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PubMed2006

Genetics, development and evolution of adaptive pigmentation in vertebrates.

The study of pigmentation has played an important role in the intersection of evolution, genetics, and developmental biology. Pigmentation's utility as a visible phenotypic marker has resulted in over 100 years of intense study of coat color mutations in laboratory mice, thereby creating an impressive list of candidate genes and an understanding of the developmental mechanisms responsible for the phenotypic effects. Variation in color and pigment patterning has also served as the focus of many classic studies of naturally occurring phenotypic variation in a wide variety of vertebrates, providing some of the most compelling cases for parallel and convergent evolution. Thus, the pigmentation model system holds much promise for understanding the nature of adaptation by linking genetic changes to variation in fitness-related traits. Here, I first discuss the historical role of pigmentation in genetics, development and evolutionary biology. I then discuss recent empirically based studies in vertebrates, which rely on these historical foundations to make connections between genotype and phenotype for ecologically important pigmentation traits. These studies provide insight into the evolutionary process by uncovering the genetic basis of adaptive traits and addressing such long-standing questions in evolutionary biology as (1) are adaptive changes predominantly caused by mutations in regulatory regions or coding regions? (2) is adaptation driven by the fixation of dominant mutations? and (3) to what extent are parallel phenotypic changes caused by similar genetic changes? It is clear that coloration has much to teach us about the molecular basis of organismal diversity, adaptation and the evolutionary process.

Adaptation, Biological↗
PubMed1991

[Carrier detection of Glanzmann's thrombasthenia by Taq I restriction fragment length polymorphism of GPIIIa gene].

Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder in which platelets fail to aggregate in second hemostasis due to qualitative and/or quantitative defect in their GPIIb/IIIa complex. In the present study, both phenotypic and genotypic assays were performed by Western blot and Southern blot techniques in 13 members of 3 GT families. 2 GT carriers of 3 probable carriers whose clinical features and GPIIb/IIIa protein were essentially normal were determined by Taq I/5' GPIIIa RFLP. There were no major deletion or insertion in GPIIIa gene in 4 patients with GT. Thus, the genetic defects in these patients is most likely due to a small change or point mutation in the nucleotide sequence of GPIIIa coding region.

Adolescent↗
PubMed1982

Genetic variation in natural populations: problem of electrophoretically cryptic alleles.

Electrophoretic studies have shown that the average frequency of heterozygous loci per individual is about 12% in Drosophila and other invertebrates and about 6% in vertebrates. It is estimated that only about two-thirds of all amino acid substitutions change net electric charge; hence, a large fraction of all genetic variation may be undetected by electrophoresis. Peptide mapping of 11 independent alleles coding for alcohol dehydrogenase in Drosophila melanogaster has uncovered one cryptic variant; thus, the frequency of electrophoretically cryptic variation is apparently low, about 9% in this sample. Nevertheless, with a simple model it is shown that this degree of cryptic variation, if it is typical of other loci, would substantially change our current estimates of genetic variation: the average heterozygosity would increase from about 12% to about 25% for invertebrates and from about 6% to 21% for vertebrates. A variety of techniques--including sequential electrophoresis and heat or urea denaturation--have been used by various investigators to detect electrophoretically cryptic variation. These techniques appear to be less effective than peptide mapping for detecting cryptic variation, but, like peptide mapping, they suggest that standard electrophoresis may detect most of the protein variation present in natural populations. The charge-state model of protein variation proposes that the "alleles" detected by electrophoresis are extremely diverse classes consisting of many electrophoretically cryptic alleles. The alcohol dehydrogenase peptide-mapping results are inconsistent with the charge-state model.

Alleles↗
PubMed2000

The p53 tumor suppressor gene: from molecular biology to clinical investigation.

The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells. Upon cellular stress, particularly that induced by DNA damage, p53 can arrest cell cycle progression, thus allowing the DNA to be repaired; or it can lead to apoptosis. These functions are achieved, in part, by the transactivational properties of p53, which activate a series of genes involved in cell cycle regulation. In cancer cells bearing a mutant p53, this protein is no longer able to control cell proliferation, resulting in inefficient DNA repair and the emergence of genetically unstable cells. The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases. One of the most striking features of the inactive mutant p53 protein is its increased stability (half-life of several hours, compared to 20 min for wild-type p53) and its accumulation in the nucleus of neoplastic cells. Therefore, positive immunostaining is indicative of abnormalities of the p53 gene and its product. Several studies have shown that p53 mutations are associated with short survival in colorectal cancer, but the use of p53 as a tumoral marker is still a matter of debate.

Apoptosis↗
PubMed1999

Coding sequence evolution.

