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Results for “deleterious mutation”

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PubMed2006

Enhanced adaptive evolution of sperm-expressed genes on the mammalian X chromosome.

Genes on the mammalian X chromosome may be under unique evolutionary pressure due to their hemizygous expression in males. Since any recessive deleterious mutation would immediately be expressed in males and, therefore, efficiently removed from the population, selective constraint could be more pronounced in X-linked genes. Conversely, if a recessive mutation were beneficial, its immediate exposure to selection would be advantageous, and would facilitate adaptive evolution. We tested for positive selection in a total of 86 genes using a maximum likelihood approach, including 40 sperm-expressed and 46 non-sperm, tissue-specific genes. We find evidence to suggest that X-linkage enhances the effects of positive selection in sperm-expressed genes in terms of the number of codons affected, and report a general trend for positively selected genes to reside on the X chromosome rather than on the autosomes. Our data suggest that hemizygous expression in males makes the X chromosome a preferred location for positively selected sperm genes that do not require postmeiotic transcription.

Adaptation, Physiological↗

PubMed1999

The evolution of dominance.

The evolution of dominance has been subject to intensive debate since Fisher first argued that modifiers would be selected for if they made wild-type alleles more dominant over mutant alleles. An alternative explanation, put forward by Wright, is that the commonly observed dominance of wild-type alleles is simply a physiological consequence of metabolic pathways. Wright's explanation has gained support over the years, largely ending the debate over the general recessivity of deleterious mutations. Nevertheless there is reason to believe that dominance relationships have been moulded by natural selection to some extent. First, the metabolic pathways are themselves products of evolutionary processes that may have led them to be more stable to perturbations, including mutations. Secondly, theoretical models and empirical experiments suggest that substantial selection for dominance modifiers exists during the spread of adaptive alleles or when a polymorphism is maintained either by overdominant selection or by migration-selection balance.

Animals↗

PubMed2000

Are the same genes responsible for intra- and interspecific variability for sex comb tooth number in Drosophila?

The identification of genes contributing to speciation has the potential to provide important insights into the mechanisms of evolution. One of the most interesting unresolved puzzles is the relationship between intraspecific variability in morphological traits and their interspecific divergence. Intraspecific polymorphisms without major detrimental side-effects may serve as a substrate for selection response during speciation. The same quantitative trait loci (QTLs) may, then, account for the trait variability both within and between species. In contrast, the vast majority of intraspecific variants could be deleterious mutations that have not yet been selected out. In this case intraspecific variation would not ultimately generate interspecific trait differences. In previous work, QTLs responsible for morphological differences between animal species, including those for the secondary sexual trait sex comb tooth number, have been mapped with the resolution of chromosome segments. Here, we mapped QTLs for which alleles segregated between two laboratory lines of Drosophila melanogaster. The two QTLs identified mapped to the X chromosome and accounted for only 8% of the between-line differences, implying that a large number of small-effect genes modify sex combs. One intraspecific QTL mapped to the same interval as the QTL for interspecific differences between D. simulans and D. mauritiana. Whether or not these effects result from the same genes requires further examination.

Animals↗

PubMed2004

Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon.

The Cdk inhibitor p21 regulates p53-mediated growth arrest following DNA damage. It is expressed during epithelial differentiation in a variety of organs including colon. We investigated susceptibility of p21-deficient mice to the colon carcinogen azoxymethane (AOM). After AOM injections, rodents develop putative premalignant lesions called aberrant crypt foci (ACF) that are localized to the distal three centimeters of the colon. p21-deficient mice developed significantly higher numbers of ACF than wild-type mice in response to AOM, and these were not restricted to distal colon. After AOM treatment, increased numbers of lymphoid aggregates were detected in p21-deficient colon. Proliferation was similar in wild type and p21-deficient colon before and after AOM injection, but AOM-induced apoptosis was detected only in wild-type crypt epithelial cells, and not in the p21-deficient colon. The proapoptotic function uncovered for p21 was unexpected, because p21 acts as an inhibitor of apoptosis in many systems, and is not required for p53-dependent apoptosis. Enhanced formation of ACF in p21-deficient mice supports a tumor suppressor function for p21 in the colon. Reduced apoptosis of colon epithelial cells with deleterious mutations may be an initiating event in the formation of ACF, with inflammatory cell cytokine expression contributing to their further expansion.

