Genome dynamics最新文献

Translocations and gross deletions constitute an important cause of both cancer and inherited disease. Such gene rearrangements are non-randomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Chromosomal rearrangements are generated by a variety of recombinational processes, each characterised by mechanism-specific DNA sequence features. Various types of recombinogenic motifs have been shown to promote non-homologous end joining whilst direct repeats may mediate homologous recombination. In addition, repetitive sequence elements can facilitate the formation of secondary structure between DNA ends at translocation or gross deletion breakpoints, and in so doing, may play a role in illegitimate recombination. Although results from DNA breakpoint studies are broadly consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for non-homologous recombination in the generation of translocations, homologous recombination and non-homologous end joining are unlikely to be mutually exclusive mechanisms. Thus, chromosomal rearrangements will often represent the net result of multiple highly complex molecular interactions that are not always readily explicable.

Though researchers are uncovering valuable information about the pig genome at unprecedented speed, the porcine genome community is barely scratching the surface as to understanding interactions of the biological code. The pig genetic linkage map has nearly 5,000 loci comprised of genes, microsatellites, and amplified fragment length polymorphism markers. Likewise, the physical map is becoming denser with nearly 6,000 markers. The long awaited sequencing efforts are providing multidimensional benefits with sequence available for comparative genomics and identifying single nucleotide polymorphisms for use in linkage and trait association studies. Scientists are using exotic and commercial breeds for quantitative trait loci scans. Additionally, candidate gene studies continue to identify chromosomal regions or genes associated with economically important traits such as growth rate, leanness, feed intake, meat quality, litter size, and disease resistance. The commercial pig industry is actively incorporating these markers in marker-assisted selection along with traditional performance information to improve said traits. Researchers are utilizing novel tools including pig microarrays along with advanced bioinformatics to identify new candidate genes, understand gene function, and piece together gene networks involved in important biological processes. Advances in pig genomics and implications to the pork industry as well as human health are reviewed.

Werner syndrome (WS) is a rare autosomal recessive genetic instability/cancer predisposition disorder that displays many symptoms of premature aging. The mimicry of agerelated phenotypes in WS, as well as its dependence on a single defective gene product, has provided the impetus for studying this fascinating disease as a model system for normative aging and its related pathologies such as atherosclerosis, neoplasia, diabetes mellitus, and osteoporosis. The gene product defective in WS, WRN, is a member of the RecQ DNA helicase family that is widely distributed in all kingdoms of life, and is believed to play a central role in genomic stability by preferentially operating on non-canonical DNA structures. Although there have been considerable advances in our understanding of the biochemistry of WRN and its interacting protein partners, the in vivo molecular function(s) of WRN remain(s) elusive. In addition to summarizing the features and clinical progression of WS, the following chapter details our current understanding of the WRN protein with respect to its biochemistry and its interacting protein partners, and considers its putative in vivo roles in various DNA transactions.

In the past fifteen years, an emerging group of genetic diseases have been described that result from DNA rearrangements rather than from single nucleotide changes. Such conditions have been referred to as genomic disorders. The predominant molecular mechanism underlying the rearrangements that cause this group of diseases and traits is nonallelic homologous recombination (NAHR) (unequal crossing-over between chromatids or chromosomes) utilizing low-copy repeats (LCRs) (also known as segmental duplications) as substrates. In contradistinction to highly repetitive sequences (e.g. Alu and LINE elements), these higher-order genomic architectural features usually span >1kb and up to hundreds of kilobases of genomic DNA, share >96% sequence identity and constitute >5% of the human genome. Many LCRs have complex structure and have arisen during primate speciation as a result of serial segmental duplications. LCRs can stimulate and/or mediate constitutional (both recurrent and nonrecurrent), evolutionary, and somatic rearrangements. Recently, copy-number variations (CNVs), also referred to as large-scale copy-number variations (LCVs) or copy-number polymorphisms (CNPs), parenthetically often associated with LCRs, have been demonstrated as a source of human variation as well as a potential cause of diseases. In addition to fluorescence in situ hybridization (FISH), pulsed-field gel electrophoresis (PFGE), and in silico analyses, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (aCGH) with BAC and PAC clones have proven to be useful diagnostic methods for the detection and characterization of DNA rearrangements with the latter enabling high-resolution genome-wide analysis. The clinical implementation of such techniques is revolutionizing clinical cytogenetics.

Amphibians have been used since the 19th century as vertebrate models for the experimentalist. Since 50 years or so, Xenopus laevis is the most widely used anuran amphibian research organism. However, because it is a pseudo-tetraploid species, its genetics has been lagging behind. Contemporary studies shift their focus to the only Xenopus species known to be diploid, the small African tropical clawed frog Xenopus tropicalis. A complete genome project is undertaken, with genetic and physical mapping going alongside cDNA and genome sequencing. Currently, X. tropicalis is the most distantly related vertebrate species to humans that still exhibits long-range synteny. Much of amphibian genetics can be learned from this genomic undertaking, and could shed light on fascinating biological processes such as embryogenesis, regeneration and metamorphosis. Moreover, Xenopus species are exciting models for the study of gene duplication because new species can evolve through allopolyploidization, a type of genome duplication that can result from hybridization among species. The current genomic resources for Xenopus briefly described here, combined with the practical experimental advantages of this non-mammalian vertebrate model, make it ideally suited for systematic functional genomic studies.

