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PubMed1998

Deleterious mutations at the mitochondrial ND3 gene in South American marsh rats (Holochilus).

Statistical analyses of DNA sequences have revealed patterns of nonneutral evolution in mitochondrial DNA of mice, humans, and Drosophila. Here we report patterns of mitochondrial sequence evolution in South American marsh rats (genus Holochilus). We sequenced the complete mitochondrial ND3 gene in 82 Holochilus brasiliensis and 21 H. vulpinus to test the neutral prediction that the ratio of nonsynonymous to synonymous nucleotide changes is the same within and between species. Within H. brasiliensis we observed a greater number of amino acid polymorphisms than expected based on interspecific comparisons. This contingency table analysis suggests that many amino acid polymorphisms are mildly deleterious. Several tests of the frequency distribution also revealed departures from a neutral, equilibrium model, and these departures were observed for both nonsynonymous and synonymous sites. In general, an excess of rare sites was observed, consistent with either a recent selective sweep or with populations not at mutation-drift equilibrium.

Amino Acid Sequence↗
PubMed1997

Male-driven evolution of DNA sequences in birds.

Assuming that new mutations arise mainly during DNA replication, sequence evolution in mammals has been seen as 'male driven' (ref. 1) because of the many more cell divisions in spermatogenesis than in oogenesis. Molecular support for this idea has been obtained from the observation of higher substitution rates in genes on the Y than on the X chromosome of primates and rodents, which are species with male heterogamety, but has not been confirmed by the reciprocal analysis of organisms with female heterogamety. The recent suggestion that an intrinsic reduction in the X-chromosome mutation rate may be confounded with male effects in previous comparisons, and the paradoxical finding of low levels of polymorphism on the primate Y chromosome indicate that the idea of male-biased mutation rate needs to be re-examined. We have analysed the molecular evolution of the gene CHD, which is present on the Z and W sex chromosomes of birds. The substitution rate at synonymous positions, as well as in intron DNA, was considerably higher on the Z chromosome than on the female-specific W chromosome, with an estimated male-to-female bias in mutation rate (alpha m) of 3.9-6.5. Thus, evolution appears to be male driven in birds--a situation that supports a neutral model of molecular evolution.

Animals↗
PubMed1993

Region-specific rates of molecular evolution: a fourfold reduction in the rate of accumulation of "silent" mutations in transcribed versus nontranscribed regions of homologous DNA fragments derived from two closely related mouse species.

We have sequenced homologous DNA fragments of 2.7 and 2.8 kbp derived from the closely related mouse species Mus musculus domesticus (M. domesticus) and Mus musculus musculus (M. musculus), respectively. These two species diverged approximately 1 million years ago. Each DNA fragment contains 1.35 kbp of the 3' end of the constitutively expressed 2.2-kbp aprt (adenine phosphoribosyltransferase) gene and a similarly sized nontranscribed region downstream of the aprt gene. The aprt gene region contains protein coding sequences (0.35 kbp), intronic sequences (0.75 kbp), and a 3' nontranslated sequence (0.25 kbp). Both the M. domesticus and M. musculus downstream regions share three partial copies of the B1 repetitive element with the M. musculus downstream region containing an additional complete copy of this element. A comparison of the 2.7- and 2.8-kbp DNA fragments revealed a total of 63 molecular alterations (i.e., mutations) that were approximately fourfold more abundant in the nontranscribed downstream region than in the transcribed aprt gene. Of the 11 mutations observed in the transcribed region, 7 were found in introns, 3 in the 3' untranslated sequence, and 1 was a synonymous change in an exon. A comparison of the human and M. domesticus aprt genes has previously revealed no homology in either the intronic or 3' nontranslated regions with the exception of a 26-bp sequence in intron 3 and sequences at the exon/intron boundaries necessary for correct mRNA splicing (Broderick et al., Proc. Natl. Acad. Sci. USA, 84:3349, 1987). Therefore, there does not appear to be selective pressure for sequences within these regions. We conclude that there is a lower rate of accumulation of "silent" mutations in the transcribed mouse aprt gene than in a contiguous nontranscribed downstream region. A possible molecular mechanism involving preferential DNA repair for the transcribed region is discussed.

Adenine Phosphoribosyltransferase↗
PubMed2005

Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy.

