Biomedical subjects

Mauro Santos

Publications and source records attributed to Mauro Santos.

14 recordsLinked to original sources

PubMed2006

Quantitative genetics of speciation: additive and non-additive genetic differentiation between Drosophila madeirensis and Drosophila subobscura.

The role of dominance and epistasis in population divergence has been an issue of much debate ever since the neoDarwinian synthesis. One of the best ways to dissect the several genetic components affecting the genetic architecture of populations is line cross analysis. Here we present a study comparing generation means of several life history-traits in two closely related Drosophila species: Drosophila subobscura, D. madeirensis as well as their F1 and F2 hybrids. This study aims to determine the relative contributions of additive and non-additive genetic parameters to the differentiation of life-history traits between these two species. The results indicate that both negative dominance and epistatic effects are very important in the differentiation of most traits. We end with considerations about the relevance of these findings for the understanding of the role of non-additive effects in speciation.

Animals↗

PubMed2006

Polymorphisms of alcohol-metabolizing enzymes and the risk for alcoholism and alcoholic liver disease in Caucasian Spanish women.

BACKGROUND: The relationship of polymorphisms of the genes that encode for alcohol-metabolizing enzymes and individual vulnerability to alcoholism and alcoholic liver disease (ALD) in women is unclear. We determined the genotypes of ADH1B, ADH1C, CYP2E1 (Dra-I and Pst-I) and ALDH2 in a group of Caucasian Spanish women. METHODS: We performed a cross-sectional case-control study. The study group was made of 220 women. Of these, 85 were alcoholic (27 without liver disease and 58 with alcoholic liver disease) and 135 were non-alcoholic (42 healthy controls and 93 with liver disease unrelated to alcohol). Genotyping of alcohol-metabolizing enzymes was performed using PCR-RFLP methods. RESULTS: The distribution of the allelic variants (alleles 1 and 2) in the whole subjects analyzed was: ADH1B 91.6% and 8.4%; ADH1C 58.4% and 41.6%; CYP2E1 Dra-I 15% and 85%; CYP2E1 Pst-I 96.8% and 3.2%; and ALDH2 100% and 0%, respectively. Carriage of genotypes containing the ADH1B*2 mutant allele significantly protected against alcoholism [odds-ratio (OR)=0.00; 95% confidence interval (95% CI): 0.00-0.94; p=0.02] but was associated with an increased risk for alcoholic liver disease among alcohol-dependent women [OR=0.43; 95% CI: 0.18-0.41; p=0.004]. Analysis of the remaining loci showed no significant associations. CONCLUSIONS: In Caucasian Spanish women the ADH1B*2 allele modulates the risk for alcohol dependence and for alcoholic liver disease. Given the small number of alcoholic women analyzed here, these data need further validation in larger cohorts.

Alcohol Dehydrogenase↗

PubMed2006

Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?

Case-control studies that have investigated the association between alcoholism and alcohol-induced liver damage and the ADH2, ADH3, CYP2E1, and ADLH2 polymorphisms have reported controversial or inconclusive results. Thus, we conducted a meta-analysis of 50 association studies of the above polymorphisms. We explored potential sources of heterogeneity and bias, performed subgroup analyses by racial background and sex, performed sensitivity analyses for studies not in Hardy-Weinberg equilibrium, and performed a subgroup analysis for cases that met strict criteria for alcoholism. The present meta-analysis underscores significant associations of ADH2*1, ADH3*2, and ALDH2*1 alleles and the risk of alcoholism (OR = 1.89 [95% CI 1.56-2.28], 1.32 [95% CI 1.12-1.57], and 4.35 [95% CI 3.04-6.23], respectively). The subsequent subgroup analyses showed association for ADH2*1 and ADH3*2 only in East Asians (OR = 2.23 [95% CI 1.81-2.74] and 1.91 [95% CI 1.45-2.53], respectively) and East Asian males (OR = 2.21 [95% CI 1.57-3.10], 1.69 [95% CI 1.10-2.59], respectively). In East Asian males, the OR for ALDH2*1 was 3.66 (95% CI 1.68-7.96). In Caucasians, sensitivity analysis revealed an association for ADH2*1 in alcoholism (OR = 1.62 [95% CI 1.22-1.89]). When strict criteria were imposed, the pattern of results remained unaltered. For liver disease, there were no significant associations for ADH2*1, ADH3*2, or ALDH2*1 in all subpopulations. The CYP2E1 polymorphism showed no association whatsoever. There is evidence that alleles are mainly dominant. In conclusion, there was heterogeneity between studies in alcoholism for ADH2, ADH3, and ALDH2, and lack of bias in all polymorphisms. The above findings reinforce the need for more rigorous studies, and for regular synthesis of studies' results.

