribution of genes showed by expression profiling to the neoplastic transformation of human fibroblasts and human mesenchymal stem cells (hMSC).