Archive of Medical Research

DNA-damage repair; the good, the bad, and the ugly.

Organisms have developed several DNA-repair pathways as well as DNA-damage checkpoints to cope with the frequent challenge of endogenous and exogenous DNA insults. In the absence or impairment of such repair or checkpoint mechanisms, the genomic integrity of the organism is often compromised. This review will focus on the functional consequences of impaired DNA-repair pathways. Although each pathway is addressed individually, it is essential to note that cross talk exists between repair pathways, and that there are instances in which a DNA-repair protein is involved in more than one pathway. It is also important to integrate DNA-repair process with DNA-damage checkpoints and cell survival, to gain a better understanding of the consequences of compromised DNA repair at both cellular and organismic levels. Functional consequences associated with impaired DNA repair include embryonic lethality, shortened life span, rapid ageing, impaired growth, and a variety of syndromes, including a pronounced manifestation of cancer.

Hakem R.

Department of Medical Biophysics, Ontario Cancer Institute/UHN, University of Toronto, Toronto, Ontario, Canada. rhakem@uhnres.utoronto.ca

Quality control of DNA break metabolism: in the \’end\’, it\’s a good thing.

DNA ends pose specific problems in the control of genetic information quality. Ends of broken DNA need to be rejoined to avoid genome rearrangements, whereas natural DNA ends of linear chromosomes, telomeres, need to be stable and hidden from the DNA damage response. Efficient DNA end metabolism, either at induced DNA breaks or telomeres, does not result from the machine-like precision of molecular reactions, but rather from messier, more stochastic processes. The necessary molecular interactions are dynamically unstable, with constructive and destructive processes occurring in competition. In the end, quality control comes from the constant building up and tearing down of inappropriate, but also appropriate reaction steps in combination with factors that only slightly shift the equilibrium to eventually favour appropriate events. Thus, paradoxically, enzymes antagonizing DNA end metabolism help to ensure that genome maintenance becomes a robust process.

Kanaar R, Wyman C, Rothstein R.

Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. r.kanaar@erasmusmc.nl

Using heparin therapy to reverse protein-losing enteropathy in a patient with CDG-Ib.

Background A 22-year-old female presented with edema, diarrhea, hypoalbuminemia and pancytopenia. She had previously been diagnosed with congenital disorder of glycosylation type Ib, and had a history of congenital hepatic fibrosis, portal hypertension and esophageal varices. In the past she had refused mannose therapy because of associated diarrhea and abdominal pain.Investigations Laboratory examinations, abdominal ultrasonography, bacterial and viral cultures of blood, urine and stools, double-balloon enteroscopy and fecal excretion test using (51)Cr-labeled albumin.Diagnosis Protein-losing enteropathy.Management Infusion of albumin followed by intravenous and subcutaneous therapy with unfractionated heparin.

Liem YS, Bode L, Freeze HH, Leebeek FW, Zandbergen AA, Wilson J; Medscape.

YS Liem is a Resident, FWG Leebeek is a Consultant Hematologist, AAM Zandbergen is an Internist and JHP Wilson is a Professor of Internal Medicine at the Erasmus University Medical Center, Rotterdam, The Netherlands.

Endoscopic variceal ligation-is there any benefit to placing more than six bands?

Tang SJ, Rockey DC.

S Tang is Director of Endoscopy and Assistant Professor of Internal Medicine at the UT Southwestern Medical Center. DC Rockey is Chief of the Division of Digestive and Liver Diseases, Professor of Internal Medicine, and Dr Carey G King Jr and Dr Henry M Winans Sr Chair in Internal Medicine at the UT Southwestern Medical Center, Dallas, TX, USA.

Benefits and risks of a fish diet-should we be eating more or less?

Jeejeebhoy KN.

KN Jeejeebhoy is a Physician at St Michael\’s Hospital, Toronto, and Emeritus Professor of Medicine at the University of Toronto, ON, Canada.

Is lansoprazole effective for the initial management of young patients with dyspepsia?

Mayer EA, Tillisch K.

