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A case of adrenoleukodystrophy in a girl. Genetic considerations.

We report the case of a girl who developed leukoencephalopathy and adrenal atrophy and died at 3 years of age. Histologically, demyelination, gliosis, perivascular lymphocytic cuffing and sudanophilia were present in the brain. The adrenal cortex was atrophic. Ultrastructurally, there were numerous cytoplasmic inclusions in brain macrophages, consisting of two leaflets separated by an intervening space of variable low electron density. Brain tissue cholesterol esters contained a high proportion of long chain fatty acids. The findings are discussed and compared with those in the literature. Emphasis is placed on the fact that the disease occurred in a girl in apparent contradiction to the commonly accepted X-linked hereditary transmission of adrenoleukodystrophy. Some possible genetic explanations for our case are put forward.

Adrenal Cortex↗

Multiple functions of a feed-forward-loop gene circuit.

The feed-forward-loop (FFL), a network motif in genetic regulatory networks, involves two transcription factors (TFs): one regulates the expression of the second, and both TFs regulate the expression of an effector gene. Analysis of FFL design principles has been initiated, but the functional significance of the FFL is still unclear. In theoretical studies so far, the TFs are assumed to interact with different signals, which is common. However, we have found examples of FFLs in Escherichia coli in which both TFs interact with the same signal. These examples belong to the type 2 incoherent class of FFLs, in which each TF acts exclusively as a repressor of transcription. Here, we analyze mathematical models of this class of circuits, examining a comprehensive array of subclasses that differ in the way a signal modulates the activities of the TFs. Through parameter variation, we characterize statistically how input/output (I/O) behavior and temporal responsiveness are predicted to depend on the wiring of signal interactions in a circuit. We find that circuits can exhibit any of 13 qualitatively distinct steady-state I/O patterns, including inducible and repressible patterns. Some subclasses exhibit as many as six patterns. Transient pulses are also possible, and the response of a circuit to a signal may be either faster or slower than that of a gene circuit in which there is only one TF. Our results provide a catalog of functions for a class of FFL circuits, whose subclasses have different breadths of possible behaviors and different typical behaviors.

Escherichia coli↗

Diffusion model of intergroup selection, with special reference to evolution of an altruistic character.

Assume a diploid species consisting of an infinite number of competing demes, each having N(e) reproducing members and in which mating is at random. Then consider a locus at which a pair of alleles A and A' are segregating, where A' is the "altruistic allele," which has selective disadvantage s' relative to A with respect to individual selection, but which is beneficial for a deme in competition with other demes; namely, a deme having A' with frequency x has the advantage c(x - x) relative to the average deme, where c is a positive constant and x is the average of x over the species. Let varphi = varphi(x;t) be the distribution function of x among demes in the species at time t. Then, we have partial differentialvarphi/ partial differentialt = L(varphi) + c(x - x)varphi, where L is the Kolmogorov forward differential operator commonly used in population genetics [i.e., L = (1/2) ( partial differential(2)/ partial differentialx(2))V(deltax) - ( partial differential/ partial differentialx)M(deltax)], and M(deltax) and V(deltax) stand for the mean and variance of the change in x per generation within demes. As to migration, assume Wright's island model and denote by m the migration rate per deme per generation. By investigating the steady state, in which mutation, migration, random drift, and intra- and interdeme selection balance each other, it is shown that the index D = c/m - 4N(e)s' serves as a good indicator for predicting which of the two forces (i.e., group selection or individual selection) prevails; if D > 0, the altruistic allele predominates, but if D < 0, it becomes rare and cannot be established in the species.

Journal Article↗

A new chondrodystrophic mutant in mice. Electron microscopy of normal and abnormal chondrogenesis.

The occurrence of a new mutation affecting cartilage and bone in mice is reported. The gene is lethal, shows autosomal recessive inheritance, and has high penetrance. It is not allelic to shorthead and probably not to phocomelia or achondroplasia. It results in a foreshortened face, cleft palate, defective trachea, and shortened long bones with flared metaphyses. Chondrocytes of epiphyseal cartilage from the mutant are not aligned in columns, and there is a decrease in the usual staining of the cartilage matrix. Electron microscope observations show large, wide collagen fibrils with "native" banding in the matrix of mutant cartilage, which are not present in normal cartilage. Possible explanations for the expression of this genetic disorder of cartilage development are put forward.

