Chromosome Research最新文献

Micronuclei, small DNA-containing structures separate from the main nucleus, were used for decades as an indicator of genotoxic damage. Micronuclei containing whole chromosomes were considered a biomarker of aneuploidy and were believed to form, upon mitotic exit, from chromosomes that lagged behind in anaphase as all other chromosomes segregated to the poles of the mitotic spindle. However, the mechanism responsible for inducing anaphase lagging chromosomes remained unknown until just over twenty years ago. Here, I summarize what preceded and what followed this discovery, highlighting some of the open questions and opportunities for future investigation.

Telomerase is a ribonucleoprotein ribonucleic enzyme that elongates telomere repeat sequences at the ends of chromosomes and contributes to cellular immortalization. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been observed to be reactivated in immortalized cells. Notably, most cancer cells have been found to have active hTERT mRNA transcription, resulting in continuous cell division, which is crucial for malignant transformation. Therefore, discovering mechanisms underlying the regulation of hTERT transcription is an attractive target for cancer-specific treatments.Loss of heterozygosity (LOH) of chromosome 3p21.3 has been frequently observed in human oral squamous cell carcinoma (OSCC). Moreover, we previously reported that HSC3 OSCC microcell hybrid clones with an introduced human chromosome 3 (HSC3#3) showed inhibition of hTERT transcription compared with the parental HSC3 cells. This study examined whether hTERT transcription regulators are present in the 3p21.3 region. We constructed a human artificial chromosome (HAC) vector (3p21.3-HAC) with only the 3p21.3-p22.2 region and performed functional analysis using the 3p21.3-HAC. HSC3 microcell hybrid clones with an introduced 3p21.3-HAC exhibited significant suppression of hTERT transcription, similar to the microcell hybrid clones with an intact chromosome 3. In contrast, HSC3 clones with truncated chromosome 3 with deletion of the 3p21.3 region (3delp21.3) showed no effect on hTERT expression levels. These results provide direct evidence that hTERT suppressor gene(s) were retained in the 3p21.3 region, suggesting that the presence of regulatory factors that control telomerase enzyme activity may be involved in the development of OSCC.

In the evolution of many organisms, periods of slow genome reorganization (= chromosomal conservatism) are interrupted by bursts of numerous chromosomal changes (= chromosomal megaevolution). Using comparative analysis of chromosome-level genome assemblies, we investigated these processes in blue butterflies (Lycaenidae). We demonstrate that the phase of chromosome number conservatism is characterized by the stability of most autosomes and dynamic evolution of the sex chromosome Z, resulting in multiple variants of NeoZ chromosomes due to autosome-sex chromosome fusions. In contrast during the phase of rapid chromosomal evolution, the explosive increase in chromosome number occurs mainly through simple chromosomal fissions. We show that chromosomal megaevolution is a highly non-random canalized process, and in two phylogenetically independent Lysandra lineages, the drastic parallel increase in number of fragmented chromosomes was achieved, at least partially, through reuse of the same ancestral chromosomal breakpoints. In species showing chromosome number doubling, we found no blocks of duplicated sequences or duplicated chromosomes, thus refuting the hypothesis of polyploidy. In the studied taxa, long blocks of interstitial telomere sequences (ITSs) consist of (TTAGG)_n arrays interspersed with telomere-specific retrotransposons. ITSs are sporadically present in rapidly evolving Lysandra karyotypes, but not in the species with ancestral chromosome number. Therefore, we hypothesize that the transposition of telomeric sequences may be triggers of the rapid chromosome number increase. Finally, we discuss the hypothetical genomic and population mechanisms of chromosomal megaevolution and argue that the disproportionally high evolutionary role of the Z sex chromosome can be additionally reinforced by sex chromosome-autosome fusions and Z-chromosome inversions.

Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles' heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

We report the first chromosome-length genome assemblies for three species in the mammalian order Pholidota: the white-bellied, Chinese, and Sunda pangolins. Surprisingly, we observe extraordinary karyotypic plasticity within this order and, in female white-bellied pangolins, the largest number of chromosomes reported in a Laurasiatherian mammal: 2n = 114. We perform the first karyotype analysis of an African pangolin and report a Y-autosome fusion in white-bellied pangolins, resulting in 2n = 113 for males. We employ a novel strategy to confirm the fusion and identify the autosome involved by finding the pseudoautosomal region (PAR) in the female genome assembly and analyzing the 3D contact frequency between PAR sequences and the rest of the genome in male and female white-bellied pangolins. Analyses of genetic variability show that white-bellied pangolins have intermediate levels of genome-wide heterozygosity relative to Chinese and Sunda pangolins, consistent with two moderate declines of historical effective population size. Our results reveal a remarkable feature of pangolin genome biology and highlight the need for further studies of these unique and endangered mammals.