Animals↗

PubMed1999

A mineral sunscreen affords genomic protection against ultraviolet (UV) B and UVA radiation: in vitro and in situ assays.

Ultraviolet (UV) radiation has been shown to be responsible for different biological effects on human skin, including the initiation of photocarcinogenesis. Both UVB and UVA have been described as mutagenic, but the processes by which they alter the DNA are different. Although cells can repair DNA damage, some deleterious mutations nevertheless appear and can promote cancer. The risk of photocarcinogenesis is acknowledged and the frequency of photogenodermatosis is increasing. In order to evaluate the protection efficacy of a high sun protection factor (SPF) mineral sunscreen against UVB- and UVA-induced genomic alterations, we have followed two approaches. First, we have tested the sunscreen for its ability to decrease the unscheduled DNA synthesis response in vitro in human fibroblasts, as an indirect measure of UVB-induced lesions (0.005 and 0.01 J/cm2), and second, we have verified its ability to reduce the in situ end-labelling intensity in human skin as a direct measure of UVA-induced single-strand breaks (10 J/cm2). Microscopic analysis clearly demonstrated the protective effect of the sunscreen against UVB and UVA. A dose-dependent effect of mineral sunscreens was observed. There was also a relationship between the SPF and genomic protection. By limiting the accumulation of UV-induced lesions on DNA, this mineral sunscreen could limit the mutation frequency.

Adult↗

PubMed1998

Associative overdominance, heterozygosity and fitness.

Our aim in this study was to examine the power of associative overdominance in creating a correlation between individual heterozygosity and fitness and in maintaining genetic polymorphism at neutral loci. This was undertaken by simulating a diploid model with five chromosomes, each with 1000 loci that could have deleterious mutations linked to neutral markers located on the same chromosomes. The simulations were carried out with various combinations of the following parameters: population size (N), number of crossovers (c), selection coefficient (s) and dominance (h). All combinations of parameter values resulted in a positive regression of the fitness on the individual marker heterozygosity, although the fitness differences were not very large when c = 2. The association between individual heterozygosity and fitness was clearest for recessive mutations (small h) with intermediate selection coefficients in small populations. The level of marker heterozygosity in the population was higher than the neutral expectation for many parameter values, even though regression of fitness on heterozygosity was not always steep at the individual level. These results agreed with the conclusion that associative overdominance could help to maintain polymorphisms in small populations. Strong selection occasionally yielded gene diversities lower than the neutral expectation, reflecting the prediction that strong selection reduces the effective population size.

Computer Simulation↗

PubMed2000

The effect of drought stress on inbreeding depression in four populations of the Mediterranean outcrossing plant Crepis sancta (Asteraceae).

The effect of physiological stress on the magnitude of inbreeding depression in plants has been the subject of few studies and is currently controversial because of contradictory results. We measured the inbreeding depression at three drought stress levels, precisely defined by a preliminary physiological experiment. We also tested the hypothesis that more highly self-compatible populations exhibit reduced inbreeding depression due to purging of deleterious mutations. The study was conducted on two populations of the annual and allogamous plant Crepis sancta collected from the French Mediterranean region and two other populations from marginal areas with various self-incompatibility levels. Drought stress did not increase inbreeding depression in terms of plant mortality but significantly increased the inbreeding depression for the date of first flowering, number of heads per plant and relative growth rate. The most self-fertile marginal population showed an absence of inbreeding depression in most of the measured traits indicating that purging could have taken place in this population. The three others populations showed relatively low and similar estimates of inbreeding depression (delta approximately 0.35). The relatively low values obtained compared to the results found in allogamous plants suggests that the absence of competition for C. sancta in our experiment probably underestimated the effects of inbreeding in natural populations where competition occurs.

