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PubMed1985

Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia.

In order to maximize the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse stem-cell spermatogonia, advantage was taken of the fact that these cells can accumulate mutations from repeated doses given over relatively long time periods. Repeated doses (100 mg/kg) of ethylnitrosourea injected intraperitoneally into male mice at weekly intervals were found to allow adequate survival and fertility with total dosages of 300 and 400 mg/kg. The specific-locus mutation frequencies at these dosages were, respectively, 1.8 and 2.2 times that obtained with the maximal practicable single dose of 250 mg/kg. The mutation frequency induced by a 400 mg/kg dosage of ethylnitrosourea is 12 times the maximal mutation frequency achievable with a single exposure to x-rays and 36 times that reported for procarbazine, the most effective chemical mutagen previously known for mouse stem-cell spermatogonia. Ethylnitrosourea is already the mutagen of choice in deliberate attempts to create mouse models for human disease and in any experiments in which a maximal mutation rate is desired. Repeated-dose regimens similar to the ones reported here should increase the efficiency of such studies.

Abnormalities, Drug-Induced↗
PubMed1999

Evolutionary demographic models for mortality plateaus.

Plateaus in the age pattern of hazard functions at extreme ages have been discovered in large populations of medflies, Drosophila, nematodes, and people. Mueller and Rose [(1996) Proc. Natl. Acad. Sci. USA 93, 15249-15253] have proposed several age-structured demographic models to represent effects of mutation accumulation and antagonistic pleiotropy on randomly evolving schedules of demographic rates. They assert that "evolutionary theory [as embodied in their models] predicts late-life mortality plateaus." This paper defines a class of Markovian models that includes those of Mueller and Rose and obtains a characterization of the possible limiting states. For the basic model, the result implies that schedules with late-life mortality plateaus above a minimal threshold are not limiting states. The models fail, but not for reasons previously conjectured. Transient states, visited early by the process, do display mortality plateaus. Other models from this class may have a role to play in reconciling observed plateaus with evolutionary theory.

Animals↗
PubMed2006

Tracing ancient mRNA hairpins.

From recent developments of the early evolution theory it follows that the earliest mRNAs were short ( approximately 20 nt) (G+C)-rich polynucleotides. These short sequences could form hairpins, which would be of high evolutionary advantage because of stability and uniqueness of their conformations. Due to mutations accumulated during billions of years of evolution, the speculated earliest hairpins would largely lose the initial complementarities. Some of the original complementary base-to-base contacts, however, may have survived. Computational analysis of modern prokaryotic mRNA sequences reveals excess population of the expected short range complementarities. The derived earliest mRNA hairpin size fully corresponds to the predicted size of ancient coding duplexes. The repertoire of the surviving hairpins traced in modern mRNA confirms duplex structure of the earliest mRNA, suggested by the early molecular evolution theory.

Bacteria↗
PubMed1998

The age-associated decrease in the amount of amplifiable full-length mitochondrial DNA in human skeletal muscle.

There has been a continuous evolution in our concept [1] that mtDNA undergoes a range of mutations with age and that such alterations lead to a decline in mitochondrial bioenergy capacity. Here we report that a wide range of deletion mutations accumulate with age and the amount of full-length mtDNA (FLmtDNA) amplifiable by extra-long PCR (XL-PCR) markedly decreases with age. An analysis of single human quadriceps muscle fibres reveals a close correlation between the decrease in FLmtDNA and the decline in cytochrome c oxidase activity, an exemplifier of mitochondrial bioenergy. However, Southern blotting analysis of unamplified genomic DNA shows that there is little decrease in FLmtDNA in aged quadriceps. The results are interpreted to indicate that while there is little change in the total mtDNA with age, nonetheless a significant proportion of this mtDNA is extensively damaged such that it cannot be amplified by XL-PCR. The amplifiable FLmtDNA, which putatively represents the functional component of the mtDNA, decreases markedly with age.

Adolescent↗
PubMed2004

Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates.

The standard view postulates a bell-shaped relationship between adherence to therapy and development of drug-resistant human immunodeficiency virus (HIV), with a resistance peak at a moderate level of adherence. This relationship has not been confirmed empirically. We statistically modeled the relationship between adherence and development of drug resistance, using empirically defined relationships of the rate of viral suppression and drug-resistance-mutation accumulation derived from patients receiving protease-inhibitor-based therapy. We found that the maximal rate of drug resistance occurs at 87% adherence and declines modestly at 100% adherence. Higher levels of viral suppression at 100% adherence (a marker of greater regimen potency) progressively reduce the overall population rate of drug resistance and shift the peak resistance rate to lower levels of adherence.