Zebrafish is one of several important teleost models for understanding principles of vertebrate developmental, molecular, organismal, genetic, evolutionary, and genomic biology. Efficient investigation of the molecular genetic basis of induced mutations depends on knowledge of the zebrafish genome. Principles of zebrafish genomic analysis, including gene mapping, ortholog identification, conservation of syntenies, genome duplication, and evolution of duplicate gene function are discussed here using as a case study the zebrafish msxa, msxb, msxc, msxd, and msxe genes, which together constitute zebrafish orthologs of tetrapod Msx1, Msx2, and Msx3. Genomic analysis suggests orthologs for this difficult to understand group of paralogs.

A particular interest in primate genetics was fueled by the release of the complete human genome sequence drafts reported in 2001 by the IHGSC and Celera Genomics. Postgenomic comparative analyses based on the complete genome sequence of the mouse started focusing on functional, evolutionary and diversity aspects of human DNA. By analyzing molecular character states in the representatives of the major primate groups one is able to reconstruct the processes that shape genomes on the lineage to humans after the mouse-human divergence. Consequently, several primate genome sequences are about to be generated during Whole Genome Shotgun (WGS) sequencing projects and are already available for two representatives of the Old World monkeys and hominoids (rhesus monkey, chimpanzee). Comparative data restricted to functional genome parts of a meaningful primate sample (ENCODE project) are underway. These data will yield a definite phylogenetic framework linking the mouse, primate related eutherians and the major primate groups, which is indispensable for any analysis of character evolution. Concerning the functional site comparative genetic research in primates on molecular phenomena that control the spatiotemporal profile of the cellular RNA and protein composition will contribute to our understanding of genotype-phenotype correlations and the emergence of human specific traits.

Animal geneticists have been searching for the molecular basis of production traits in livestock species, including sheep, for over 40 years. Phenotypes of interest in sheep include fertility, reproduction, growth rate and efficiency, milk production, carcass quality and composition, wool characteristics, and disease resistance. The development of an ovine genome map containing molecular markers and genes has greatly advanced the identification of genetic regions containing quantitative trait loci (QTL) in sheep. Other genomic resources available for researchers investigating traits in sheep include an ovine radiation hybrid panel, large insert genomic libraries, and large-scale sequencing projects. In order to continue the identification of genes controlling important phenotypes in sheep, development of the ovine comparative map should continue.

Urochordates or tunicates possess a notochord, dorsal neural tube, and gill slits, features characteristic of all chordates, and thus they are a sister group of vertebrates, including humans. Urochordates consist of larvaceans, ascidians, and thaliaceans. The draft genome has been decoded in ascidians, Ciona intestinalis and C. savignyi. The C. intestinalis genome is composed of approximately 160 Mbp, similar to other invertebrate genomes, and contains approximately 16,000 protein-coding genes that represent the basic set of chordate genes without the extensive gene duplications seen in vertebrates. The C. intestinalis gene models are intensively annotated and supported by corresponding cDNAs. With the aid of two-color fluorescent in situ hybridization of BAC clones, approximately 65% of the assembled genome information has been mapped onto the 14 pairs of C. intestinalis chromosomes. In addition, a genome project is ongoing in a larvacean, Oikopleura dioica, and its genome is estimated to be 60 Mbp, with a very compacted arrangement of genes. Although the urochordate genomes have lineage-specific innovations such as horizontal acquisition of the cellulose synthase gene from bacteria and spliced-leader trans-splicing of mRNAs, applicable modern techniques have made urochordates serious contenders in the illumination of the basic principles underlying genome dynamics of vertebrates.

The general model that dominant diseases are caused by mutations that result in a gain or change in function of the corresponding protein was challenged by the discovery that the myotonic dystrophy type 1 mutation is a CTG expansion located in the 3' untranslated portion of a kinase gene. The subsequent discovery that a similar transcribed but untranslated CCTG expansion in an intron causes the same multisystemic features in myotonic dystrophy type 2 (DM2), along with other developments in the DM1 field, demonstrate a mechanism in which these expansion mutations cause disease through a gain of function mechanism triggered by the accumulation of transcripts containing CUG or CCUG repeat expansions. A similar RNA gain of function mechanism has also been implicated in fragile X tremor ataxia syndrome (FXTAS) and may play a role in pathogenesis of other non-coding repeat expansion diseases, including spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12 and Huntington disease-like 2.