Analysis of Variance↗

PubMed2001

Inbreeding depression in two populations of Arenaria uniflora (Caryophyllaceae) with contrasting mating systems.

I used parallel family-structured crossing designs to investigate the relative performance of self and outcross progeny in selfing and predominantly outcrossing populations of the annual plant Arenaria uniflora. The selfer population experienced much lower inbreeding depression (delta = 0.05 +/- 0.02 SE) than the outcrossers (delta = 0.19 +/- 0.02 SE). The negative association between genetic load and selfing rate suggests that purgable partially recessive alleles are the primary source of inbreeding depression, as does its late expression in both populations. Inbreeding depression in the selfer population, which naturally consists of highly inbred lines, was used to calculate the mean dominance (h = 0.33) and incidence rate (U = 0.30) of deleterious mutations. In the outcrosser population, significant variation among individuals in the expression of inbreeding depression may reflect lineage-specific differences in inbreeding history or, more probably, random variation in mutational load. The low (<< 0.5) inbreeding depression of outcrossers suggests that the maintenance of a mixed mating system in some A. uniflora populations and the evolution of nearly cleistogamous self-pollination in others may reflect local pollinator-mediated selection for selfing rather than the constant 3:2 genetic advantage invoked by many models.

Analysis of Variance↗

PubMed2001

Acetaminophen UDP-glucuronosyltransferase in ferrets: species and gender differences, and sequence analysis of ferret UGT1A6.

The principal objective of this study was to determine whether ferrets glucuronidate acetaminophen more slowly compared with other species, and if so investigate the molecular basis for the difference. Acetaminophen-UDP-glucuronosyltransferase (UGT) activities were measured using hepatic microsomes from eight ferrets, four humans, four cats, four dogs, rat, mouse, cow, horse, monkey, pig and rabbit. Gender differences between male and female ferret livers were explored using enzyme kinetic analysis. Immunoblotting of microsomal proteins was also performed using UGT-specific antibodies. Finally, the exon 1 region of UGT1A6, a major acetaminophen-UGT, was sequenced. Glucuronidation of acetaminophen was relatively slow in ferret livers compared with livers from all other species except cat. Gender differences were also apparent, with intrinsic clearance (Vmax/Km) values significantly higher in male compared with female ferret livers. Furthermore, Vmax values correlated with densitometric measurements of two protein bands identified with a UGT1A subfamily-specific antibody. No deleterious mutations were identified in the exon 1 or flanking regions of the ferret UGT1A6 gene. In conclusion, like cats, ferret livers glucuronidate acetaminophen relatively slowly. However, unlike cats, in which UGT1A6 is encoded by a pseudogene and dysfunctional, there are no defects in the ferret UGT1A6 gene which could account for the low activity.

Acetaminophen↗

PubMed2002

Extremely low levels of genetic polymorphism in endosymbionts (Buchnera) of aphids (Pemphigus).

Molecular evolutionary studies have suggested that vertically transmitted endosymbionts are subject to accumulation of deleterious mutations through genetic drift. Predictions of this hypothesis for patterns of intraspecific polymorphism were borne out in the single relevant study available, on the symbiont Buchnera aphidicola of Uroleucon ambrosiae. In order to examine the generality of this result, we surveyed DNA sequence variation in Buchnera of the distantly related aphid, Pemphigus obesinymphae. In contrast to Uroleucon species, Pemphigus species have complex life cycles with few dispersal stages. Despite these differences, P. obesinymphae showed patterns of variation at two Buchnera loci and one mitochondrial locus that were remarkably similar to those reported previously for Buchnera of U. ambrosiae. In the western US, Buchnera was nearly monomorphic, and in the eastern US, synonymous divergence ranged from 0.08 to 0.16%. Most polymorphisms involved rare alleles, consistent with a recent range of ancestral polymorphism, probably due to demographic fluctuations in aphid populations. These results support the generality of small effective population size in Buchnera and their aphid hosts.