Adult↗
PubMed2026

Pervasive positive selection on X-linked ampliconic genes in primates.

Mammalian sex chromosomes harbour ampliconic gene families, which are multi-copy genes with ≥97% sequence identity, predominantly expressed in testis tissue and essential for male fertility. The amplification of testis-specific genes is conserved across mammals, yet the specific gene families that expand show striking lineage-specific variation. Previous studies suggest a dynamic turnover with adaptive evolution for several of these families, but their analysis has been limited by the quality of reference genomes of repetitive regions. To characterise the molecular evolutionary processes of ampliconic gene families on both sex chromosomes, we analysed telomere-to-telomere genome assemblies from eight primate species spanning 25 million years of evolution. We identified 53 X-linked and 19 Y-linked ampliconic gene families with dynamic copy number variation. Gene conversion through palindromic pairing and tandem arrays maintained high sequence similarity despite accumulating mutations. X-linked families maintained conserved chromosomal positions despite copy number changes, whereas Y-linked families showed frequent positional turnover. Strikingly, multiple X-linked families (GAGE, SSX, CSAG, and VCX) showed pervasive positive selection across the primate phylogeny and multiple (MAGEB, CT45, HSFX) showed lineage specific positive selection. Y-linked families predominantly evolve under purifying selection. Examining intraspecific copy number variation of the X-linked ampliconic families in chimpanzees, humans, and gorillas, we found variation among individuals but clear differences between species, with the largest families varying the most. These patterns could suggest that sperm competition, meiotic drive, or dosage-dependent selection drive the rapid, lineage-specific evolution of testis-expressed ampliconic genes in primates.

Journal Article↗
PubMed1995

P-element-induced variation in metabolic regulation in Drosophila.

Movement of transposable elements have demonstrated to be a cause of genetic variation that is relevant to quantitative characters in Drosophila. Here a particular class of P-element-induced variation known to be mediated through changes in expression of targeted enzyme-encoding genes is examined. Balancer chromosome and 139 third-chromosome lines of Drosophila melanogaster bearing unique stable P-element insertions in a common genetic background. Lines that were homozygous for second-chromosome P-element insertions were significantly more heterogeneous than control lines in 10 of 16 characters, whereas third-chromosome insertion lines were heterogeneous in 11 of the 16 traits. The average mutational variance per insertion relative to environmental variance (Vm/Ve) was 5.7 x 10(-2), and estimates varied widely across characters. The distributions of mutational effects tended to be skewed, with a longer tail toward high enzyme activities. Mutational effects deviated from a normal distribution in 15 of the 16 traits and significant outlier lines were found in both a positive and negative direction in several characters. Pleiotropic effects of single P-element insertions were quantified by correlation, and, after correcting for simultaneous tests, of the 91 correlations, 37 were significant at the 5% level. The pattern of pleiotropic effects derviated both from the equilibrium genetic correlations quantified in a previous study and from the correlations of mutational effects in a mutation-accumulation experiment, suggesting that multiple forces are at play that shape extant variation.

Adaptation, Biological↗
PubMed1996

Selfish operons: horizontal transfer may drive the evolution of gene clusters.

A model is presented whereby the formation of gene clusters in bacteria is mediated by transfer of DNA within and among taxa. Bacterial operons are typically composed of genes whose products contribute to a single function. If this function is subject to weak selection or to long periods with no selection, the contributing genes may accumulate mutations and be lost by genetic drift. From a cell's perspective, once several genes are lost, the function can be restored only if all missing genes were acquired simultaneously by lateral transfer. The probability of transfer of multiple genes increases when genes are physically proximate. From a gene's perspective horizontal transfer provides a way to escape evolutionary loss by allowing colonization of organisms lacking the encoded functions. Since organism bearing clustered genes are more likely to act as successful donors, clustered genes would spread among bacterial genomes. The physical proximity of genes may be considered a selfish property of the operon since it affects the probability of successful horizontal transfer but may provide no physiological benefit to the host. This process predicts a mosaic structure of modern genomes in which ancestral chromosomal material is interspersed with novel, horizontally transferred operons providing peripheral metabolic functions.

Alleles↗
PubMed2002

Rates of R1 and R2 retrotransposition and elimination from the rDNA locus of Drosophila melanogaster.