Animals↗

New lipids in enteral feeding.

PURPOSE OF REVIEW: Lipid sources for enteral nutrition continue to be an exciting area of investigation. It is timely to review recent developments which have largely contributed to thrust enteral feeding into a new era. RECENT FINDINGS: Although much more research needs to be done, there is a better understanding of the competitive relationships between n-6/n-3 fatty acids in conditions of metabolic and immune stress as well as in autoimmune and degenerative diseases. Although structured lipids are more completely absorbed and cleared, other more important clinical benefits need to be documented before they can be considered cost-effective. Immune enhancing formulas are the subject of controversy and some have been shown to be more effective than others. Enteral formulations with short-chain fatty acids are promising but more experimental work on the normal, and the sick colon is needed. Finally, there are a few isolated studies suggesting that enteral feeding with liposomes and with lipolytic products may have advantages when the digestive phase needs to be circumvented. The era of nutrigenomics, in which the effect of specific lipids on genes and proteins is being explored, is with us. We can look forward to nutrigenetics when the effect of genetic variation on the interaction between diet and disease will guide our practice. SUMMARY: Clinicians already have access to lipid sources and formulations which allow them to individualize enteral feeding programs. More clinical and technological research needs to be carried out, however, before products can be tailored to produce optimal effects in specific conditions.

Digestion↗

A global search reveals epistatic interaction between QTL for early growth in the chicken.

We have identified quantitative trait loci (QTL) explaining a large proportion of the variation in body weights at different ages and growth between chronological ages in an F(2) intercross between red junglefowl and White Leghorn chickens. QTL were mapped using forward selection for loci with significant marginal genetic effects and with a simultaneous search for epistatic QTL pairs. We found 22 significant loci contributing to these traits, nine of these were only found by the simultaneous two-dimensional search, which demonstrates the power of this approach for detecting loci affecting complex traits. We have also estimated the relative contribution of additive, dominance, and epistasis effects to growth and the contribution of epistasis was more pronounced prior to 46 days of age, whereas additive genetic effects explained the major portion of the genetic variance later in life. Several of the detected loci affected either early or late growth but not both. Very few loci affected the entire growth process, which points out that early and late growth, at least to some extent, have different genetic regulation.

Aging↗

Moving forward with chemical mutagenesis in the mouse.

The study of genetic variation in mice offers a powerful experimental platform for understanding gene function. Complex trait analysis, gene-targeting and gene-trapping technologies, as well as insertional and chemical mutagenesis approaches are becoming increasingly sophisticated and provide a variety of options for cataloguing gene activities and interactions. In this review we discuss fundamental and practical concepts related to chemical mutagenesis and we highlight the growing list of strategies for performing mutagenesis screens in mice. Gene-driven and diverse types of phenotype-driven screens provide several options for the recovery of the invaluable variety of alleles generated by chemical mutagenesis. The unique advantages offered using chemical mutagenesis compare favourably to and complement the spectrum of approaches available for functional annotation of the mammalian genome.

Animals↗

Complete nucleotide sequence of the cotton (Gossypium barbadense L.) chloroplast genome with a comparative analysis of sequences among 9 dicot plants.

Recently, the complete chloroplast genome sequences of many important crop plants were determined, and this can be considered a major step forward toward exploiting the usefulness of chloroplast genetic engineering technology. Economically, cotton is one of the most important crop plants for many countries. To further our understanding of this important crop, we determined the complete nucleotide sequence of the chloroplast genome from cotton (Gossypium barbadense L.). The chloroplast genome of cotton is 160,317 base pairs (bp) in length, and is composed of a large single copy (LSC) of 88,841 bp, a small single copy (SSC) of 20,294 bp, and two identical inverted repeat (IR) regions of 25,591 bp each. The genome contains 114 unique genes, of which 17 genes are duplicated in the IRs. In addition, many open reading frames (ORFs) and hypothetical chloroplast reading frames (ycfs) with unknown functions were deduced. Compared to the chloroplast genomes from 8 other dicot plants, the cotton chloroplast genome showed a high degree of similarity of the overall structure, gene organization, and gene content. Furthermore, the sequences of the genes showed high degrees of identity at the DNA and amino acid levels. The cotton chloroplast genome was somewhat longer than the chloroplast genomes of most of the other dicot plants compared here. However, this elongation of the cotton chloroplast genome was found to be due mainly to expansions of the intergenic regions and introns (non-coding DNA). Moreover, these expansions occurred predominantly in the LSC and SSC regions.