Complex I has a vital role in the energy production of the cell, and the clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults. It has been estimated that the cause of complex I deficiency, especially in children, is often a mutation in the nuclear-encoded genes and, more rarely, in the genes encoded by mitochondrial DNA. We sequenced nine complex I subunit coding genes, NDUFAB1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1 and NDUFV2, in 13 children with defined complex I deficiency. Two novel substitutions were found: a synonymous replacement 201A>T in NDUFV2 and a non-synonymous base exchange 52C>T in NDUFS8. The 52C>T substitution produced the replacement Arg18Cys in the leading peptide of the TYKY subunit. This novel missense mutation was found as a heterozygote in one patient and her mother, but not among 202 healthy controls nor among 107 children with undefined encephalomyopathy. Bioinformatic analyses suggested that Arg18Cys could lead to marked changes in the physicochemical properties of the mitochondrial-targeting peptide of TYKY, but we could not see changes in the assembly or activity of complex I or in the transcription of NDUFS8 in the fibroblasts of our patient. We suggest that Arg18Cys in the leading peptide of the TYKY subunit is not solely pathogenic, and that other genetic factors contribute to the disease-causing potential of this mutation.

Alleles↗
PubMed1996

Unbiased estimation of symmetrical directional mutation pressure from protein-coding DNA.

The most generally applicable procedure for obtaining estimates of the symmetrical, or strandnonspecific, directional mutation pressure (microD) on protein-coding DNA sequences is to determine the G+C content at synonymous codon sites (Psyn), and to divide Psyn by twice the arithmetic mean of the G+C content at synonymous codon sites of a large number of randomly generated, synonymously coding DNA sequences (Psyn). Unfortunately, the original procedure yields biased estimates of Psyn and microD and is computationally expensive. We here present a fast procedure for estimating unbiased microD values. The procedure employs direct calculation of Psyn (approximately Psyn) and two normalization procedures, one for Psyn < or = Psyn and another for Psyn > or = Psyn. The normalization removes a bias sometimes caused by codons specifying arginine, asparagine, isoleucine, and leucine. Consequently, comparison of protein-coding genes that are translated using different genetic codes is facilitated.

Animals↗
PubMed2005

Comparative analyses of codon and amino acid usage in symbiotic island and core genome in nitrogen-fixing symbiotic bacterium Bradyrhizobium japonicum.

Genes involved in the symbiotic interactions between the nitrogen-fixing endosymbiont Bradyrhizobium japonicum, and its leguminous host are mostly clustered in a symbiotic island (SI), acquired by the bacterium through a process of horizontal transfer. A comparative analysis of the codon and amino acid usage in core and SI genes/proteins of B. japonicum has been carried out in the present study. The mutational bias, translational selection, and gene length are found to be the major sources of variation in synonymous codon usage in the core genome as well as in SI, the strength of translational selection being higher in core genes than in SI. In core proteins, hydrophobicity is the main source of variation in amino acid usage, expressivity and aromaticity being the second and third important sources. But in SI proteins, aromaticity is the chief source of variation, followed by expressivity and hydrophobicity. In SI proteins, both the mean molecular weight and mean aromaticity of individual proteins exhibit significant positive correlation with gene expressivity, which violate the cost-minimization hypothesis. Investigation of nucleotide substitution patterns in B. japonicum and Mesorhizobium loti orthologous genes reveals that both synonymous and non-synonymous sites of highly expressed genes are more conserved than their lowly expressed counterparts and this conservation is more pronounced in the genes present in core genome than in SI.

Amino Acids↗
PubMed2001

Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans.

The Toll-like receptor 4 protein acts as the transducing subunit of the lipopolysaccharide receptor complex and assists in the detection of Gram-negative pathogens within the mammalian host. Several lines of evidence support the view that variation at the TLR4 locus may alter host susceptibility to Gram-negative infection or the outcome of infection. Here, we surveyed TLR4 sequence variation in the complete coding region (2.4 kb) in 348 individuals from several population samples; in addition, a subset of the individuals was surveyed at 1.1 kb of intronic sequence. More than 90% of the chromosomes examined encoded the same structural isoform of TLR4, while the rest harbored 12 rare amino acid variants. Conversely, the variants at silent sites (intronic and synonymous positions) occur at both low and high frequencies and are consistent with a neutral model of mutation and random drift. The spectrum of allele frequencies for amino acid variants shows a significant skew toward lower frequencies relative to both the neutral model and the pattern observed at linked silent sites. This is consistent with the hypothesis that weak purifying selection acted on TLR4 and that most mutations affecting TLR4 protein structure have at least mildly deleterious phenotypic effects. These results may imply that genetic variants contributing to disease susceptibility occur at low frequencies in the population and suggest strategies for optimizing the design of disease-mapping studies.

