Genome dynamics最新文献

Normal human somatic cells contain 46 chromosomes (22 pairs of autosomes and two sex chromosomes). Chromosome missegregation leads to abnormal numbers of chromosomes or aneuploidy. This form of genetic instability alters the dosages of large subsets of genes, which can result in severe disease phenotypes. Most human cancer cells are aneuploid. It is generally believed that aneuploidy contributes to cancer formation. The spindle checkpoint is a cell-cycle surveillance mechanism that ensures the fidelity of chromosome segregation during mitosis and meiosis. In this article, we review our current understanding of the molecular basis of the spindle checkpoint and the recent evidence that links the malfunction of this checkpoint to aneuploidy and tumorigenesis.

Tetraodon is a small brackish water tropical fish that is endowed with the smallest known vertebrate genome. This property has been exploited by sequencing, followed by analyses and comparisons to other vertebrate genomes that have yielded unexpected findings. The paucity of repeats, extreme gene density, rapid molecular evolution and chromosome stability are some of the characteristics of the Tetraodon genome. The organization of paralogous and orthologous genes in the genome have been key elements to prove that a whole genome duplication has occurred at the root of the teleost lineage, providing at the same time a much clearer picture of the ancestral teleost genome.

The mapping, sequencing and analysis of the human genome is a milestone in biomedical research and a fundamental advance in self-knowledge. Because the sequence was intended to serve as a universal and permanent foundation of biomedical research, enormous international efforts were undertaken to reach the highest level of accuracy and completeness possible. The current assembly of the 24 DNA molecules covers approximately 99% of the euchromatic portion. Including gaps, the euchromatin is approximately 2.88 Gb and the overall size of the human genome approximately 3.08 Gb. Repeated sequences account for more than half of the human genome. Remarkable is the high proportion of segmental duplications. Until recently it was assumed that tiny variations in an otherwise universal reference sequence are the genetic bases of individual human traits. Now, with the nearly-complete reference in hands, it becomes increasingly evident, that our concept of genome plasticity has to be extended from seemingly fixed human segmental duplications to interindividual, large-scale structural polymorphisms.

In approximately 20 years, bovine genomics has progressed from synteny mapping of protein gene products to a nearly completed 7.5x whole genome sequence. The cattle genome map serves as a prototype for genomic studies in other bovids such as goats, sheep, and river buffalo in which chromosome arms are totally conserved at the current level of cytogenetic and map comparison. Cattle genomics has contributed to the discovery of genes underlying economically important phenotypes including quantitative traits, to the development of bovine models of human diseases, and to our understanding of mammalian chromosome evolution.

Marsupials and monotremes are 'alternative mammals', independent experiments of mammalian evolution that diverged from placental mammals 180 and 210 million years ago (MYA), respectively. Marsupials (e.g. kangaroo, opossum) and monotremes (e.g. platypus) differ from placental mammals in many characteristics, particularly reproduction. With their early divergence from placentals, they fill the phylogenetic gap between the mammal-reptile divergence 310 MYA and the placental radiation 100 MYA. Their genomes are similar in size to those of placentals, but their chromosomes are quite distinctive. Marsupials have a few very large and very conserved chromosomes, while monotremes show a reptile-like size dichotomy and have a unique chain of ten sex chromosomes. Studies of gene arrangement in marsupials and monotremes have delivered many surprises that necessitate re-evaluation of the function and control of several genes in all mammals including humans, and provide new insights into the evolution of the mammalian genome, particularly the sex chromosomes. With the imminent sequencing of the genomes of two marsupials (the short-tailed grey Brazilian opossum and an Australian model kangaroo) and the platypus, much more detailed comparisons become possible. Even the first few analyses of marsupial and platypus sequences confirm the value of sequence comparisons for finding new genes and regulatory regions and exploring their function, as well as deducing how they evolved.

Nijmegen breakage syndrome (NBS) is a rare recessive genetic disorder, characterized by bird-like facial appearance, early growth retardation, congenital microcephaly, immunodeficiency and high frequency of malignancies. NBS belongs to the so-called chromosome instability syndromes; in fact, NBS cells display spontaneous chromosomal aberrations and are hypersensitive to DNA double-strand break-inducing agents, such as ionizing radiations. NBS1, the gene underlying the disease, is located on human chromosome 8q21. The disease appears to be prevalent in the Eastern and Central European population where more than 90% of patients are homozygous for the founder mutation 657del5 leading to a truncated variant of the protein. NBS1 forms a multimeric complex with MRE11/RAD50 nuclease at the C-terminus and retains or recruits them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by PI3-kinase family, such as ATM, in response to DNA damage. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. NBS cells also show to be defective in the activation of intra-S phase checkpoint. We review here some cellular and molecular aspects of NBS, which might contribute to the clinical symptoms of the disease.

Colorectal cancer (CRC) still represents the model of choice to study the mechanisms underlying tumor initiation and progression. Accordingly, CRC has been central in the analysis of the role played by chromosomal instability (CIN) in tumor initiation and progression. Although loss of APC tumor suppressor function initiates the adenoma-carcinoma sequence in the vast majority of CRCs through constitutive activation of Wnt/beta-catenin signaling, the APC gene also represents a candidate CIN gene in CRC. Accordingly, two studies published in 2001 showed that truncating Apc mutations can lead to both quantitative and qualitative ploidy changes in primary mouse cell lines, mainly due to kinetochore and centrosome abnormalities. Here, we review and discuss the more recent literature on APC's functional activities possibly related to its role in eliciting CIN in tumor initiation and progression. We propose a model where loss and/or truncation of APC cause mitotic spindle defects that, upon somatic inactivation of other putative CIN genes (e.g. spindle and cell cycle checkpoint genes, DNA repair, telomere maintenance, etc.) underlie aneuploidy as observed in the majority of CRCs.

Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic crossover, gene conversion, back mutation and compensating mutations in cis have all been observed in revertant, and, consequently, mosaic FA-patients, leading to improved bone marrow function. There probably is no other experiment of nature in our species in which causes and consequences of genetic instability, including the role of reactive oxygen species, can be better documented and explored than in FA.

Nearly 50% of the human genome is composed of fossils from the remains of past transposable element duplication. Mobilization continues in the genomes of extant humans but is now restricted to retrotransposons, a class of mobile elements that move via a copy and paste mechanism. Currently active retrotransposable elements include Long INterspersed Elements (LINEs), Short INterspersed Elements (SINEs) and SVA (SINE/VNTR/Alu) elements. Retrotransposons are responsible for creating genetic variation and on occasion, disease-causing mutations, within the human genome. Approximately 0.27% of all human disease mutations are attributable to retrotransposable elements. Different mechanisms of genome alteration created by retrotransposable elements include insertional mutagenesis, recombination, retrotransposition-mediated and gene conversion-mediated deletion, and 3' transduction. Although researchers in the field of human genetics have discovered many mutational mechanisms for retrotransposable elements, their contribution to genetic variation within humans is still being resolved.