Base Sequence↗

Genetic screening of compounds used in drug abuse treatment. III. LAAM.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vivo and in vitro assays. This third report in the series describes the results for one of these compounds, LAAM (L-alpha-acetyl methadol). Previous reports described results from a three phase testing program for Naltrexone and Methadone. LAAM is related chemically to the narcotic analgesic oxymorphine, and is related chemically to a narcotic antagonist, naloxone. LAAM exhibited genetic activity in the ad-3 forward-mutation test in Neurospora crassa and also was weakly mutagenic in the mouse lymphoma forward-mutation assay. Further analysis of the ad-3 mutants from N. crassa indicated that they were the result of a parasexual phenomenon rather than forward mutation. There was one confirmed translocation carrier in the heritable translocation study, which by conservative interpretation might imply some germ-cell risk associated with exposure to LAAM.

Animals↗

The infant of the diabetic mother: The critical developmental windows.

The 1989 St Vincents Declaration stated, as a 5-year goal, ".that the outcome of the diabetic pregnancy should approach that of non-diabetic pregnancies" and indeed, over the last 20 years, significant reductions in spontaneous abortions, stillbirths, congenital malformations and perinatal mortality have been achieved. However, recent reports have shown that even in western countries, spontaneous abortions may be as high as 17%, stillbirths rate to be 5-times greater, congenital malformations to range from 4 to l0 times the usual rate, perinatal mortality to be 5-fold, neonatal mortality 15 times greater and that infant mortality might be trebled as the result of diabetic pregnancies. It can be argued that these bad results are the consequences of poor medical and social care, from prior to conception to perineonatal services and they most probably are. Nevertheless, even in the best series, corrected rates for diabetes-related malformations are considerably higher than the rest of the population and macrosomia poses a major problem, ranging from 20% in gestational diabetes to 35% or more in pre-existing diabetes. Again, it can be argued that good metabolic control has not been achieved or that good is not necessarily optimal. Alternatively, it can be put forward that there might be an abnormal genetic background contribution (and the evidence is pretty scanty) or that there might be other metabolic fuels besides glucose operating at different developmental stages of pregnancy and accounting for the aetiopathogenesis of the whole syndrome of the infant of the diabetic mother from congenital malformations to macrosomia, hypoglycaemia, RDS, polycythaemia, hyperbilirrubinaemia and so forth. Over the last 10 years there has been increasing evidence from animal and human studies to support the theory that in addition to sugars, other metabolic fuels, from ketones to deranged lipid peroxidation, may be responsible for the pathomechanisms of congenital malformations providing that they are present at certain (high) levels for a reasonable amount of time and especially at crucial developmental windows. Similarly, the same general principles of multifactorial influences at critical gestational ages have been postulated to explain the macrosomia, respiratory complications, the hypoglycaemia and the whole metabolic disturbances of the infant of the diabetic mother. It is quite possible that some, or all of these metabolic fuels may per se or in synergy, play a significant role and it is quite conceivable that besides the classical approach to strict glucose control, other dietary manipulations with supplementation or replacement of deficient substracts, free oxygen radical scavengers and antioxidants, might hold a promise for the near future. Whether the unfavourable intra-uterine diabetic millieu will also condition the later appearance of adult diseases from cardiovascular disorders to insulin resistant syndromes, remains to be confirmed, or conversely, disproved. For the moment, although priority should focus on pre-conceptional planning and strict metabolic control throughout pregnancy, special attention should nevertheless be paid to the various, but critical, developmental stages of the diabetic pregnancy.

Congenital Abnormalities↗

Ketone compound smelling ability: study in Hungarian twins.

On the basis of their earlier experiments the authors assumed that the ability to recognize the smell of two ketone compounds, acetone and methylethylketone (MEK), might be determined genetically. In the present work of smelling test was performed in adult Hungarian twins, 61 like sexed DZ pairs and 87 MZ pairs. No connection was found between twin zygosity and intra-pair concordance for MEK, while in the case of acetone smelling some connection may exist. A highly significant correlation was found between the smelling ability to acetone and MEK. Females seemed to be better smellers than males. Comparing the taste perception for PTC to the smell perception for acetone the supposition of a possible genetic linkage between the two traits, put forward by other authors, could not definitely be confirmed.