Alleles↗
PubMed2002

Sequence analysis of the GP, NP, VP40 and VP24 genes of Ebola virus isolated from deceased, surviving and asymptomatically infected individuals during the 1996 outbreak in Gabon: comparative studies and phylogenetic characterization.

The aims of this study were to determine if the clinical outcome of Ebola virus (EBOV) infection is associated with virus genetic structure and to document the genetic changes in the Gabon strains of EBOV by sequencing the GP, NP, VP40 and VP24 genes from deceased and surviving symptomatic and asymptomatic individuals. GP and NP sequences were identical in the three groups of patients and only one silent substitution occurred in the VP40 and VP24 genes in asymptomatic individuals. A strain from an asymptomatic individual had a reverse substitution to the Gabon-94 sequence, indicating that minor virus variants may cocirculate during an outbreak. These results suggest that the different clinical outcomes of EBOV infection do not result from virus mutations. Phylogenetic analysis confirmed that Gabon-96 belonged to the Zaire subtype of EBOV and revealed that synonymous substitution rates were higher than nonsynonymous substitution rates in the GP, VP40 and VP24 genes. In contrast, nonsynonymous substitutions predominated over synonymous substitutions in the NP gene of the two Gabon strains, pointing to divergent evolution of these strains and to selective pressures on this gene.

Amino Acid Sequence↗
PubMed2006

Variability patterns and positively selected sites at the gametophytic self-incompatibility pollen SFB gene in a wild self-incompatible Prunus spinosa (Rosaceae) population.

Current models for the generation of new gametophytic self-incompatibility specificities require that neutral variability segregates within specificity classes. Furthermore, one of the models predicts greater ratios of nonsynonymous to synonymous substitutions in pollen than in pistil specificity genes. All models assume that new specificities arise by mutation only. To test these models, 21 SFB (the pollen S-locus) alleles from a wild Prunus spinosa (Rosaceae) population were obtained. For seven of these, the corresponding S-haplotype was also characterized. The SFB data set was also used to identify positively selected sites. Those sites are likely to be the ones responsible for defining pollen specificities. Of the 23 sites identified as being positively selected, 21 are located in the variable (including a new region described here) and hypervariable regions. Little variability is found within specificity classes. There is no evidence for selective sweeps being more frequent in pollen than in pistil specificity genes. The S-RNase and the SFB genes have only partially correlated evolutionary histories. None of the models is compatible with the variability patterns found in the SFB and the S-haplotype data.

Alleles↗
PubMed2004

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes.

BACKGROUND: Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. RESULTS: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. CONCLUSIONS: Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.

Animals↗
PubMed1996

Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation.

Affinity maturation of antibodies requires localized hypermutation and antigen selection. Hypermutation is particularly active in certain regions (notably the CDRs of light and heavy chains) due to the local accumulation of hot spots. We have now analyzed the role of individual nucleotides in the origin of hot spots and show that mutability is largely defined by the nucleotide sequence. We compared the mutability profile of wild-type and modified kappa transgenes that contain silent mutations in the CDR1 segment. We found a new hot spot created at the third base of Ser-31 when its wild-type AGT codon was substituted by AGC. Two major hot spots associated with this AGC vanished when Ser-31 was encoded by the synonymous TCA. In addition to these, which were the most prominent changes, there were compensatory alterations in mutability of residues not directly related to the introduced silent mutations, so that the average hypermutation remained constant. Thus, mutations arising early in the immune response, even silent ones, could affect the mutability of critical residues and alter the pattern of affinity maturation. When analyzing hybridomas, we detected such alterations, but they seemed to better correlate with changes in average rather than local mutation rates. Overall, this paper shows how evolution could have optimized the mutability of individual residues to minimize deleterious mutations. Thus, the optimal strategy for affinity maturation may involve the incorporation of multiple point mutations before antigen selection of the relevant cells.

Animals↗
PubMed1999

Substitution rates of organelle and nuclear genes in sharks: implicating metabolic rate (again).