EA Mayer is Professor of Medicine, and K Tillisch is Assistant Professor of Medicine, both at the Center for Neurobiology of Stress, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

Genetics of variation in adiponectin in pedigreed baboons: evidence for pleiotropic effects on adipocyte volume and serum adiponectin.

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h(2)=0.19+/-0.07, P=0.01) and protein levels (h(2)=0.28+/-0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (rho(G)=-0.51, P=0.03), cell volume (rho(G)=-0.73, P=0.04), serum triglycerides (rho(G)=-0.67, P=0.03), and between adiponectin mRNA and glucose (rho(G)=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.Heredity advance online publication, 20 February 2008; doi:10.1038/sj.hdy.6801089.

Tejero ME, Voruganti VS, Rodríguez-Sánchez IP, Proffitt JM, Blangero J, Cox LA, Mahaney MC, Rogers J, Vandeberg JL, Cole SA, Comuzzie AG.

1Department of Genetics at Southwest Foundation for Biomedical Research, San Antonio, TX, USA.

Floral evolution: One-sided evolution or two? A reply to Ennos.

Hodges SA, Whittall JB.

Mitochondrial and nuclear DNA variability in the living fossil Triops cancriformis (Bosc, 1801) (Crustacea, Branchiopoda, Notostraca).

The living fossil Triops cancriformis comprises bisexual (either gonochoric or hermaphroditic) and unisexual populations. Genetic surveys have recently revealed a general trend of low differentiation of 12S and 16S mitochondrial genes. We, therefore, surveyed further mitochondrial (COI gene and control region) and nuclear markers (dinucleotide microsatellites) to assess the genetic variability and to establish any relationship with the different reproductive modes found in European populations. The mitochondrial analyses confirmed the pattern of low variability. Hence, the low mitochondrial genetic variability appears as a common feature of the genus Triops. The microsatellite analysis found that Italian populations are monomorphic or exhibit little polymorphism, while other European samples display a higher degree of polymorphism and private alleles. Spanish, Austrian and Italian populations show patterns of Hardy-Weinberg disequilibrium that could be explained by the mode of reproduction, or by a higher frequency of null alleles in these populations. The low diversity and differentiation among Italian populations lead us to question the Monopolization Hypothesis. One microsatellite locus appears to be sex-linked, with heterozygotes detected only in males and hermaphrodites.Heredity advance online publication, 20 February 2008; doi:10.1038/hdy.2008.3.

Mantovani B, Cesari M, Luchetti A, Scanabissi F.

1Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna, Italy.

How multilocus genotypic pattern helps to understand the history of selfing populations: a case study in Medicago truncatula.

The occurrence of populations exhibiting high genetic diversity in predominantly selfing species remains a puzzling question, since under regular selfing genetic diversity is expected to be depleted at a faster rate than under outcrossing. Fine-scale population genetics approaches may help to answer this question. Here we study a natural population of the legume Medicago truncatula in which both the fine-scale spatial structure and the selfing rate are characterized using three different methods. Selfing rate estimates were very high ( approximately 99%) irrespective of the method used. A clear pattern of isolation by distance reflecting small seed dispersal distances was detected. Combining genotypic data over loci, we could define 34 multilocus genotypes. Among those, six highly inbred genotypes (lines) represented more than 75% of the individuals studied and harboured all the allelic variation present in the population. We also detected a large set of multilocus genotypes resembling recombinant inbred lines between the most frequent lines occurring in the population. This finding illustrates the importance of rare recombination in redistributing available allelic diversity into new genotypic combinations. This study shows how multilocus and fine-scale spatial analyses may help to understand the population history of self-fertilizing species, especially to make inferences about the relative role of foundation/migration and recombination events in such populations.Heredity advance online publication, 20 February 2008; doi:10.1038/hdy.2008.5.

Siol M, Prosperi JM, Bonnin I, Ronfort J.

1UMR 1097 Diversité et Adaptations des Plantes Cultivées, INRA Montpellier, Domaine de Melgueil, Mauguio, France.