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PubMedDate not supplied

Integrating genomics into US public health.

This paper presents an overview of how the US government is currently addressing the complex issue of integrating genomics into public health. The author, a public health provider with many years of experience, including several years spent in genetics and maternal and child health, is currently a senior advisor to the Surgeon General of the United States. At the time of the third biennial Asan-Harvard Medical International Symposium, "Genomics and Proteomics: Impact on Medicine and Health," in Seoul, Korea, July 3-4, 2001, the US Surgeon General was Dr. David Satcher. Dr. Allan Noonan attended the symposium as Dr. Satcher's representative. Dr. Noonan's paper discusses the challenges facing the US public health system as it strives to integrate and promote genomics and proteomics into its efforts to reduce morbidity and mortality in the US population.

Centers for Disease Control and Prevention, U.S.↗
PubMed2004

Chromatin remodeling and the maintenance of genome integrity.

DNA damage of any type is threatening for a cell. If lesions are left unrepaired, genomic instability can arise, faithful transmission of genetic information is greatly compromised eventually leading the cell to undergo apoptosis or carcinogenesis. In order to access/detect and repair these damages, repair factors must circumvent the natural repressive barrier of chromatin. This review will present recent progress showing the intricate link between chromatin, its remodeling and the DNA repair process. Several studies demonstrated that one of the first events following specific types of DNA damage is the phosphorylation of histone H2A. This mark or the damage itself are responsible for the association of chromatin-modifying complexes near damaged DNA. These complexes are able to change the chromatin structure around the wounded DNA in order to allow the repair machinery to gain access and repair the lesion. Chromatin modifiers include ATP-dependent remodelers such as SWI/SNF and Rad54 as well as histone acetyltransferases (HATs) like SAGA/NuA4-related complexes and p300/CBP, which have been shown to facilitate DNA accessibility and repair in different pathways leading to the maintenance of genome integrity.

Acetyltransferases↗
PubMed2025

Genomically integrated cassettes swapping: bringing modularity to the strain level in Saccharomyces cerevisiae.

A large variety of synthetic biology toolkits for the introduction of multiple expression cassettes is available for Saccharomyces cerevisiae. Unfortunately, none of these tools is designed to allow the modification - exchange or removal - of the cassettes already integrated into the genome in a standardized way. The application of the modularity principle therefore ends to the steps preceding the final host engineering, making microbial cell factories construction stiff and strictly sequential. In this work, we describe a system that easily allows CRISPR-mediated swapping or removal of previously integrated cassettes, thus bringing the modularity to the strain level, enhancing the possibility of modifying existing strains with a reduced number of steps. In the system, each cassette is tagged with specific barcodes, which can be used as targets for CRISPR nucleases (Cas9 and Cas12a), allowing the excision of the construct from the genome and its substitution with another expression cassette or the restoration of the wild type locus in one single standardized step. The system has been applied to the previously developed Easy-MISE toolkit and tested by swapping fluorescent protein expression cassettes with an efficiency of ∼90% quantified by PCR and flow cytometry.

Saccharomyces cerevisiae↗
PubMed1995

Specific mutations in alpha- and gamma-subunits of F1-ATPase affect mitochondrial genome integrity in the petite-negative yeast Kluyveromyces lactis.

We have shown previously that mutations in nuclear genes, termed MGI, for mitochondrial genome integrity, can convert the petite-negative yeast Kluyveromyces lactis into a petite-positive form with the ability to produce mitochondrial genome deletion mutants (Chen and Clark-Walker, Genetics, 133, 517-525, 1993). Here we describe that two genes, MGI2 and MGI5, encode the alpha- and gamma-subunits of mitochondrial F1-ATPase. Specific mutations, Phe443-->Ser and Ala333-->Val in MGI2, and Thr275-->Ala in MGI5, confer on cells the ability to produce petite mutants spontaneously with deletions in mitochondrial (mt) DNA and the capacity to lose their mitochondrial genomes upon treatment with ethidium bromide. Structural integrity of the F1 complex seems to be needed for expression of the Mgi- phenotype as null mutations in MGI2 and MGI5 remove the ability to form mtDNA deletions. It is suggested that mgi mutations allow petites to survive because an aberrant F1 complex prevents collapse of the mitochondrial inner membrane potential that normally occurs on loss of mtDNA-encoded F0 subunits.