R1 and R2 elements are non-LTR retrotransposons that insert specifically into the 28S rRNA genes of arthropods. The process of concerted evolution of the rDNA locus should give rise to rapid turnover of these mobile elements compared to elements that insert at sites throughout a genome. To estimate the rate of R1 and R2 turnover we have examined the insertion of new elements and elimination of old elements in the Harwich mutation accumulation lines of Drosophila melanogaster, a set of inbred lines maintained for >350 generations. Nearly 300 new insertion and elimination events were observed in the 19 Harwich lines. The retrotransposition rate for R1 was 18 times higher than the retrotransposition rate for R2. Both rates were within the range previously found for retrotransposons that insert outside the rDNA loci in D. melanogaster. The elimination rates of R1 and R2 from the rDNA locus were similar to each other but over two orders of magnitude higher than that found for other retrotransposons. The high rates of R1 and R2 elimination from the rDNA locus confirm that these elements must maintain relatively high rates of retrotransposition to ensure their continued presence in this locus.

Animals↗
PubMed2003

Bacterial evolution through the selective loss of beneficial Genes. Trade-offs in expression involving two loci.

The loss of preexisting genes or gene activities during evolution is a major mechanism of ecological specialization. Evolutionary processes that can account for gene loss or inactivation have so far been restricted to one of two mechanisms: direct selection for the loss of gene activities that are disadvantageous under the conditions of selection (i.e., antagonistic pleiotropy) and selection-independent genetic drift of neutral (or nearly neutral) mutations (i.e., mutation accumulation). In this study we demonstrate with an evolved strain of Escherichia coli that a third, distinct mechanism exists by which gene activities can be lost. This selection-dependent mechanism involves the expropriation of one gene's upstream regulatory element by a second gene via a homologous recombination event. Resulting from this genetic exchange is the activation of the second gene and a concomitant inactivation of the first gene. This gene-for-gene expression tradeoff provides a net fitness gain, even if the forfeited activity of the first gene can play a positive role in fitness under the conditions of selection.

Adaptation, Physiological↗
PubMed2003

R1 and R2 retrotransposition and deletion in the rDNA loci on the X and Y chromosomes of Drosophila melanogaster.

The non-LTR retrotransposons R1 and R2 insert into the 28S rRNA genes of arthropods. Comparisons among Drosophila lineages have shown that these elements are vertically inherited, while studies within species have indicated a rapid turnover of individual copies (elimination of old copies and the insertion of new copies). To better understand the turnover of R1 and R2, 200 retrotranspositions and nearly 100 eliminations have been scored in the Harwich mutation-accumulation lines of Drosophila melanogaster. Because the rDNA arrays in D. melanogaster are present on the X and Y chromosomes and no exchanges were detected in these lines, it was possible to show that R1 retrotranspositions occur predominantly in the male germ line, while R2 retrotranspositions were more evenly divided between the germ lines of both sexes. The rate of elimination of elements from the Y rDNA array was twice that of the X rDNA array with both chromosomal loci containing regions where the rate of elimination was on average eight times higher. Most R1 and R2 eliminations appear to occur by large intrachromosomal events (i.e., loop-out events) that involve multiple rDNA units. These findings are interpreted in light of the known abundance of R1 and R2 elements in the X and Y rDNA loci of D. melanogaster.

Animals↗
PubMed2004

Late paternity and stillbirth risk.

BACKGROUND: The role of paternal ageing on the incidence of some genetic diseases in offspring depends on the hypothesis that spontaneous mutations accumulate due to continuous cell divisions during spermatogenesis. We examined the effect of paternal age on the complex multifactorial character, stillbirth. METHODS: In 3,619,647 Italian singletons born in 1990-1996 we evaluated stillbirth risk as a function of paternal ageing by means of multiple logistic regression models, which included maternal age and family education, as categorical covariates and interactions. The categorical risk was estimated for mothers and fathers beyond threshold ages of 35 and 40 years, respectively. RESULTS: Stillbirth risk increases with paternal ageing in mothers > or =30 years old, and maternal age and family education modify the impact. In families with low education, the risk accounts for odds ratio (OR) 1.015 [95% confidence interval (CI) 1.01-1.02] in mothers aged 30-34 years, and for OR 1.032 (95% CI 1.02-1.04) in mothers aged > or =35 years; in families with higher education the risk accounts for OR 1.008 (95% CI 1.00-1.02) and OR 1.025 (95% CI 1.01-1.04), respectively, in mothers aged 30-34 and > or =35 years. In these latter families, for mothers aged <35 and fathers > or =40 years the risk accounts for OR 1.12 (95% CI 1.00-1.25). CONCLUSIONS: The effect of paternal ageing on stillbirth risk is revealed in mothers aged > or =30 years and is modified by family education. In mothers aged 30-34 years from families with high education, the increase imputable to paternal ageing might be indicative of a genetic component.