Alcohol Dehydrogenase↗

PubMed2006

Symmetry breaking in interspecific Drosophila hybrids is not due to developmental noise.

Hybrids from crosses of different species have been reported to display decreased developmental stability when compared to their pure species, which is conventionally attributed to a breakdown of coadapted gene complexes. Drosophila subobscura and its close relative D. madeirensis were hybridized in the laboratory to test the hypothesis that genuine fluctuating asymmetry, measured as the within-individual variance between right and left wings that results from random perturbations in development, would significantly increase after interspecific hybridization. When sires of D. subobscura were mated to heterospecific females following a hybrid half-sib breeding design, F1 hybrid females showed a large bilateral asymmetry with a substantial proportion of individuals having an asymmetric index larger than 5% of total wing size. Such an anomaly, however, cannot be plainly explained by an increase of developmental instability in hybrids but is the result of some aberrant developmental processes. Our findings suggest that interspecific hybrids are as able as their parents to buffer developmental noise, notwithstanding the fact that their proper bilateral development can be harshly compromised. Together with the low correspondence between the co-variation structures of the interindividual genetic components and the within-individual ones from a Procrustes analysis, our data also suggest that the underlying processes that control (genetic) canalization and developmental stability do not share a common mechanism. We argue that the conventional account of decreased developmental stability in interspecific hybrids needs to be reappraised.

Animals↗

PubMed2005

Coexistence and error propagation in pre-biotic vesicle models: a group selection approach.

Compartmentalization of unlinked, competing templates is widely accepted as a necessary step towards the evolution of complex organisms. However, preservation of information by templates confined to isolated vesicles of finite size faces much harder obstacles than by free templates: random drift allied to mutation pressure wipe out any template that does not replicate perfectly, no matter how small the error probability might be. In addition, drift alone hinders the coexistence of distinct templates in a same compartment. Here, we investigate the conditions for group selection to prevail over drift and mutation and hence to guarantee the maintenance and coexistence of distinct templates in a vesicle. Group selection is implemented through a vesicle survival probability that depends on the template composition. By considering the limit case of an infinite number of vesicles, each one carrying a finite number of templates, we were able to derive a set of recursion equations for the frequencies of vesicles with different template compositions. Numerical iteration of these recursions allows the exact characterization of the steady state of the vesicle population-a quasispecies of vesicles-thus revealing the values of the mutation and group selection intensities for which template coexistence is possible. Within the main assumption of the model-a fixed, finite or infinite, number of vesicles-we find no fundamental impediment to the coexistence of an arbitrary number of template types with the same replication rate inside a vesicle, except of course for the vesicle capacity. Group selection in the form of vesicle selection is a must for compartmentalized primordial genetic systems even in the absence of intra-genomic competition of different templates.

Animals↗

PubMed2005

Real ribozymes suggest a relaxed error threshold.

