The gibbon karyotype is known to be extensively rearranged when compared to the human and to the ancestral primate karyotype. By combining a bioinformatics (paired-end sequence analysis) approach and a molecular cytogenetics approach, we have refined the synteny block arrangement of the white-cheeked gibbon (Nomascus leucogenys, NLE) with respect to the human genome. We provide the first detailed clone framework map of the gibbon genome and refine the location of 86 evolutionary breakpoints to <1 Mb resolution. An additional 12 breakpoints, mapping primarily to centromeric and telomeric regions, were mapped to ∼5 Mb resolution. Our combined FISH and BES analysis indicates that we have effectively subcloned 49 of these breakpoints within NLE gibbon BAC clones, mapped to a median resolution of 79.7 kb. Interestingly, many of the intervals associated with translocations were gene-rich, including some genes associated with normal skeletal development. Comparisons of NLE breakpoints with those of other gibbon species reveal variability in the position, suggesting that chromosomal rearrangement has been a longstanding property of this particular ape lineage. Our data emphasize the synergistic effect of combining computational genomics and cytogenetics and provide a framework for ultimate sequence and assembly of the gibbon genome.[Supplemental material is available online at www.genome.org.]Hominidae (humans and great apes) and, to a lesser extent, Old World monkeys, possess karyotypes closely resembling the hypothetical hominoid ancestor. Most evolutionary chromosomal rearrangements between ape lineages involve pericentric (including the centromere) or paracentric (not including the centromere) inversions (Yunis and Prakash 1982). In contrast, comparative studies of gibbons (small apes, family Hylobatidae) indicate that the karyotypes of all 12 (or more) species appear highly derived, with an unusually large number (n > 40) of chromosomal fissions and translocations (Jauch et al. 1992; Koehler et al. 1995a,b;Muller and Wienberg 2001;Murphy et al. 2001;Nie et al. 2001;Muller et al. 2002Muller et al. , 2003Ferguson-Smith et al. 2005;Froenicke 2005). Their chromosomal numbers range from 2n = 38 (hoolock gibbons) to 2n = 52 (Nomascus) and differ from other ape lineages in showing an accelerated rate of chromosomal translocation during evolution.Gibbons, then, provide a unique perspective of a highly rearranged ape genome with two major advantages: (1) neutrally evolving DNA shows a relatively short genetic distance (<0.05 substitutions/site) to the high-quality human reference sequence; and (2) the gibbon represents a phylogenetic link between the great apes and the Old World monkeys, providing a unique perspective of evolutionary change between 15 and 20 million years of species separation (Goodman 1999). The evolutionary relatedness of human and gibbon species facilitates crossspecies FISH experiments and comparative sequence analyses to provide exquisite resolution in refining evolutionary breakpoints of chromosomal ...

BackgroundPrevious studies of higher order chromatin organization in nuclei of mammalian species revealed both structural consistency and species-specific differences between cell lines and during early embryonic development. Here, we extended our studies to nuclear landscapes in the human myelopoietic lineage representing a somatic cell differentiation system. Our longterm goal is a search for structural features of nuclei, which are restricted to certain cell types/species, as compared to features, which are evolutionary highly conserved, arguing for their basic functional roles in nuclear organization.ResultsCommon human hematopoietic progenitors, myeloid precursor cells, differentiated monocytes and granulocytes analyzed by super-resolution fluorescence microscopy and electron microscopy revealed profound differences with respect to global chromatin arrangements, the nuclear space occupied by the interchromatin compartment and the distribution of nuclear pores. In contrast, we noted a consistent organization in all cell types with regard to two co-aligned networks, an active (ANC) and an inactive (INC) nuclear compartment delineated by functionally relevant hallmarks. The ANC is enriched in active RNA polymerase II, splicing speckles and histone signatures for transcriptionally competent chromatin (H3K4me3), whereas the INC carries marks for repressed chromatin (H3K9me3).ConclusionsOur findings substantiate the conservation of the recently published ANC-INC network model of mammalian nuclear organization during human myelopoiesis irrespective of profound changes of the global nuclear architecture observed during this differentiation process. According to this model, two spatially co-aligned and functionally interacting active and inactive nuclear compartments (ANC and INC) pervade the nuclear space.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0038-0) contains supplementary material, which is available to authorized users.

Background: Evolutionary-new centromeres (ENCs) result from the seeding of a centromere at an ectopic location along the chromosome during evolution. The novel centromere rapidly acquires the complex structure typical of eukaryote centromeres. This phenomenon has played an important role in shaping primate karyotypes. A recent study on the evolutionary-new centromere of macaque chromosome 4 (human 6) showed that the evolutionary-new centromere domain was deeply restructured, following the seeding, with respect to the corresponding human region assumed as ancestral. It was also demonstrated that the region was devoid of genes. We hypothesized that these two observations were not merely coincidental and that the absence of genes in the seeding area constituted a crucial condition for the evolutionary-new centromere fixation in the population.

Panels of BAC clones used in FISH experiments allow a detailed definition of chromosomal marker arrangement and orientation during evolution. This approach has disclosed the centromere repositioning phenomenon, consisting in the activation of a novel, fully functional centromere in an ectopic location, concomitant with the inactivation of the old centromere. In this study, appropriate panels of BAC clones were used to track the chromosome 11 evolutionary history in primates and nonprimate boreoeutherian mammals. Chromosome 11 synteny was found to be highly conserved in both primate and boreoeutherian mammalian ancestors. Amazingly, we detected four centromere repositioning events in primates (in Old World monkeys, in gibbons, in orangutans, and in the Homo-Pan-Gorilla (H-P-G) clade ancestor), and one in Equidae. Both H-P-G and Lar gibbon novel centromeres were flanked by large duplicons with high sequence similarity. Outgroup species analysis revealed that this duplicon was absent in phylogenetically more distant primates. The chromosome 11 ancestral centromere was probably located near the HSA11q telomere. The domain of this inactivated centromere, in humans, is almost devoid of segmental duplications. An inversion occurred in chromosome 11 in the common ancestor of H-P-G. A large duplicon, again absent in outgroup species, was found located adjacent to the inversion breakpoints. In Hominoidea, almost all the five largest duplicons of this chromosome appeared involved in significant evolutionary architectural changes.

We here describe a leukemogenic role of the homeobox gene UNCX, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of UNCX in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. UNCX is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. UNCX expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. UNCX-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as MAP2K1 and CCNA1, was revealed. Similar results were obtained in UNCX-transduced CD34+ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that UNCX expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type NPM1. We also observed that UNCX expression significantly associates with an increased frequency of acute promyelocytic leukemia with PML-RARA and AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.