Acetone↗

Fpg protein protects Escherichia coli K-12 from mutation induction by the carcinogen 4-nitroquinoline 1-oxide.

This paper investigates the role of the fpg gene product in protecting Escherichia coli cells against the lethal and mutagenic effects of 4-nitroquinoline 1-oxide (4NQO). To this end, the araD81 mutation which make the cells sensitive to L-arabinose was combined with an fpg-1::Knr allele, in either an uvrA+ or uvrA-, umuC+ or umuC-, genetic background. Mutation induction was monitored by selecting forward mutations to L-arabinose resistance (Arar). The formamidopyrimidine-DNA glycosylase (Fpg protein) protected bacteria from 4NQO-induced mutagenesis since Fpg- defective cells showed greater Arar mutation induction than fpg+ bacteria did. This was confirmed since the increased sensitivity of the fpg- cells to mutagenesis by 4NQO was suppressed when the Fpg protein was overproduced by placing the fpg gene in a multicopy plasmid vector. The fpg- mutation had no detectable influence on 4NQO mutagenesis in a uvrA- genetic background, but its effect was magnified in umuC- cells. No influence on cell survival was observed after 4NQO treatment. Our data suggest that 8-hydroxyguanine, a non-lethal, non-bulky and directly miscoding lesion, might be responsible for the detected influence of Fpg protein expression on mutation induction by 4NQO. This is in agreement with the reported in vivo formation of 8-hydroxyguanine in cellular DNA after 4NQO exposure. The increased 4NQO-induction of GC to TA transversions on fpg- bacteria further support such a possibility. This work reinforces the role of Fpg protein in the bacterial defense against the mutagenicity by genotoxic agents.

4-Nitroquinoline-1-oxide↗

The genetic code: what is it good for? An analysis of the effects of selection pressures on genetic codes.

How did the "universal" genetic code arise? Several hypotheses have been put forward, and the code has been analyzed extensively by authors looking for clues to selection pressures that might have acted during its evolution. But this approach has been ineffective. Although an impressive number of properties has been attributed to the universal code, it has been impossible to determine whether selection on any of these properties was important in the code's evolution or whether the observed properties arose as a consequence of selection on some other characteristic. Therefore we turned the question around and asked, what would a genetic code look like if it had evolved in response to various different selection pressures? To address this question, we constructed a genetic algorithm. We found first that selecting on a particular measure yields codes that are similar to each other. Second, we found that the universal code is far from minimized with respect to the effects of mutations (or translation errors) on the amino acid compositions of proteins. Finally, we found that the codes that most closely resembled real codes were those generated by selecting on aspects of the code's structure, not those generated by selecting to minimize the effects of amino acid substitutions on proteins. This suggests that the universal genetic code has been selected for a particular structure-a structure that confers an important flexibility on the evolution of genes and proteins-and that the particular assignments of amino acids to codons are secondary.

Algorithms↗

Yeast mutants sensitive to trimethoprim.

Wild-type strains of Saccharomyces cerevisiae are resistant to growth inhibition by the folate antagonist trimethoprim. A mutant strain sensitive to trimethoprim was isolated. It was found to be sensitive to both ultraviolet light and X-irradiation. Genetic tests revealed that it was allelic with a known radiation-sensitive strain of Saccharomyces cerevisiae, rad 6-I. Strains harbouring a variety of mutant alleles conferring radiation-sensitivity were tested for sensitivity to trimethoprim. It was found that rad 6-I and each of the four known alleles of rad 18 conferred sensitivity to the drug, but all other rad mutants tested were trimethoprim-resistant. All trimethoprim-sensitive strains, including double mutants of rad 6 rad 18, gave rise to trimethoprim-resistant outgrowths at a rather high frequency (similar to 10-minus 5). Several resistant outgrowths were analysed. A wide variation in phenotype with respect of UV-sensitivty was found. Genetical analysis revealed that resistance to trimethoprim resulted from forward mutations at separate loci rather than back mutations of rad 6 or rad 18 alleles.

Alleles↗

Calling is an honest indicator of paternal genetic quality in poison frogs.