Cellular quiescence is an important physiological state both in unicellular and multicellular eukaryotes. Quiescent cells are halted for proliferation and stop the cell cycle at the G₀ stage. Using fission yeast as a model organism, we have previously found that several subunits of a conserved chromatin remodeling complex, Ino80C (INOsitol requiring nucleosome remodeling factor), are required for survival in quiescence. Here, we demonstrate that Ino80C has a key function in the regulation of gene expression in G₀ cells. We show that null mutants for two Ino80C subunits, Iec1 and Ies2, a putative subunit Arp42, a null mutant for the histone variant H2A.Z, and a null mutant for the Inositol kinase Asp1 have very similar phenotypes in quiescence. These mutants show reduced transcription genome-wide and specifically fail to activate 149 quiescence genes, of which many are localized to the subtelomeric regions. Using spike in normalized ChIP-seq experiments, we show that there is a global reduction of H2A.Z levels in quiescent wild-type cells but not in iec1∆ cells and that a subtelomeric chromosome boundary element is strongly affected by Ino80C. Based on these observations, we propose a model in which Ino80C is evicting H2A.Z from chromatin in quiescent cells, thereby inactivating the subtelomeric boundary element, leading to a reorganization of the chromosome structure and activation of genes required to survive in quiescence.

Centromeres in eukaryotes are composed of highly repetitive DNAs, which evolve rapidly and are thought to achieve a favorable structure in mature centromeres. However, how the centromeric repeat evolves into an adaptive structure is largely unknown. We characterized the centromeric sequences of Gossypium anomalum through chromatin immunoprecipitation against CENH3 antibodies. We revealed that the G. anomalum centromeres contained only retrotransposon-like repeats but were depleted in long arrays of satellites. These retrotransposon-like centromeric repeats were present in the African-Asian and Australian lineage species, suggesting that they might have arisen in the common ancestor of these diploid species. Intriguingly, we observed a substantial increase and decrease in copy numbers among African-Asian and Australian lineages, respectively, for the retrotransposon-derived centromeric repeats without apparent structure or sequence variation in cotton. This result indicates that the sequence content is not a decisive aspect of the adaptive evolution of centromeric repeats or at least retrotransposon-like centromeric repeats. In addition, two active genes with potential roles in gametogenesis or flowering were identified in CENH3 nucleosome-binding regions. Our results provide new insights into the constitution of centromeric repetitive DNA and the adaptive evolution of centromeric repeats in plants.

Alterations of human karyotype caused by chromosomal rearrangements are often associated with considerable phenotypic effects. Studying molecular mechanisms underlying these effects requires an efficient and scalable experimental model. Here, we propose a Cre-LoxP-based approach for the generation of combinatorial diversity of chromosomal rearrangements. We demonstrate that using the developed system, both intra- and inter-chromosomal rearrangements can be induced in the human haploid HAP1 cells, although the latter is significantly less effective. The obtained genetically modified HAP1 cell line can be used to dissect genomic effects associated with intra-chromosomal structural variations.

Intrachromosomal rearrangements involve a single chromosome and can be formed by several proposed mechanisms. We reported two patients with intrachromosomal duplications and deletions, whose rearrangements and breakpoints were characterized through karyotyping, chromosomal microarray, fluorescence in situ hybridization, whole-genome sequencing, and Sanger sequencing. Inverted duplications associated with terminal deletions, known as inv-dup-del rearrangements, were found in 13q and 15q in these patients. The presence of microhomology at the junction points led to the proposal of the Fold-back mechanism for their formation. The use of different high-resolution techniques allowed for a better characterization of the rearrangements, with Sanger sequencing of the junction points being essential to infer the mechanisms of formation as it revealed microhomologies that were missed by the previous techniques. A karyotype-phenotype correlation was also performed for the characterized rearrangements.

Chromosomal rearrangements are often associated with local adaptation and speciation because they suppress recombination, and as a result, rearrangements have been implicated in disrupting gene flow. Although there is strong evidence to suggest that chromosome rearrangements are a factor in genetic isolation of divergent populations, the underlying mechanism remains elusive. Here, we applied an integrative cytogenetics and genomics approach testing whether chromosomal rearrangements are the initial process, or a consequence, of population divergence in the dwarf goanna, Varanus acanthurus. Specifically, we tested whether chromosome rearrangements are indicators of genetic barriers that can be used to identify divergent populations by looking at gene flow within and between populations with rearrangements. We found that gene flow was present between individuals with chromosome rearrangements within populations, but there was no gene flow between populations that had similar chromosome rearrangements. Moreover, we identified a correlation between reduced genetic variation in populations with a higher frequency of homozygous submetacentric individuals. These findings suggest that chromosomal rearrangements were widespread prior to divergence, and because we found populations with higher frequencies of submetacentric chromosomes were associated with lower genetic diversity, this could indicate that polymorphisms within populations are early indicators of genetic drift.