Explore the vast range of titles available.

Accurate chromosome segregation during mitosis requires the physical separation of sister chromatids before nuclear envelope reassembly (NER). However, how these two processes are coordinated remains unknown. Here, we identified a conserved feedback control mechanism that delays chromosome decondensation and NER in response to incomplete chromosome separation during anaphase. A midzone-associated Aurora B gradient was found to monitor chromosome position along the division axis and to prevent premature chromosome decondensation by retaining Condensin I. PP1/PP2A phosphatases counteracted this gradient and promoted chromosome decondensation and NER. Thus, an Aurora B gradient appears to mediate a surveillance mechanism that prevents chromosome decondensation and NER until effective separation of sister chromatids is achieved. This allows the correction and reintegration of lagging chromosomes in the main nuclei before completion of NER.

X and Y chromosomes in mammals are different in size and gene content due to an evolutionary process of differentiation and degeneration of the Y chromosome. Nevertheless, these chromosomes usually share a small region of homology, the pseudoautosomal region (PAR), which allows them to perform a partial synapsis and undergo reciprocal recombination during meiosis, which ensures their segregation. However, in some mammalian species the PAR has been lost, which challenges the pairing and segregation of sex chromosomes in meiosis. The African pygmy mouse Mus mattheyi shows completely differentiated sex chromosomes, representing an uncommon evolutionary situation among mouse species. We have performed a detailed analysis of the location of proteins involved in synaptonemal complex assembly (SYCP3), recombination (RPA, RAD51 and MLH1) and sex chromosome inactivation (γH2AX) in this species. We found that neither synapsis nor chiasmata are found between sex chromosomes and their pairing is notably delayed compared to autosomes. Interestingly, the Y chromosome only incorporates RPA and RAD51 in a reduced fraction of spermatocytes, indicating a particular DNA repair dynamic on this chromosome. The analysis of segregation revealed that sex chromosomes are associated until metaphase-I just by a chromatin contact. Unexpectedly, both sex chromosomes remain labelled with γH2AX during first meiotic division. This chromatin contact is probably enough to maintain sex chromosome association up to anaphase-I and, therefore, could be relevant to ensure their reductional segregation. The results presented suggest that the regulation of both DNA repair and epigenetic modifications in the sex chromosomes can have a great impact on the divergence of sex chromosomes and their proper transmission, widening our understanding on the relationship between meiosis and the evolution of sex chromosomes in mammals.

Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. The mechanism for chromothripsis, “shattered” chromosomes that can be observed in cancer cells, is unknown; here, using live-cell imaging and single-cell sequencing, chromothripsis is shown to occur after a chromosome is isolated into a micronucleus, an abnormal nuclear structure. Chromothripsis recreated Chromothripsis, a dramatic chromosomal event involving massive chromosome breakage and rearrangement, typically restricted to one or a few of a cell's chromosomes, has been observed in various cancers and congenital diseases. A new study uses a combination of live-cell imaging and single-cell genome sequencing to recreate chromothripsis-like rearrangements. The results show that after single chromosomes are missegregated into so-called micronuclei, they can shatter. After cell division, these fragments can be incorporated back into the genome, generating rearrangements that in some cases bear all the hallmark features of chromothripsis. Chromosome shattering in micronuclei can also lead to the formation of small circular chromosome fragments, the initial step in forming 'double minute chromosomes', which carry amplified oncogenes in cancer. This study thus provides the first experimental demonstration of a molecular mechanism underlying chromothripsis.

Cancer genomes are frequently characterized by numerical and structural chromosomal abnormalities. Here we integrated a centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy termed CEN-SELECT, to systematically interrogate the structural landscape of mis-segregated chromosomes. We show that single-chromosome mis-segregation into a micronucleus can directly trigger a broad spectrum of genomic rearrangement types. Cytogenetic profiling revealed that mis-segregated chromosomes exhibit 120-fold-higher susceptibility to developing seven major categories of structural aberrations, including translocations, insertions, deletions, and complex reassembly through chromothripsis coupled to classical non-homologous end joining. Whole-genome sequencing of clonally propagated rearrangements identified random patterns of clustered breakpoints with copy-number alterations resulting in interspersed gene deletions and extrachromosomal DNA amplification events. We conclude that individual chromosome segregation errors during mitotic cell division are sufficient to drive extensive structural variations that recapitulate genomic features commonly associated with human disease. Cytogenetic and whole-genome-sequencing analyses using CEN-SELECT show that mitotic segregation errors generate a broad spectrum of chromosomal aberrations that recapitulate the complex structural features of cancer genomes.

A mechanism to explain chromosomal instability (CIN) in colorectal cancer is demonstrated; three new CIN-suppressor genes ( PIGN , MEX3C and ZNF516 ) encoded on chromosome 18q are identified, the loss of which leads to DNA replication stress, resulting in structural and numerical chromosome segregation errors, which are shown to be identical to phenotypes seen in CIN cells. Cause of chromosome instability in colorectal cancer Chromosomal instability (CIN) occurs in most solid tumours and is associated with poor prognosis and drug resistance. This study demonstrates a link between CIN in colorectal cancer and the loss of a region on chromosome 18q. The authors identify three previously unknown CIN-suppressor genes in this region that, when lost, lead to replication stress resulting in structural and numerical chromosome segregation errors. Supplementing tumour cell lines with nucleosides alleviates replication-associated damage, limits chromosome segregation errors after CIN-suppressor gene silencing and attenuates segregation errors and DNA damage in CIN + cells. These findings point to a genetic mechanism — distinct from mitotic defects — that causes chromosome instability in colorectal tumours and that might be pharmacologically reversible. Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity 1 , 2 . CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance 3 , 4 . Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN + colorectal cancer (CRC) cells relative to CIN − CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes ( PIGN (also known as MCD4 ), MEX3C ( RKHD2 ) and ZNF516 ( KIAA0222 )) encoded on chromosome 18q that are subject to frequent copy number loss in CIN + CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma–carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage 5 , reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN + cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.