The error threshold for replication, the critical copying fidelity below which the fittest genotype deterministically disappears, limits the length of the genome that can be maintained by selection. Primordial replication must have been error-prone, and so early replicators are thought to have been necessarily short. The error threshold also depends on the fitness landscape. In an RNA world, many neutral and compensatory mutations can raise the threshold, below which the functional phenotype, rather than a particular sequence, is still present. Here we show, on the basis of comparative analysis of two extensively mutagenized ribozymes, that with a copying fidelity of 0.999 per digit per replication the phenotypic error threshold rises well above 7,000 nucleotides, which permits the selective maintenance of a functionally rich riboorganism with a genome of more than 100 different genes, the size of a tRNA. This requires an order of magnitude of improvement in the accuracy of in vitro-generated polymerase ribozymes. Incidentally, this genome size coincides with that estimated for a minimal cell achieved by top-down analysis, omitting the genes dealing with translation.

Base Pairing↗

PubMed2005

Genetics and geometry of canalization and developmental stability in Drosophila subobscura.

BACKGROUND: Many properties of organisms show great robustness against genetic and environmental perturbations. The terms canalization and developmental stability were originally proposed to describe the ability of an organism to resist perturbations and to produce a predictable target phenotype regardless of random developmental noise. However, the extent to which canalization and developmental stability are controlled by the same set of genes and share underlying regulatory mechanisms is largely unresolved. RESULTS: We have analyzed the effects of clinical genetic variation (inversion polymorphism) on wing asymmetry by applying the methods of geometric morphometrics in the context of quantitative genetics using isochromosomal lines of Drosophila subobscura. For the analysis of overall size, developmental stability was positively correlated with levels of heterozygosity and development at the optimal temperature. For analyses of shape, the overall comparisons by matrix correlations indicate that inter- and intraindividual variation levels were poorly correlated, a result also supported when comparing the vectors describing patterns of variation of landmark position. The lack of similarity was basically due to the discrepancy between the genetic and environmental components of the interindividual variation. Finally, the analyses have also underscored the presence of genetic variation for directional asymmetry. CONCLUSIONS: The results strongly support the hypothesis that environmental canalization and developmental stability share underlying regulatory mechanisms, but environmental and genetic canalization are not functionally the same. A likely explanation for this lack of association is that natural wing shape variation in Drosophila populations is loosely related to individual fitness.

Analysis of Variance↗

PubMed2004

Temperature-related genetic changes in laboratory populations of Drosophila subobscura: evidence against simple climatic-based explanations for latitudinal clines.

Parallel latitudinal clines to the long-standing ones in the original Palearctic populations have independently evolved at different rates for chromosomal polymorphism and body size in South and North American populations of Drosophila subobscura since colonization around 25 years ago. This strongly suggests that (micro) evolutionary changes are largely predictable, but the underlying mechanisms are unknown. The putative role of temperature per se was investigated by using three sets of populations at each of three temperatures (13 degrees , 18 degrees , and 22 degrees C) spanning much of the tolerable range for this species. We found a lower chromosomal diversity at the warmest temperature; a quick and consistent shift in gene arrangement frequencies in response to temperature; an evolutionary decrease in wing size, mediated by both cell area and cell number, at 18 degrees C; no relationship between wing size and those inversions involved in latitudinal clines; and a shortening of the basal length of longitudinal vein IV relative to its total length with increasing standard dose. The trends for chromosomal polymorphism and body size were generally inconsistent from simple climatic-based explanations of worldwide latitudinal patterns. The findings are discussed in the light of available information on D. subobscura and results from earlier thermal selection experiments with various Drosophila species.

Animals↗

PubMed2004

Recombination in primeval genomes: a step forward but still a long leap from maintaining a sizable genome.

A stubborn question in early molecular evolution is how to sustain the "minimum" informational length required for the basic features of life with a putative low-copying fidelity RNA polymerase ribozyme. Proposals to circumvent the information crisis have primarily focused on networks of cooperative molecules or compartmentalization of non-cooperative unlinked templates, but success has been very limited so far. Lehman (2003) has recently suggested that recombination--a frequently ignored player in early evolution--could have been crucial to building up primeval genomes of sizable length. Here we investigate this claim by assuming (without loss of generality) that genes were already enclosed in a compartment (vesicle, protocell). The numerical results show a quite intricate interplay among mutation, recombination, and gene redundancy. Provided that the minimum number of gene copies per protocell was enough for recombination to recreate wildtype templates--but not too high to impose an unbearable burden of mutants--informational content could have increased by at least 25% by keeping the same mutational load as that for a population without recombination. However, the upper bound of informational length would still be far from the "minimal life" provisions.