Dramatic progress has been made in the past ten years in the development of statistical and experimental techniques for investigating features of molecular evolution. Applied to coding regions, these techniques have produced remarkable advances in our understanding of selection for codon usage but, ironically, have had little impact on our understanding of protein evolution. That may be about to change.

Animals↗
PubMed1993

A new substitution matrix for protein sequence searches based on contact frequencies in protein structures.

The instabilities of the native structures of mutant proteins with an amino acid exchange are estimated by using the contact energy and the number of contacts for each type of amino acid pair, which were estimated from 18,192 residue-residue contacts observed in 42 crystals of globular proteins. They were then used to evaluate a transition probability matrix of codon substitutions and a log relatedness odds matrix, which is used as a scoring matrix to measure the similarity between protein sequences. To consider amino acid substitutions in homologous proteins, base mutation rates and the effects of the genetic code are also taken into account. The average fitness of an amino acid exchange is approximated to be proportional to the structural stability of the mutant protein, which is then approximated by the average energy change of the protein native structure expected for the amino acid exchange with neglect of the energy change of the denatured state. In global and local homology searches, this scoring matrix tends to yield significantly higher alignment scores than either the unitary matrix or the genetic code matrix, and also may yield higher alignment scores for distantly related protein pairs than MDM78. One of advantages of this scoring matrix is that the equilibrium frequencies of codons and also base mutation rates can be adjusted.

Codon↗
PubMed2005

LGI1 gene mutation screening in sporadic partial epilepsy with auditory features.

Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy. We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations. Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene. The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.

Adult↗
PubMed1989

Site-specific DNA endonuclease and RNA maturase activities of two homologous intron-encoded proteins from yeast mitochondria.

Two introns of the mitochondrial genome 777-3A of S. cerevisiae, bl4 in cob and al4 in coxl genes, contain ORFs that can be translated into two homologous proteins. We changed the UGA, AUA, and CUN codons of these ORFs to the universal genetic code, in order to study the functions of their translated products in E. coli and in yeast, by retargeting the nuclear encoded protein into mitochondria. The p27bl4 protein has been shown to be required for the splicing of both introns bl4 and al4. The homologous p28al4 protein is highly toxic to E. coli. It can specifically cleave double-stranded DNA at a sequence representing the junction of the two fused flanking exons. We present evidence that this system is a good model for studying the role of mitochondrial intron-encoded proteins in the rearrangement of genetic information at both the RNA (RNA splicing-bl4 maturase) and DNA levels (intron transposition-al4 transposase).

Base Sequence↗
PubMed2003

Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant?

The present review outlines the clinical relevance of pharmacokinetic drug interactions within the HMG-CoA reductase inhibitor class. These interactions can result in markedly increased or decreased plasma concentrations of some drugs within this class. However, the relationship between altered plasma concentrations and adverse effects or toxicity may not be linear. It is likely that other variables affect this concentration-effect relationship including: rapid changes in the concentration, concomitant lipid-lowering therapy or host genetic factors that code for different forms or amounts of metabolising enzymes and drug receptors. It is not currently possible to predict which patients will manifest clinically important drug-drug interactions, nor what concentration of an HMG-CoA reductase inhibitor will cause rhabdomyolysis. Thus, until prescribers have better scientific information from which to develop a 'therapeutic range' for each agent, caution should be exercised. In particular, patients taking a CYP3A4-metabolised agent, e.g. atorvastatin, simvastatin and lovastatin, should not be started on a CYP3A4 inhibitor or inducer without close monitoring.

Beverages↗
PubMed1999

Theoretical biology in the third millennium.

During the 20th century our understanding of genetics and the processes of gene expression have undergone revolutionary change. Improved technology has identified the components of the living cell, and knowledge of the genetic code allows us to visualize the pathway from genotype to phenotype. We can now sequence entire genes, and improved cloning techniques enable us to transfer genes between organisms, giving a better understanding of their function. Due to the improved power of analytical tools databases of sequence information are growing at an exponential rate. Soon complete sequences of genomes and the three-dimensional structure of all proteins may be known. The question we face in the new millennium is how to apply this data in a meaningful way. Since the genes carry the specification of an organism, and because they also record evolutionary changes, we need to design a theoretical framework that can take account of the flow of information through biological systems.

Animals↗
PubMed1995

Evolution of the aminoacyl-tRNA synthetases and the origin of the genetic code.