Animals↗

PubMed1999

Emergence of recombinant strains of Helicobacter pylori during human infection.

Genetic recombination can be important evolutionarily in speeding the adaptation of organisms to new environments and in purging deleterious mutations. Here, we describe polymerase chain reaction (PCR), hybridization and DNA sequence-based evidence of six such exchanges between two strains of Helicobacter pylori during natural mixed infection of a patient in Lithuania. One parent strain contained the 37 kb long, virulence-associated cag pathogenicity island (PAI), and the other strain lacked this PAI. Most H. pylori from the patient had descended from the cag+ parent, but had become cag- during infection. This had resulted from transfer of DNA containing the 'empty site' allele from the cag- strain and homologous recombination, not from excision of the cag PAI without DNA transfer. Other cases of recombination involved genes for an outer membrane protein (omp5 and omp29; also called HP0227 and HP1342) and a putative phosphoenolpyruvate synthase (ppsA; HP0121). Replacement of a short patch of DNA sequence (36-124 bp) was also seen. As the chance of forming any given recombinant is small, the abundance of recombinants in this patient suggests selection for particular recombinant genotypes during years of chronic infection. We suggest that genetic exchange among unrelated H. pylori strains, as documented here, is important because of the diversity of this gastric pathogen and its human hosts. Certain H. pylori recombinants may grow better in a given host than either parent. The vigour of growth, in turn, could impact on the severity of disease that infection can elicit.

Adolescent↗

PubMed2004

Evolution of fungal sex chromosomes.

Sexual reproduction enables organisms to shuffle two parental genomes to produce recombinant progeny, and to purge the genome of deleterious mutations. Sex is conserved in virtually all organisms, from bacteria and fungi to plants and animals, and yet the mechanisms by which sexual identity are established share both conserved general features and are remarkably diverse. In animals, sexual identity is established by dimorphic sex chromosomes, whereas in fungi a specialized region of the genome, known as the mating-type locus, governs the establishment of cell type identity and differs in DNA sequence between cells of different mating-types. Recent studies on the mating-type loci of fungi and algae reveal features shared with the mammalian X and Y chromosomes, suggesting that these represent early steps in the evolution of sex chromosomes.

Animals↗

PubMed2002

Adaptive loss of ultraviolet-sensitive/violet-sensitive (UVS/VS) cone opsin in the blind mole rat (Spalax ehrenbergi).

In previous studies, fully functional rod and long-wavelength-sensitive (LWS) cone photopigments have been isolated from the eye of the subterranean blind mole rat (Spalax ehrenbergi superspecies). Spalax possesses subcutaneous atrophied eyes and lacks any ability to respond to visual images. By contrast this animal retains the ability to entrain circadian rhythms of locomotor behaviour to environmental light cues. As this is the only known function of the eye, the rod and LWS photopigments are thought to mediate this response. Most mammals are dichromats possessing, in addition to a single rod photopigment, two classes of cone photopigment, LWS and ultraviolet-sensitive/violet-sensitive (UVS/VS) with differing spectral sensitivities which mediate colour vision. In this paper we explore whether Spalax is a dichromat and has the potential to use colour discrimination for photoentrainment. Using immunocytochemistry and molecular approaches we demonstrate that Spalax is a LWS monochromat. Spalax lacks a functional UVS/VS cone photopigment due to the accumulation of several deleterious mutational changes that have rendered the gene nonfunctional. Using phylogenetic analysis we show that the loss of this class of photoreceptor is likely to have arisen from the visual ecology of this species, and is not an artefact of having an ancestor which lacked a functional UVS/VS cone photopigment. We conclude that colour discrimination is not a prerequisite for photoentrainment in this species.

Adaptation, Biological↗

PubMed2004

Human endogenous retrovirus K solo-LTR formation and insertional polymorphisms: implications for human and viral evolution.