Chromosome Positioning↗

PubMed2004

Genetic polymorphisms of ADH2, ADH3, CYP4502E1 Dra-I and Pst-I, and ALDH2 in Spanish men: lack of association with alcoholism and alcoholic liver disease.

BACKGROUND/AIMS: The relationship between polymorphisms at the alcohol dehydrogenase 2 (ADH(2)), ADH(3), CYP(450)2E1 and aldehyde dehydrogenase 2 (ALDH(2)) loci and the individual predisposition to alcoholism and alcoholic liver disease in Caucasians is controversial. METHODS: We determined the genotypes of ADH(2), ADH(3), CYP(450)2E1 (Pst-I and Dra-I) and ALDH(2) in 519 male Spaniards: 264 alcoholic subjects (47 without liver disease, 118 with non-cirrhotic liver disease and 99 with cirrhosis) and 255 non-alcoholic subjects (64 healthy controls, 110 with non-cirrhotic non-alcoholic liver disease and 81 with cirrhosis unrelated to alcohol). Genotyping was performed using PCR-RFLP methods on white cell DNA. RESULTS: The distribution of the allelic variants (allele *1 and allele *2) in the whole subjects analyzed was: ADH(2) 93.1% and 6.9%; ADH(3) 55.7 and 44.3%; CYP(450)2E1 Dra-I 11.2 and 88.8%; CYP(450)2E1 Pst-I 96.2 and 3.8% and ALDH2 100 and 0%, respectively. No differences were observed in the allelic distributions of the alcoholic and non-alcoholic subjects for the loci examined. Allele distribution in alcoholics with no liver disease, with alcoholic steatosis or hepatitis, and with cirrhosis was also similar. CONCLUSIONS: ADH(2), ADH(3), and CYP(450)2E1 Pst-I and Dra-I genetic variations are not related to alcoholism or susceptibility to alcoholic liver disease in our male population. ALDH(2) locus is monomorphic.

Adult↗

PubMed2003

The evolutionary history of Drosophila buzzatii. XXXV. Inversion polymorphism and nucleotide variability in different regions of the second chromosome.

Inversions are portions of a chromosome where the gene order is reversed relative to a standard reference orientation. Because of reduced levels of recombination in heterokaryotypes, inversions have a potentially important effect on patterns of nucleotide variability in those genomic regions close to, or included in, the inverted fragments. Here we report sequence variation at three anonymous regions (STSs) located at different positions in relation to second-chromosome inversion breakpoints in 29 isochromosomal lines derived from an Argentinean population of Drosophila buzzatii. In agreement with previous findings in Drosophila, gene flux (crossing over and/or gene conversion) between arrangements seems to appreciably increase as we approach the middle sections of inversion 2j, and patterns of nucleotide variability within, as well as genetic differentiation between chromosome arrangements, are comparable to those observed at the molecular marker outside the inverted fragments. On the other hand, nucleotide diversity near the proximal breakpoint of inversion 2j is reduced when contrasted with that found at the other regions, particularly in the case of derived inverted chromosomes. Using the data from the breakpoint, we estimate that the inversion polymorphism is approximately 1.63 N generations old, where N is the effective population size. An excess of low-frequency segregating polymorphisms is detected; mostly in the ancestral 2st arrangement and probably indicating a population expansion that predates the coalescent time of inversion 2j. Heterogeneity in mutation rates between the markers linked to the inversions may be sufficient to explain the different levels of nucleotide diversity observed. When considered in the context of other studies on patterns of variation relative to physical distance to inversion breakpoints, our data appear to be consistent with the conclusion that inversions are unlikely to be "long-lived" balanced polymorphisms.

Animals↗

PubMed2003

Quantitative-genetic analysis of wing form and bilateral asymmetry in isochromosomal lines of Drosophila subobscura using Procrustes methods.