Amino Acid Sequence↗
PubMed1999

Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis.

Cancer is a multi-step process evolving as the result of the accumulation of a number of mutational events. The growing body of evidence implicating genetic instability as a key feature of this evolutionary process and the risk of malignancy associated with chromosomal instability syndromes highlight the importance of understanding the mechanisms that cells use to maintain the integrity of their genomes. Classic examples of inherited chromosomal instability with cancer predisposition are Bloom's syndrome, ataxia telangiectasia, and Fanconi anaemia, although the mechanisms involved are far from understood. Selected features of these inherited disorders are reviewed to provide a background to the more recently discovered inducible chromosomal instability, a phenotype in which apparently normal cells that have survived ionizing radiation and certain chemical insults may produce descendants exhibiting a high frequency of de novo chromosome aberrations and gene mutations. The phenotype is induced at frequencies considerably greater than conventional mutation frequencies but little is understood of the underlying mechanism(s). To date, chromosomal instability induced by ionizing radiation has been the most extensively studied phenotype and it is evident that the expression of inducible instability has a strong dependence on the type of radiation exposure, the cell type irradiated, and the genetic 'predisposition' of the irradiated cell.

Animals↗
PubMed2006

Protecting genomic integrity in somatic cells and embryonic stem cells.

Mutation frequencies at some loci in mammalian somatic cells in vivo approach 10(-4). The majority of these events occur as a consequence of loss of heterozygosity (LOH) due to mitotic recombination. Such high levels of DNA damage in somatic cells, which can accumulate with age, will cause injury and, after a latency period, may lead to somatic disease and ultimately death. This high level of DNA damage is untenable for germ cells, and by extrapolation for embryonic stem (ES) cells, that must recreate the organism. ES cells cannot tolerate such a high frequency of damage since mutations will immediately impact the altered cell, and subsequently the entire organism. Most importantly, the mutations may be passed on to future generations. ES cells, therefore, must have robust mechanisms to protect the integrity of their genomes. We have examined two such mechanisms. Firstly, we have shown that mutation frequencies and frequencies of mitotic recombination in ES cells are about 100-fold lower than in adult somatic cells or in isogenic mouse embryonic fibroblasts (MEFs). A second complementary protective mechanism eliminates those ES cells that have acquired a mutational burden, thereby maintaining a pristine population. Consistent with this hypothesis, ES cells lack a G1 checkpoint, and the two known signaling pathways that mediate the checkpoint are compromised. The checkpoint kinase, Chk2, which participates in both pathways is sequestered at centrosomes in ES cells and does not phosphorylate its substrates (i.e. p53 and Cdc25A) that must be modified to produce a G1 arrest. Ectopic expression of Chk2 does not rescue the p53-mediated pathway, but does restore the pathway mediated by Cdc25A. Wild type ES cells exposed to ionizing radiation do not accumulate in G1 but do so in S-phase and in G2. ES cells that ectopically express Chk2 undergo cell cycle arrest in G1 as well as G2, and appear to be protected from apoptosis.

Adenine Phosphoribosyltransferase↗
PubMed1999

Plasmid DNA malaria vaccine: the potential for genomic integration after intramuscular injection.