Human endogenous retroviruses (HERVs) are a potential source of genetic diversity in the human genome. Although many of these elements have been inactivated over time by the accumulation of deleterious mutations or internal recombination leading to solo-LTR formation, several members of the HERV-K family have been identified that remain nearly intact and probably represent recent integration events. To determine whether HERV-K elements have caused recent changes in the human genome, we have undertaken a study of the level of HERV-K polymorphism that exists in the human population. By using a high-resolution unblotting technique, we analyzed 13 human-specific HERV-K elements in 18 individuals. We found that solo LTRs have formed at five of these loci. These results enable the estimation of HERV solo-LTR formation in the human genome and indicate that these events occur much more frequently than described in inbred mice. Detailed sequence analysis of one provirus shows that solo-LTR formation occurred at least three separate times in recent history. An unoccupied preintegration site also was present at this locus in two individuals, indicating that although the age of this provirus is estimated to be approximately 1.2 million years, it has not yet become fixed in the human population.

Endogenous Retroviruses↗

PubMed2005

Evidence from opsin genes rejects nocturnality in ancestral primates.

It is firmly believed that ancestral primates were nocturnal, with nocturnality having been maintained in most prosimian lineages. Under this traditional view, the opsin genes in all nocturnal prosimians should have undergone similar degrees of functional relaxation and accumulated similar extents of deleterious mutations. This expectation is rejected by the short-wavelength (S) opsin gene sequences from 14 representative prosimians. We found severe defects of the S opsin gene only in lorisiforms, but no defect in five nocturnal and two diurnal lemur species and only minor defects in two tarsiers and two nocturnal lemurs. Further, the nonsynonymous-to-synonymous rate ratio of the S opsin gene is highest in the lorisiforms and varies among the other prosimian branches, indicating different time periods of functional relaxation among lineages. These observations suggest that the ancestral primates were diurnal or cathemeral and that nocturnality has evolved several times in the prosimians, first in the lorisiforms but much later in other lineages. This view is further supported by the distribution pattern of the middle-wavelength (M) and long-wavelength (L) opsin genes among prosimians.

Adaptation, Biological↗

PubMed2006

Epistasis correlates to genomic complexity.

Whether systematic genetic interactions (epistasis) occur at the genomic scale remains a challenging topic in evolutionary biology. Epistasis should make a significant contribution to variation in complex traits and influence the evolution of genetic systems as sex, diploidy, dominance, or the contamination of genomes with deleterious mutations. We have collected data from widely different organisms and quantified epistasis in a common, per-generation scale. Simpler genomes, such as those of RNA viruses, display antagonistic epistasis (mutations have smaller effects together than expected); bacterial microorganisms do not apparently deviate from independent effects, whereas in multicellular eukaryotes, a transition toward synergistic epistasis occurs (mutations have larger effects together than expected). We propose that antagonistic epistasis might be a property of compact genomes with few nonpleiotropic biological functions, whereas in complex genomes, synergism might emerge from mutational robustness.

Animals↗

PubMed2006

Ameiotic recombination in asexual lineages of Daphnia.

Despite the enormous theoretical attention given to the evolutionary consequences of sexual reproduction, the validity of the key assumptions on which the theory depends rarely has been evaluated. It is often argued that a reduced ability to purge deleterious mutations condemns asexual lineages to an early extinction. However, most well characterized asexual lineages fail to exhibit the high levels of neutral allelic divergence expected in the absence of recombination. With purely descriptive data, it is difficult to evaluate whether this pattern is a consequence of the rapid demise of asexual lineages, an unusual degree of mutational stability, or recombination. Here, we show in mutation-accumulation lines of asexual Daphnia that the rate of loss of nucleotide heterozygosity by ameiotic recombination is substantially greater than the rate of introduction of new variation by mutation. This suggests that the evolutionary potential of asexual diploid species is not only a matter of mutation accumulation and reduced efficiency of selection, and [corrected] it underscores the limited utility of using neutral allelic divergence as an indicator of ancient asexuality.

Animals↗

PubMed2002

Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure.

Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in Rs1h, the murine ortholog of the human RS1 gene. We show that pathologic changes in hemizygous Rs1h(-/Y) male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and Rs1h(-/Y) mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.

Animals↗