Several competing hypotheses have been put forward to explain why females of many species mate preferentially with males possessing the most conspicuous signals (e.g., ornaments, displays, or songs). We performed a laboratory experiment using two species of poison frogs, Dendrobates leucomelas and Epipedobates tricolor, to test the hypothesis that male calling performance is an honest indicator of parental quality. Our analyses are based on data from behavioral observations of mating activities of captive-reared individuals (and their offspring) that were housed in terraria for four consecutive breeding seasons. Male mating success increased with male calling rate and chirp duration in both species, suggesting that females preferred males with more elaborate calls. Because calling performance improved with age in D. leucomelas, female poison frogs that prefer males with more elaborate calls in the wild may end up mating with older males that have already proven their ability to survive. Females that mated with good callers obtained higher quality offspring. Eggs fertilized by males with high calling rates and long chirp durations had higher hatching success and produced tadpoles that were more likely to metamorphose into surviving frogs. As a consequence, females that mated with males with high calling performance obtained more surviving offspring per egg, compared to females that mated with poor callers. Collectively, our findings comply with the notion that female poison frogs prefer to mate with good callers because calling performance is a reliable predictor of offspring quality. The possible influence of maternal allocation and reasons for the strong effect size compared to previous studies are discussed.

Aging↗

Escherichia coli DNA polymerase IV mutator activity: genetic requirements and mutational specificity.

The dinB gene of Escherichia coli is known to be involved in the untargeted mutagenesis of lambda phage. Recently, we have demonstrated that this damage-inducible and SOS-controlled gene encodes a novel DNA polymerase, DNA Pol IV, which is able to dramatically increase the untargeted mutagenesis of F' plasmid. At the amino acid level, DNA Pol IV shares sequence homologies with E. coli UmuC (DNA Pol V), Rev1p, and Rad30p (DNA polymerase eta) of Saccharomyces cerevisiae and human Rad30A (XPV) proteins, all of which are involved in translesion DNA synthesis. To better characterize the Pol IV-dependent untargeted mutagenesis, i.e., the DNA Pol IV mutator activity, we analyzed the genetic requirements of this activity and determined the forward mutation spectrum generated by this protein within the cII gene of lambda phage. The results indicated that the DNA Pol IV mutator activity is independent of polA, polB, recA, umuDC, uvrA, and mutS functions. The analysis of more than 300 independent mutations obtained in the wild-type or mutS background revealed that the mutator activity clearly promotes single-nucleotide substitutions as well as one-base deletions in the ratio of about 1:2. The base changes were strikingly biased for substitutions toward G:C base pairs, and about 70% of them occurred in 5'-GX-3' sequences, where X represents the base (T, A, or C) that is mutated to G. These results are discussed with respect to the recently described biochemical characteristics of DNA Pol IV.

Adenosine Triphosphatases↗

Forward telescoping bias in reported age of onset: an example from cigarette smoking.

Age at the onset of a disorder is one of its key descriptive characteristics. Early onset may indicate increased risk of a severe course and increased genetic liability. However, retrospectively reported onset in surveys is subject to forward telescoping, a bias in which respondents report events closer to the time of interview than is true. We examined the effect of this bias on age of onset for smoking initiation and daily smoking. Data came from the 1966-77 birth cohorts interviewed in the cross-sectional National Household Surveys on Drug Abuse (NHDSA) 1979-98 (N = 82,122). An association between age at onset and age at interview, within birth year, was found for experimenters and for daily smokers. This was indicative of forward telescoping. As age at interview increased from 12 to 25 the probability of reporting early onset dropped by half. An association was also found between early onset of daily smoking and age at interview. This response bias differed significantly by sex and race, created significant misclassification of smokers as late instead of early onset cases, and biased cohort comparisons from cross-sectional data. These results suggest efforts need to be made to limit the effect of forward telescoping in epidemiological studies by survey question and sampling design.

Adult↗

Bioinorganic chemistry in the postgenomic era.

Genome sequencing has revolutionized all fields of life sciences. Bioinorganic chemistry is certainly not immune to this influence, which is presenting unprecedented challenges. A new goal for bioinorganic chemistry is the investigation of the linkages between inorganic elements and genomic information. This requires new advancements andor the development of new expertise in fields such as bioinformatics and genetics but also provides a driving force to push forward the exploitation of traditional analytical techniques and spectroscopic tools. The "case study" of metal homeostasis in cells is discussed to provide a flavor of the current evolution of the field.

Base Sequence↗