Rates of nucleotide substitution for nuclear genes are thought to be governed primarily by the number of germ line replication events (the so-called "generation time" hypothesis). In contrast, rates of mitochondrial DNA evolution appear to be set primarily by DNA damage pathways of mutation mediated by mutagenic by-products of oxidative phosphorylation (the so-called "metabolic-rate" hypothesis). Comparison of synonymous substitution rates estimated for the mitochondrial cytochrome b gene and nuclear-encoded dlx, hsp70, and RAG-1 genes in mammals and sharks shows that rates of molecular evolution for sharks are approximately an order of magnitude slower than those for mammals for both nuclear and mitochondrial genes. In addition, there is significant positive covariation of substitution rate for mitochondrial and nuclear genes within sharks. These results, interpreted in light of the pervasiveness of DNA damage by mutagenic by-products of oxygen metabolism to both nuclear and mitochondrial genes and coupled with increasing evidence for cross-genome activity of DNA repair enzymes, suggest that molecular clocks for mitochondrial and nuclear genes may be set primarily by common mutational mechanisms.

Animals↗
PubMed1993

Male-driven evolution of DNA sequences.

It is commonly believed that the mutation rate is much higher in the human male germ line than in the female germ line because the number of germ-cell divisions per generation is much larger in males than in females. But direct estimation of mutation rates is difficult, relying mainly on sex-linked genetic diseases, so the ratio (alpha m) of male to female mutation rates is not clear. It has been noted that if alpha m is very large, then the rate of synonymous substitution in X-linked genes should be only 2/3 of that in autosomal genes, and comparison of human and rodent genes supported this prediction. As the number of X-linked genes used in the study was small and the X-linked and autosomal sequences were non-homologous, and given that the synonymous rate varies among genes, we sequenced the last intron (approximately 1 kb) of the Y-linked and X-linked zinc-finger-protein genes (ZFY and ZFX) in humans, orang-utans, baboons and squirrel monkeys. The ratio Y/X of the substitution rate in the Y-linked intron to that in the X-linked intron is approximately 2.3, which is close to that estimated from synonymous rates in the ZFY and ZFX genes and implies alpha m approximately 6. This estimate of alpha m supports the view that the evolution of DNA sequences in higher primates is male-driven. It is, however, much lower than the previous estimate and therefore raises a number of issues.

Animals↗
PubMed2001

The acetylcholinesterase gene and organophosphorus resistance in the Australian sheep blowfly, Lucilia cuprina.

Acetylcholinesterase (AChE), encoded by the Ace gene, is the primary target of organophosphorous (OP) and carbamate insecticides. Ace mutations have been identified in OP resistants strains of Drosophila melanogaster. However, in the Australian sheep blowfly, Lucilia cuprina, resistance in field and laboratory generated strains is determined by point mutations in the Rop-1 gene, which encodes a carboxylesterase, E3. To investigate the apparent bias for the Rop-1/E3 mechanism in the evolution of OP resistance in L. cuprina, we have cloned the Ace gene from this species and characterized its product. Southern hybridization indicates the existence of a single Ace gene in L. cuprina. The amino acid sequence of L. cuprina AChE shares 85.3% identity with D. melanogaster and 92.4% with Musca domestica AChE. Five point mutations in Ace associated with reduced sensitivity to OP insecticides have been previously detected in resistant strains of D. melanogaster. These residues are identical in susceptible strains of D. melanogaster and L. cuprina, although different codons are used. Each of the amino acid substitutions that confer OP resistance in D. melanogaster could also occur in L. cuprina by a single non-synonymous substitution. These data suggest that the resistance mechanism used in L. cuprina is determined by factors other than codon bias. The same point mutations, singly and in combination, were introduced into the Ace gene of L. cuprina by site-directed mutagenesis and the resulting AChE enzymes expressed using a baculovirus system to characterise their kinetic properties and interactions with OP insecticides. The K(m) of wild type AChE for acetylthiocholine (ASCh) is 23.13 microM and the point mutations change the affinity to the substrate. The turnover number of Lucilia AChE for ASCh was estimated to be 1.27x10(3) min(-1), similar to Drosophila or housefly AChE. The single amino acid replacements reduce the affinities of the AChE for OPs and give up to 8.7-fold OP insensitivity, while combined mutations give up to 35-fold insensitivity. However, other published studies indicate these same mutations yield higher levels of OP insensitivity in D. melanogaster and A. aegypti. The inhibition data indicate that the wild type form of AChE of L. cuprina is 12.4-fold less sensitive to OP inhibition than the susceptible form of E3, suggesting that the carboxylesterases may have a role in the protection of AChE via a sequestration mechanism. This provides a possible explanation for the bias towards the evolution of resistance via the Rop-1/E3 mechanism in L. cuprina.

Acetylcholinesterase↗
PubMed2005

[From gene to disease; incontinentia pigmenti and the NEMO-gene].