Plasmid-based (naked DNA) genetic vaccines are now entering clinical trials to test their safety and efficacy in healthy human volunteers. A safety concern unique to this new class of vaccines is the potential risk of deleterious integration into host cell genomic DNA following direct intramuscular injection. To address this issue experimentally, a preclinical safety study was conducted in mice to determine the structural nature of plasmid DNA sequences persisting in total muscle DNA at both 30 and 60 days following a single intramuscular injection of a plasmid expressing the Plasmodium falciparum circumsporozoite protein. In a protocol described for the first time, total DNA was extracted from muscle tissue and was subsequently linearized with a restriction endonuclease to enable agarose gel size fractionation of all extrachromosomal plasmid DNAs from high molecular weight mouse genomic DNA. Using PCR assays to quantitate plasmid-specific sequences, it was found that the amount of plasmid DNA persisting in muscle tissue varied but averaged about 10 fg per microgram of genomic DNA (in the range of 1500 copies per 150,000 genomes). In two of four separate experimental injections of mouse muscle, PCR assays of genomic DNA fractions indicated that agarose gel purification removed plasmid DNA down to a level of < or =3 copies per 150,000 mouse genomes. In the two other experimental samples, 3-30 copies of plasmid DNA remained associated with purified genomic DNA. The time following injection (i.e., 30 or 60 days) was not a factor in the number of copies of plasmid associating with genomic DNA and it was not possible to conclude if such sequences were covalently linked to genomic DNA or simply adventitiously associated with the genomic DNA. However, if an assumption is made that the highest level plasmid DNA found associated with genomic DNA (i.e., 30 copies) represented covalently integrated plasmid inserts and that each insert resulted in a mutational event, the calculated rate of mutation would be 3000 times less than the spontaneous mutation rate for mammalian genomes. This level of integration, if it should occur, was not considered to pose a significant safety concern.

Animals↗
PubMed2006

SIGMA: a system for integrative genomic microarray analysis of cancer genomes.

BACKGROUND: The prevalence of high resolution profiling of genomes has created a need for the integrative analysis of information generated from multiple methodologies and platforms. Although the majority of data in the public domain are gene expression profiles, and expression analysis software are available, the increase of array CGH studies has enabled integration of high throughput genomic and gene expression datasets. However, tools for direct mining and analysis of array CGH data are limited. Hence, there is a great need for analytical and display software tailored to cross platform integrative analysis of cancer genomes. RESULTS: We have created a user-friendly java application to facilitate sophisticated visualization and analysis such as cross-tumor and cross-platform comparisons. To demonstrate the utility of this software, we assembled array CGH data representing Affymetrix SNP chip, Stanford cDNA arrays and whole genome tiling path array platforms for cross comparison. This cancer genome database contains 267 profiles from commonly used cancer cell lines representing 14 different tissue types. CONCLUSION: In this study we have developed an application for the visualization and analysis of data from high resolution array CGH platforms that can be adapted for analysis of multiple types of high throughput genomic datasets. Furthermore, we invite researchers using array CGH technology to deposit both their raw and processed data, as this will be a continually expanding database of cancer genomes. This publicly available resource, the System for Integrative Genomic Microarray Analysis (SIGMA) of cancer genomes, can be accessed at http://sigma.bccrc.ca.

Adenocarcinoma↗
PubMed2026

Pragmatic Phenotype-Electrophysiology-Genomics Integration in Pediatric Congenital Myasthenic Syndromes: Insights From 36 Patients in a Single-Center Study in China.

AIMS: To characterize the clinical, electrophysiological, and genetic spectrum of pediatric CMS and evaluate genotype-informed outcomes using an integrated phenotype-electrophysiology-genomics approach. METHODS: We retrospectively reviewed 36 pediatric CMS patients evaluated at a single center between 2015 and 2025. Clinical features, RNS, targeted NGS/WES variants, ventilator use, treatments, ACMG/AMP classifications, and MG-ADL outcomes were analyzed. RESULTS: Of 36 patients, 28 (77.8%) developed symptoms in the neonatal period or infancy. Biallelic variants involved 17 CMS genes; postsynaptic CMS was most common (55.6%, 20/36). COLQ and CHRNE were the most frequent genes (13.9%, 5/36 each), followed by CHAT (11.1%, 4/36). VUS were detected in 19 patients (52.8%, 19/36), including 8 with biallelic VUS supported by phenotype, neuromuscular transmission findings, treatment response, and follow-up. RNS showed a &#x2265;&#x2009;10% decrement in 16/21 tested patients (76.2%). CHAT-CMS was associated with higher ventilator use (3/4 vs. 6/32; p&#x2009;=&#x2009;0.041) and early mortality (3/4 vs. 1/32; p&#x2009;=&#x2009;0.002). Median MG-ADL improved from 5 to 3 after genotype-informed therapy. CONCLUSION: Pediatric CMS shows marked genetic heterogeneity and frequent VUS-related uncertainty. Integrating phenotype, electrophysiology, and genomics supports diagnosis and mechanism-guided therapy. CHAT-CMS is high risk for early respiratory failure and mortality.