Adult↗
PubMed1995

Somatic hypermutation of VHS107 genes is not associated with gene conversion among family members.

Murine B cells proliferating in the germinal centers of peripheral lymphoid tissue accumulate mutations in their rearranged variable regions, a diversification process which contributes to affinity maturation of the antibody response. The highly targeted nature of the hypermutation process could be explained by a somatic gene conversion mechanism. Well characterized examples of such an activity in B cells are seen during diversification of the chicken and rabbit Ig repertoires. The genomic organization, low complexity and high degree of homology exhibited by the four members of the murine VHS107 gene family suggested that these gene segments may be suitable candidates for the search of gene conversion events derived from upstream VHS107 counterparts. After an immune response to a complex T cell-dependent antigen (sheep red blood cells), rearranged V13, V11 and V1 genes were isolated from splenic extrafollicular and germinal center B cells. Extensive somatic mutation was evident in V11 and V1 sequences. When these sequences were examined, as well as V1 sequences isolated from phosphorylcholine-specific hybridomas, the observed nucleotide changes were not associated with any gene conversion between family members, suggesting instead that they arose by a mechanism which introduces point mutations.

Animals↗
PubMed2004

Human-specific amino acid changes found in 103 protein-coding genes.

We humans have many characteristics that are different from those of the great apes. These human-specific characters must have arisen through mutations accumulated in the genome of our direct ancestor after the divergence of the last common ancestor with chimpanzee. Gene trees of human and great apes are necessary for extracting these human-specific genetic changes. We conducted a systematic analysis of 103 protein-coding genes for human, chimpanzee, gorilla, and orangutan. Nucleotide sequences for 18 genes were newly determined for this study, and those for the remaining genes were retrieved from the DDBJ/EMBL/GenBank database. The total number of amino acid changes in the human lineage was 147 for 26,199 codons (0.56%). The total number of amino acid changes in the human genome was, thus, estimated to be about 80,000. We applied the acceleration index test and Fisher's synonymous/nonsynonymous exact test for each gene tree to detect any human-specific enhancement of amino acid changes compared with ape branches. Six and two genes were shown to have significantly higher nonsynonymous changes at the human lineage from the acceleration index and exact tests, respectively. We also compared the distribution of the differences of the nonsynonymous substitutions on the human lineage and those on the great ape lineage. Two genes were more conserved in the ape lineage, whereas one gene was more conserved in the human lineage. These results suggest that a small proportion of protein-coding genes started to evolve differently in the human lineage after it diverged from the ape lineage.

Animals↗
PubMed1991

Revised genomic consensus for the hypermethylated CpG island region of the human L1 transposon and integration sites of full length L1 elements from recombinant clones made using methylation-tolerant host strains.

Efficient recovery of clones from the 5' end of the human L1 dispersed repetitive elements necessitates the use of deletion mcr- host strains since this region contains a CpG island which is hypermethylated in vivo. Clones recovered with conventional mcr+ hosts seem to have been derived preferentially from L1 members which have accumulated mutations that have removed sites of methylation. We present a revised consensus from the 5' presumptive control region of these elements. This revised consensus contains a consensus RNA polymerase III promoter which would permit the synthesis of transcripts from the 5' end of full length L1 elements. Such potential transcripts are likely to exhibit a high degree of secondary structure. In addition, we have determined the flanking sequences for 6 full length L1 elements. The majority of full length L1 clones show no convincing evidence for target site duplication in the insertion site as commonly observed with truncated L1 elements. These data would be consistent with two mechanisms of integration of transposing L1 elements with different mechanisms predominating for full length and truncated elements.

Base Sequence↗
PubMed2002

Comprehensive analysis of amino acid and nucleotide composition in eukaryotic genomes, comparing genes and pseudogenes.