The aminoacyl-tRNA synthetases exist as two enzyme families which were apparently generated by divergent evolution from two primordial synthetases. The two classes of enzymes exhibit intriguing familial relationships, in that they are distributed nonrandomly within the codon-amino acid matrix of the genetic code. For example, all XCX codons code for amino acids handled by class II synthetases, and all but one of the XUX codons code for amino acids handled by class I synthetases. One interpretation of these patterns is that the synthetases coevolved with the genetic code. The more likely explanation, however, is that the synthetases evolved in the context of an already-established genetic code--a code which developed earlier in an RNA world. The rules which governed the development of the genetic code, and led to certain patterns in the coding catalog between codons and amino acids, would also have governed the subsequent evolution of the synthetases in the context of a fixed code, leading to patterns in synthetase distribution such as those observed. These rules are (1) conservative evolution of amino acid and adapter binding sites and (2) minimization of the disruptive effects on protein structure caused by codon meaning changes.

Amino Acids↗
PubMed1981

The promoter-proximal region of the Bacillus licheniformis penicillinase gene: Nucleotide sequence and predicted leader peptide sequence.

Penicillinase (beta-lactamase) is a major species of secreted protein produced by Bacillus licheniformis 749. From the pTB2 recombinant plasmid containing the cloned entire penicillinase (penP) gene, we have isolated and sequenced a 446-bp HpaII fragment carrying the beginning of penP. The 3'-end coding region of 216-bp on this DNA fragment codes for the first 72 amino acids of the prepenicillinase protein. The deduced structure of the leader peptide consists of a 34 amino acid signal sequence with a hydrophilic N-terminal region and a central hydrophobic core.

Bacillus↗
PubMed1984

Synthesis of pigment-binding protein in toluene-treated Rhodopseudomonas capsulata and in cell-free systems.

Pigment-binding protein of the facultatively phototrophic bacterium Rhodospeudomonas capsulata could be selectively synthesized in toluene-treated cells as well as in homologous and heterologous cell-free translation systems by isolated polysomes. It is shown that the pigment-binding polypeptides of the light-harvesting complexes are encoded by messenger RNA of extreme longevity. The dependence of their synthesis on the concomitant synthesis of tetrapyrroles was demonstrated in the toluene-treated cells. The large Mr-28 000 polypeptide of the reaction center and the Mr-10 000 pigment-binding polypeptide of the light-harvesting complex II were found to be synthesized by free (water-soluble) polysomes without a cleavable 'leader' or 'signal' peptide [reviewed by W. Wickner (1979) Annu. Rev. Biochem. 48, 23-45]. The Mr-10 000 polypeptide, as synthesized in vitro, was studied in more detail. Unlike the membrane-assembled polypeptide in vivo it was insoluble in an organic solvent mixture (chloroform/methanol 1:1, v/v). After detergent denaturation in the presence of membrane isolated from the organism it became organic-solvent-soluble. Obviously the polypeptide could be induced to assume alternative conformations in which its apolar residues were either exposed to the solvent or buried within. These findings, in agreement with Wickner's hypothesis, indicate that the Mr-10 000 polypeptide may enter the lipid bilayer by a 'membrane-triggered' conformational change.

Bacterial Proteins↗
PubMed1980

The influence of codon context on genetic code translation.

A class of mutations that increase the deficiency of a suppressor tRNA in translating a particular amber codon has been characterized. The increased efficiency is due to a mutation resulting in a change in the mRNA that affects the nucleotide adjacent to the 3' side of the UAG triplet. Thus the interaction of tRNA with mRNA is influenced by mRNA sequences outside the triplet codon.

Base Sequence↗
PubMed2006

Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors--smoking and the Y402H variant of the complement factor H gene (CFH)--we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.

Aged↗
PubMed1989

Codon reassignment (codon capture) in evolution.

The genetic code, once thought to be "frozen," shows variations from the universal code. Variations are found in mitochondria, Mycoplasma, and ciliated protozoa. The variations result from reassignment of codons, especially stop codons. The reassignments take place by disappearance of a codon from coding sequences, followed by its reappearance in a new role. Simultaneously, a changed anticodon must appear. We discuss the role of directional mutation pressure in the events, and we also describe the possibility that such events have taken place during early evolution of the genetic code and can occur during its present evolution.

Animals↗
PubMed1985

Conservation of the secondary structure of protein during evolution and the role of the genetic code.

In this communication we demonstrate, in a group of modern proteins, following an algorithm described by Argyle (1980), that the ordination of the amino acids in terms of the most frequent substitutions agrees with the conservation of the alpha-helix, beta-sheet, and beta-turn formation tendencies during evolution. The same correspondence has been demonstrated for the conservation of the physico-chemical properties in the amino acid substitutions. Both parameters are similar in showing higher correlation with the most frequent amino acid substitutions than with the feasibility of changes at the level of the respective codons. Some kind of restrictions for the expression of the genomic changes, due to the conservation of the secondary structure of proteins and/or the physicochemical properties of the substituted amino acids, could account for the differences found between the distribution of the amino acid substitutions and the most probable codon changes.

Amino Acids↗