Fluctuating asymmetry (FA) is often used as a measure of underlying developmental instability (DI), motivated by the idea that morphological variance is maladaptive. Whether or not DI has evolutionary potential is a highly disputed topic, marred by methodological problems and fuzzy prejudices. We report here some results from an ongoing study of the effects of karyotype, homozygosity and temperature on wing form and bilateral asymmetry using isochromosomal lines of Drosophila subobscura. Our approach uses the recently developed methodologies in geometric morphometrics to analyse shape configurations of landmarks within the standard statistical framework employed in studies of bilateral asymmetries, and we have extended these methods to partition the individual variation and the variation in asymmetries into genetic and environmental causal components. The analyses revealed temperature-dependent expression of genetic variation for wing size and wing shape, directional asymmetry (DA) of wing size, increased asymmetries at suboptimal temperature, and a transition from FA to DA in males as a result of increase in the rearing temperature. No genetic variation was generally detected for FA in our samples, but these are preliminary results because no crosses between lines were carried out and, therefore, the contribution of dominance was not taken into account. In addition, only a subset of the standing genetic variation was represented in the experiments.

Animals↗

PubMed2003

Origin of sex revisited.

Why did sex ever arise in the first place? Why it does not disappear in view of the greater efficiency of asexuals? These are clearly two different questions, and we suggest here that the solution for the origin of sex does not necessarily come from theoretical considerations based on currently existing genetic systems. Thus, while we agree with a number of authors in that the emergence of sex (understood as the exchange of genetic material between genomes) is deeply rooted in the origin of life and happened during the very early stages in the transition from individual genes ('replicators') to bacteria-like cells ('reproducers'), we challenge the idea that recombinational repair was the major selective force for the emergence of sex. Taking the stochastic corrector model as a starting point, we provide arguments that question the putative costs of redundancy in primitive protocells. In addition, if genes that cause intragenomic conflict (i.e., parasites) are taken into account, it is certainly wrong to suggest that cellular fusion would be beneficial at the population level (although this strong claim needs some qualifications). However, when a continuous input of deleterious mutations that impair the fitness of the protocell as a whole is considered in the model (in the realistic range in which stable mutant distributions of quasi-species within compartments are established), there are circumstances when sex could be beneficial as a side effect of the dynamic equilibrium between cellular fusion-mutation-selection. The scenario we have explored numerically is fully consistent with the idea that the universal ancestor was not a discrete entity but an ensemble of proto-organisms that exchanged much genetic information.

Biological Evolution↗

PubMed2002

"Living" under the challenge of information decay: the stochastic corrector model vs. hypercycles.

The combined problem of having a large genome size when the accuracy of replication was a limiting factor is probably the most difficult transition to explain at the late stages of RNA world. One solution has been to suggest the existence of a cyclically coupled system of autocatalytic and cross-catalytic molecular mutualists, where each member helps the following member and receives help from the preceding one (i.e., a "hypercycle"). However, such a system is evolutionarily unstable when mutations are taken into account because it lacks individuality. In time, the cooperating networks of genes should have been encapsulated in a cell-like structure. But once the cell was invented, it closely aligned genes' common interests and helped to reduce gene selfishness, so there was no need for hypercycles. A simple package of competing genes, described by the "stochastic corrector model" (SCM), could have provided the solution. Until now, there is no clear demonstration that the proposed mechanisms (compartmentalized hypercycles and the stochastic corrector model) do in fact solve the error threshold problem. Here, we present a Monte Carlo model to test the viability of protocell populations that enclose a hypercyclic (HPC) or a non-hypercyclic (SCM) system when faced with realistic mutation rates before the evolution of efficient enzymic machinery for replication. The numerical results indicate that both systems are efficient information integrators and are able to overcome the danger of information decay in the absence of accurate replication. However, a population of SCM protocells can tolerate higher deleterious mutation rates and reaches an equilibrium mutational load lower than that in a population of HPC protocells.

Animals↗