Chromosome segregation errors during cell divisions generate aneuploidies and micronuclei, which can undergo extensive chromosomal rearrangements such as chromothripsis 1 – 5 . Selective pressures then shape distinct aneuploidy and rearrangement patterns—for example, in cancer 6 , 7 —but it is unknown whether initial biases in segregation errors and micronucleation exist for particular chromosomes. Using single-cell DNA sequencing 8 after an error-prone mitosis in untransformed, diploid cell lines and organoids, we show that chromosomes have different segregation error frequencies that result in non-random aneuploidy landscapes. Isolation and sequencing of single micronuclei from these cells showed that mis-segregating chromosomes frequently also preferentially become entrapped in micronuclei. A similar bias was found in naturally occurring micronuclei of two cancer cell lines. We find that segregation error frequencies of individual chromosomes correlate with their location in the interphase nucleus, and show that this is highest for peripheral chromosomes behind spindle poles. Randomization of chromosome positions, Cas9-mediated live tracking and forced repositioning of individual chromosomes showed that a greater distance from the nuclear centre directly increases the propensity to mis-segregate. Accordingly, chromothripsis in cancer genomes 9 and aneuploidies in early development 10 occur more frequently for larger chromosomes, which are preferentially located near the nuclear periphery. Our findings reveal a direct link between nuclear chromosome positions, segregation error frequencies and micronucleus content, with implications for our understanding of tumour genome evolution and the origins of specific aneuploidies during development. Using single-cell DNA sequencing after an error-prone mitosis in untransformed, diploid cell lines and organoids, chromosomes are shown to have different segregation error frequencies that result in non-random aneuploidy landscapes.

Depletion of the cohesin-associated protein Wapl in mice is shown to increase the residence time of cohesin on DNA, which leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes; the findings suggest that cohesin could have an architectural role in interphase chromosome organization. Wapl protein's role in chromosome organization Cohesin has important functions during chromosome segregation but is also thought to help organize chromatin fibres into loops during interphase. Here, Jan-Michael Peters and colleagues show that depletion of the cohesin-associated protein Wapl increases the residence time of cohesin on DNA, which in turn leads to clustering of cohesin in axial structures and causes chromatin condensation in interphase chromosomes. Depletion of Wapl also affects gene expression and leads to defects in chromosome segregation. These findings indicate that the dynamic interaction of cohesin with DNA, as mediated by Wapl, is an important determinant of chromatin structure, and that cohesin could have an architectural role in interphase chromosome organization. Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures 1 , 2 , 3 , 4 , 5 , 6 , 7 , but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl 8 , 9 stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin–DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin–DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc ), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.

Polyploidization and recombination are two important processes driving evolution through the building and reshaping of genomes. Allopolyploids arise from hybridization and chromosome doubling among distinct, yet related species. Polyploids may display novel variation relative to their progenitors, and the sources of this variation lie not only in the acquisition of extra gene dosages, but also in the genomic changes that occur after divergent genomes unite. Genomic changes (deletions, duplications, and translocations) have been detected in both recently formed natural polyploids and resynthesized polyploids. In resynthesized Brassica napus allopolyploids, there is evidence that many genetic changes are the consequence of homoeologous recombination. Homoeologous recombination can generate novel gene combinations and phenotypes, but may also destabilize the karyotype and lead to aberrant meiotic behavior and reduced fertility. Thus, natural selection plays a role in the establishment and maintenance of fertile natural allopolyploids that have stabilized chromosome inheritance and a few advantageous chromosomal rearrangements. We discuss the evidence for genome rearrangements that result from homoeologous recombination in resynthesized B. napus and how these observations may inform phenomena such as chromosome replacement, aneuploidy, non-reciprocal translocations and gene conversion seen in other polyploids.

Genotyping by sequencing (GBS) is the latest application of next-generation sequencing protocols for the purposes of discovering and genotyping SNPs in a variety of crop species and populations. Unlike other high-density genotyping technologies which have mainly been applied to general interest “reference” genomes, the low cost of GBS makes it an attractive means of saturating mapping and breeding populations with a high density of SNP markers. One barrier to the widespread use of GBS has been the difficulty of the bioinformatics analysis as the approach is accompanied by a high number of erroneous SNP calls which are not easily diagnosed or corrected. In this study, we use a 384-plex GBS protocol to add 30,984 markers to an indica (IR64) × japonica (Azucena) mapping population consisting of 176 recombinant inbred lines of rice (Oryza sativa) and we release our imputation and error correction pipeline to address initial GBS data sparsity and error, and streamline the process of adding SNPs to RIL populations. Using the final imputed and corrected dataset of 30,984 markers, we were able to map recombination hot and cold spots and regions of segregation distortion across the genome with a high degree of accuracy, thus identifying regions of the genome containing putative sterility loci. We mapped QTL for leaf width and aluminum tolerance, and were able to identify additional QTL for both phenotypes when using the full set of 30,984 SNPs that were not identified using a subset of only 1,464 SNPs, including a previously unreported QTL for aluminum tolerance located directly within a recombination hotspot on chromosome 1. These results suggest that adding a high density of SNP markers to a mapping or breeding population through GBS has a great value for numerous applications in rice breeding and genetics research.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1 , 2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion. A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.