Incontinentia pigmenti (IP; MIM308310) is a rare neurocutaneous X-dominant inherited disorder. Besides skin and neurological abnormalities, there is also ophthalmologic and dental involvement. The first stage is characterised by inflammation and apoptosis of the skin and central nervous system. The first stage consists of vesicles and the second of verrucous elements; the third stage is characterised by hyperpigmentation while the fourth is characterised by slightly atrophic hypopigmentations. The skin abnormalities follow the lines of Blaschko. The disorder is observed almost exclusively in girls, but diseased boys are more seriously affected. The IP gene is localised on chromosome Xq28. Mutations in the NEMO-gene are responsible for IP. This gene codes for the nuclear factor-KB essential modulator protein (NEMO; synonym: inhibitor kappaB kinase (IKK)y). In the absence of serious neurological symptoms, the prognosis is not poor.

Female↗
PubMed2002

Microsatellite variability in peach [ Prunus persica (L.) Batsch]: cultivar identification, marker mutation, pedigree inferences and population structure.

A collection of 212 peach and nectarine cultivars covering a wide variation of the species were studied with 16 polymorphic single-locus microsatellite, or simple-sequence repeat (SSR), markers. The average number of alleles per locus was 7.3, 35% of the cultivar x locus combinations analyzed were heterozygous and 87% of the cultivars studied could be individually identified. Most of the groups where two or more cultivars had the same SSR fingerprint included known peach mutants or possible synonymies. Pedigree information was tested with the SSR data. Five unexpected genotypes, due to a mutation at five SSR loci were found when comparing the SSR fingerprint of 14 known mutant cultivars and putative synonymous cultivars. The pedigree data were not consistent with the observed data in 11 out of 38 cases that could be analyzed. The group of non-melting fruit flesh cultivars, generally used by the canning industry, was more variable and genetically distant than the rest of the cultivars tested. Based on their level of homozygosity it was possible to separate those cultivars that were obtained by modern breeding technologies from those that were selected from traditional orchards after generations of seed propagation. The former had a distribution of genotypic frequencies close to a random mating model while the latter had a higher level of homozygosity. The implications of these data for the use of SSR fingerprints in breeder's rights protection and peach breeding are discussed.

Heterozygote↗
PubMedDate not supplied

Pattern of nucleotide substitution and the extent of purifying selection in retroviruses.

The patterns of point mutation and nucleotide substitution are inferred from nucleotide differences in three coding and two noncoding regions of retroviral genomes. Evidence is presented in favor of the view that the majority of mutations accumulate at the reverse transcription stage. Purifying selection is apparently very weak at the amino acid level, and almost nonexistent between synonymous codons. The pattern of purifying selection obeys the rules previously established in vertebrates [Gojobori T, Li W-H, Graur D (1982) J Mol Evol 18:360-369]; i.e., the magnitude of purifying selection at the amino acid level is negatively correlated with Grantham's [Grantham R (1974) Science 185: 862-864] chemical distances between the amino acids interchanged. We refute Modiano et al.'s [Modiano G, Battistuzzi G, Motulsky AG (1981) Proc Natl Acad Sci USA 78:1110-1114] hypothesis, according to which the pattern of mutation is preadapted to buffer against deleterious mutations. On the contrary, the pattern of mutation reduces the level of conservativeness from that imposed on the amino acid substitution pattern by the structure of the genetic code. The extraordinarily high rate of nucleotide substitution in retroviruses in comparison with that in other organisms is apparently caused by an extremely high rate of mutation coupled with a lack of stringent purifying selection at both the codon and the amino acid levels.

Animals↗
PubMed2007

Phylogenetic evidence for deleterious mutation load in RNA viruses and its contribution to viral evolution.

Populations of RNA viruses are often characterized by abundant genetic variation. However, the relative fitness of these mutations is largely unknown, although this information is central to our understanding of viral emergence, immune evasion, and drug resistance. Here we develop a phylogenetic method, based on the distribution of nonsynonymous and synonymous changes, to assess the relative fitness of polymorphisms in the structural genes of 143 RNA viruses. This reveals that a substantial proportion of the amino acid variation observed in natural populations of RNA viruses comprises transient deleterious mutations that are later purged by purifying selection, potentially limiting virus adaptability. We also demonstrate, for the first time, the existence of a relationship between amino acid variability and the phylogenetic distribution of polymorphisms. From this relationship, we propose an empirical threshold for the maximum viable deleterious mutation load in RNA viruses.

Amino Acid Sequence↗