Humans↗
PubMed2001

The integrated genome map of Mycobacterium leprae.

The integrated map of the Mycobacterium leprae genome unveiled for the first time the genomic organization of this obligate intracellular parasite. Selected cosmid clones, isolated from a genomic library created in the cosmid vector Lorist6, were identified as representing nearly the complete genome and were subsequently used in the M. leprae genome sequencing project. Now a new version of the integrated map of M. leprae can be presented, combining the mapping results from the Lorist6 cosmids with data obtained from a second genomic library constructed in an Escherichia coli-mycobacterium shuttle cosmid, pYUB18. More than 98% of the M. leprae genome is now covered by overlapping large insert genomic clones representing a renewable source of well defined DNA segments and a powerful tool for functional genomics.

Animals↗
PubMed1996

The mitochondrial genome integrity gene, MGI1, of Kluyveromyces lactis encodes the beta-subunit of F1-ATPase.

In a previous report, we found that mutations at the mitochondrial genome integrity locus, MGI1, can convert Kluyveromyces lactis into a petite-positive yeast. In this report, we describe the isolation of the MGI1 gene and show that it encodes the beta-subunit of the mitochondrial F1-ATPase. The site of mutation in four independently isolated mgi1 alleles is at Arg435, which has changed to Gly in three cases and Ile in the fourth isolate. Disruption of MGI1 does not lead to the production of mitochondrial genome deletion mutants, indicating that an assembled F1 complex is needed for the "gain-of-function" phenotype found in mgi1 point mutants. The location of Arg435 in the beta-subunit, as deduced from the three-dimensional structure of the bovine F1-ATPase, together with mutational sites in the previously identified mgi2 and mgi5 alleles, suggests that interaction of the beta- and alpha- (MGI2) subunits with the gamma-subunit (MGI5) is likely to be affected by the mutations.

Amino Acid Sequence↗
PubMed1999

Defending genome integrity during DNA replication: a proposed role for RecQ family helicases.

The RecQ family of DNA helicases have been shown to be important for the maintenance of genomic integrity in all organisms analysed to date. In human cells, representatives of this family include the proteins defective in the cancer predisposition disorder Bloom's syndrome and the premature ageing condition, Werner's syndrome. Several pieces of evidence suggest that RecQ family helicases form associations with one or more of the cellular topoisomerases, and together these heteromeric complexes manipulate DNA structure to effect efficient DNA replication, genetic recombination, or both. Here, we propose that RecQ helicases are required for ensuring that structural abnormalities arising during replication, such as at sites where replication forks encounter DNA lesions, are corrected with high fidelity. In mutants defective in these proteins, not only is replication abnormal, but cells display aberrant responses to DNA-damaging agents or inhibitors of DNA synthesis. We suggest that RecQ helicases may be important for the integration of cellular responses to these insults, such as by linking cell cycle checkpoint responses to recombinational repair.

Adenosine Triphosphatases↗
PubMed2005

DNA repair mechanisms in plants: crucial sensors and effectors for the maintenance of genome integrity.

As obligate phototrophs, plants harness energy from sunlight to split water, producing oxygen and reducing power. This lifestyle exposes plants to particularly high levels of genotoxic stress that threatens genomic integrity, leading to mutation, developmental arrest and cell death. Plants, which with algae are the only photosynthetic eukaryotes, have evolved very effective pathways for DNA damage signalling and repair, and this review summarises our current understanding of these processes in the responses of plants to genotoxic stress. We also identify how the use of new and emerging technologies can complement established physiological and ecological studies to progress the application of this knowledge in biotechnology.

Base Pair Mismatch↗
PubMed2006

Rad9, an evolutionarily conserved gene with multiple functions for preserving genomic integrity.

The Rad9 gene is evolutionarily conserved. Analysis of the gene from yeast, mouse and human reveal roles in multiple, fundamental biological processes primarily but not exclusively important for regulating genomic integrity. The encoded mammalian proteins participate in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, and apoptosis. Other functions include a role in embryogenesis, the transactivation of multiple target genes, co-repression of androgen-induced transcription activity of the androgen receptor, a 3'-5' exonuclease activity, and the regulation of ribonucleotide synthesis. Analyses of the functions of Rad9, and in particular its role in regulating and coordinating numerous fundamental biological activities, should not only provide information about the molecular mechanisms of several individual cellular processes, but might also lend insight into the more global control and coordination of what at least superficially present as independent pathways.