Based on searches for disabled homologs to known proteins, we have identified a large population of pseudogenes in four sequenced eukaryotic genomes-the worm, yeast, fly and human (chromosomes 21 and 22 only). Each of our nearly 2500 pseudogenes is characterized by one or more disablements mid-domain, such as premature stops and frameshifts. Here, we perform a comprehensive survey of the amino acid and nucleotide composition of these pseudogenes in comparison to that of functional genes and intergenic DNA. We show that pseudogenes invariably have an amino acid composition intermediate between genes and translated intergenic DNA. Although the degree of intermediacy varies among the four organisms, in all cases, it is most evident for amino acid types that differ most in occurrence between genes and intergenic regions. The same intermediacy also applies to codon frequencies, especially in the worm and human. Moreover, the intermediate composition of pseudogenes applies even though the composition of the genes in the four organisms is markedly different, showing a strong correlation with the overall A/T content of the genomic sequence. Pseudogenes can be divided into 'ancient' and 'modern' subsets, based on the level of sequence identity with their closest matching homolog (within the same genome). Modern pseudogenes usually have a much closer sequence composition to genes than ancient pseudogenes. Collectively, our results indicate that the composition of pseudogenes that are under no selective constraints progressively drifts from that of coding DNA towards non-coding DNA. Therefore, we propose that the degree to which pseudogenes approach a random sequence composition may be useful in dating different sets of pseudogenes, as well as to assess the rate at which intergenic DNA accumulates mutations. Our compositional analyses with the interactive viewer are available over the web at http://genecensus.org/pseudogene.

Amino Acid Sequence↗
PubMed1999

Halobacterial rhodopsins.

Following the discovery of the bacteriorhodopsin proton pump in Halobacterium halobium (salinarum), not only the halorhodopsin halide pump and two photosensor rhodopsins (sensory rhodopsin and phoborhodopsin) in the same species, but also homologs of these four rhodopsins in strains of other genera of Halobacteriaceae have been reported. Twenty-eight full (and partial) sequences of the genomic DNA of these rhodopsins have been analyzed. The deduced amino acid sequences have led to new strategies and tactics for understanding bacterial rhodopsins on a comparative basis, as summarized briefly in this article. The data discussed include (i) alignment of the sequences to qualify/characterize the conserved residues; (ii) assignment of residues that cause differences in function(s)/properties; and (iii) phylogeny of the halobacterial rhodopsins to suggest their evolutionary paths. The four kinds of rhodopsin in each strain are assumed, on the basis of their genera-specific distributions, to have arisen by at least two gene-duplication processes during evolution prior to generic speciation. The first duplication of the rhodopsin ancestor gene yielded two genes, each of which was duplicated again to give four genes in the ancestor halobacterium. The bacterium carrying four rhodopsin genes, after accumulating mutations, became ready for generic speciation and the delivery of four rhodopsins to each species. The original rhodopsin ancestor is speculated to be closest to the proton pump (bacteriorhodopsin).

Amino Acid Sequence↗
PubMed1993

Sequence relationship of retrotransposable elements R1 and R2 within and between divergent insect species.

R1 and R2 are retrotransposable elements that integrate at specific sites in the 28S ribosomal RNA (rRNA) genes of Bombyx mori and Drosophila melanogaster. We have previously shown that most insect species contain insertions in their 28S genes at the R1 and/or R2 site. We have sequenced the 3' half of R1 and R2 elements from three additional insect species: the fungus gnat, Sciara coprophila (Diptera); the Japanese beetle, Popillia japonica (Colleoptera); and the parasitic wasp, Nasonia vitripennis (Hymenoptera). The elements were obtained by screening lambda phage genomic clones containing rDNA units and by a polymerase chain reaction approach using degenerate primers to conserved sequences in the reverse-transcriptase domain, in combination with a second primer to the 28S gene 3' of the insertion site. Comparisons of the sequences of R1 and R2 from four insect orders suggest that the organization of their open-reading frames has been conserved and is therefore likely to be similar throughout insects. This sequence analysis also indicates that, except for 5' truncations generated during the retrotransposition process itself, most elements have not accumulated mutations that would make them inactive. Popillia japonica and N. vitripennis differed from previously described species, in that (a) P. japonica contained multiple families of R2 and (b) N. vitripennis contained multiple families of R1. Nucleotide sequence identity between these different families is low. Amino acid sequence identity of their open-reading frames averaged only 41% for the R2 families of P. japonica and 35% for the R1 families of N. vitripennis. The presence of multiple highly divergent families of elements within a species suggests either that each insertion family is able to maintain its copy number without eliminating the other families in its competition for a limited number of 28S genes or that there has been extensive horizontal transfer of R1 and R2 elements between insect species.

Amino Acid Sequence↗