Animals↗
PubMed2003

Junonia coenia densovirus-based vectors for stable transgene expression in Sf9 cells: influence of the densovirus sequences on genomic integration.

The invertebrate parvovirus Junonia coenia densovirus (JcDNV) shares similarities with terminal hairpins and nonstructural (NS) protein activities of adeno-associated virus (AAV) despite their evolutionary divergence (B. Dumas, M. Jourdan, A. M. Pascaud, and M. Bergoin, Virology, 191:202-222, 1992, and C. Ding, M. Urabe, M. Bergoin, and R. M. Kotin, J. Virol. 76:338-345, 2002). We demonstrate here that persistent transgene expression in insect cells results from stable integration of transfected JcDNV-derived vectors into the host genome. To assess the integrative properties of JcDNV vectors, the green fluorescent protein (GFP) gfp marker gene was fused in frame into the major open reading frame (ORF1) of the viral sequence under the control of the P9 capsid protein promoter. In addition, the influence of the nonstructural proteins on the posttransfection maintenance of the vectors was examined by interruption of one or all three NS ORFs. Following transfection of Sf9 cells with each of the JcDNV constructs, clones showing persistent GFP expression were isolated. Structural analyses revealed that the majority of the JcDNV plasmid sequence was integrated into the genome of the fluorescent clones. Integration was observed whether or not NS proteins were expressed. However, the presence of NS genes in the constructs greatly influenced the number of integrated copies and their distribution in the host genome. Disruption of NS genes expression resulted in integration of head-to-tail concatemers at multiple sites within the genome. Further analyses demonstrated that the cis JcDNV 5' inverted terminal repeat region was the primary site of recombination. Sequence analyses of integration junctions showed rearrangements of both flanking and internal sequences for most integrations. These findings demonstrate that JcDNV vectors integrate into insect cells in a manner similar to AAV plasmids in mammalian cells.

Animals↗
PubMed2005

Disease gene discovery through integrative genomics.

The availability of complete genome sequences and the wealth of large-scale biological data sets now provide an unprecedented opportunity to elucidate the genetic basis of rare and common human diseases. Here we review some of the emerging genomics technologies and data resources that can be used to infer gene function to prioritize candidate genes. We then describe some computational strategies for integrating these large-scale data sets to provide more faithful descriptions of gene function, and how such approaches have recently been applied to discover genes underlying Mendelian disorders. Finally, we discuss future prospects and challenges for using integrative genomics to systematically discover not only single genes but also entire gene networks that underlie and modify human disease.

Databases, Genetic↗
PubMed2004

Integrating genomics into Eucalyptus breeding.

The advent of high throughput genomic technologies has opened new perspectives in the speed, scale and detail with which one can investigate genes, genomes and complex traits in Eucalyptus species. A genomic approach to a more detailed understanding of important metabolic and physiological processes, which affect tree growth and stress resistance, and the identification of genes and their allelic variants, which determine the major chemical and physical features of wood properties, should eventually lead to new opportunities for directed genetic modifications of far-reaching economic impact in forest industry. It should be kept in mind, however, that basic breeding strategies, coupled with sophisticated quantitative methods, breeder's experience and breeder's intuition, will continue to generate significant genetic gains and have a clear measurable impact on production forestry. Even with a much more global view of genetic processes, genomics will only succeed in contributing to the development of improved industrial forests if it is strongly interconnected with intensive fieldwork and creative breeding. Integrated genomic projects involving multi-species expressed sequence tag sequencing and quantitative trait locus detection, single nucleotide polymorphism discovery for association mapping, and the development of a gene-rich physical map for the Eucalyptus genome will quickly move toward linking phenotypes to genes that control the wood formation processes that define industrial-level traits. Exploiting the full power of the superior natural phenotypic variation in wood properties found in Eucalyptus genetic resources will undoubtedly be a key factor to reach this goal.

Breeding↗