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PubMedDate not supplied

Does fitness erode in the absence of selection? An experimental test with Tribolium.

In the absence of natural selection, average fitness in the population is expected to decline due to the accumulation of deleterious mutations. Replicate populations of flour beetles (Tribolium confusum) were maintained for 22 generations in the virtual absence of selection (random mating, favorable environment, excess of food, and mortality of only 3%). Larva-to-adult survivorship rates were similar in the stock population and selection-free populations. In contrast, starvation resistance of adult beetles from selection-free populations was significantly reduced (by more than 2% per generation). When tested in the favorable environment, beetles in one selection-free population had significantly slower development and smaller sizes of females than beetles from the stock population. Since such changes in these fitness components are usually maladaptive, they indicate possible erosion of fitness under relaxed selection at the rate of 0.1-0.2% per generation. No fitness erosion was detectable in the second selection-free population.

Animals↗

PubMed2026

Genomic erosion in the assessment of species' extinction risk and recovery potential.

Many species are undergoing rapid population declines and environmental deterioration, leading to genomic erosion. Here we define genomic erosion as the loss of genetic diversity, accumulation of deleterious mutations, maladaptation, and introgression, all of which can undermine individual fitness and long-term population viability. Critically, this process continues even after demographic recovery due to a time-lagged impact of genetic drift, which is known as drift debt. Current conservation assessments, such as the International Union for Conservation of Nature Red List, focus on short-term extinction risk and do not capture the long-term consequences of genomic erosion. Likewise, the longer-term assessments of the International Union for Conservation of Nature Green Status may overestimate population recovery by failing to account for the enduring effects of genomic erosion. As genome sequencing becomes increasingly accessible, there is a growing opportunity to quantify genomic erosion and integrate it into conservation planning. Here, we use genomic simulations to illustrate how different genomic metrics are sensitive to the drift debt. We test how ancestral effective population size (Ne) and bottleneck history influence the tempo and severity of genomic erosion. Furthermore, we demonstrate how these dynamics shape genetic load and additive genetic variation, which are key indicators of long-term evolutionary potential. Finally, we present a proof-of-concept for a Genomic Green Status framework that aligns genomic metrics with conservation impact assessments, laying the foundation for genomics-informed strategies to support species recovery.

Extinction, Biological↗

PubMed1998

Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes.

BACKGROUND: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. METHODS: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. RESULTS: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. CONCLUSIONS: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.

Breast Neoplasms↗

PubMed2000

CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

BACKGROUND: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed. RESULTS: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years. CONCLUSIONS: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.

Adult↗

PubMed2003

Evidence of recombination in putative ancient asexuals.

Ancient asexuals have been considered to be a contradiction of the basic tenets of evolutionary theory. Barred from rearranging genetic variation by recombination, their reduced number of gene arrangements is thought to hamper their response to changing environments. For the same reason, it should be difficult for them to avoid the build-up of deleterious mutations. Several groups of taxonomically diverse organisms are thought to be ancient asexuals, although clear evidence for or against the existence of recombination events is scarce. Several methods have recently been developed for predicting recombination events by analyzing aligned sequences of a given region of DNA that all originate from one species. The methods are based on phylogenetic, substitution, and compatibility analyses. Here we present the results of analyses of sequence data from different loci studied in several groups of evolutionarily distant species that are considered to be ancient asexuals, using seven different types of analysis. The groups of organisms were the arbuscular mycorrhizal fungi (Glomales), Darwinula stevensoni (Darwinuloidea crustacean ostracods) and the bdelloid rotifers (Bdelloidea), which are thought to have been asexual for the last 400, 25-100, and 35-40 Myr, respectively. The seven different analytical methods evaluated the evolutionary relationships among haplotypes, and these methods had previously been shown to be reliable for predicting the occurrence of recombination events. Despite the different degree of genetic variation among the different groups of organisms, at least some evidence for recombination was found in all species groups. In particular, predictions of recombination events in the arbuscular mycorrhizal fungi were frequent. Predictions of recombination were also found for sequence data that have previously been used to infer the absence of recombination in bdelloid rotifers. Although our results have to be taken with some caution because they could signal very ancient recombination events or possibly other genetic variation of nonrecombinant origin, they suggest that some cryptic recombination events may exist in these organisms.

Animals↗

PubMed2003

Increased rates of sequence evolution in endosymbiotic bacteria and fungi with small effective population sizes.

Mutualistic, maternally transmitted endosymbiotic microorganisms undergo severe population bottlenecks at each host generation, resulting in a reduction in effective population size (Ne). Previous studies of Buchnera, the primary endosymbiont of aphids, and of several other species of endosymbiotic bacteria have shown that these species exhibit an increase in the rate of substitution of slightly deleterious mutations, among other predicted effects of increased drift due to small Ne, such as reduced codon bias. However, these studies have been limited in taxonomic scope, and it was therefore not clear whether the increase in rate is a general feature of endosymbiont lineages. Here, we test the prediction that a long-term reduction in Ne causes an increase in substitution rate using DNA sequences of the 16S rRNA gene from 13 phylogenetically independent comparisons between taxonomically diverse endosymbiotic microorganisms and their free-living relatives. Maximum likelihood and distance-based methods both indicate a significant increase in substitution rate in a wide range of bacterial and fungal endosymbionts compared to closely related free-living lineages. We use the same data set to test whether 16S genes from endosymbionts display increased A + T content, another indicator of increased genetic drift, and find that there is no significant difference in base composition between endosymbiont and nonendosymbiont 16S genes. However, analysis of an additional data set of whole bacterial genomes demonstrates that, while host-dependent bacteria have significantly increased genomic A + T content, the base content of the 16S gene tends to vary less than that of the whole genome. It is possible that selection for stability of rRNA is strong enough to overcome the effects of drift toward increased A + T content in endosymbiont 16S genes, despite the reduced effective population sizes of these organisms.

Animals↗

PubMed2004

The genomic rate of adaptive amino acid substitution in Drosophila.

The proportion of amino acid substitutions driven by adaptive evolution can potentially be estimated from polymorphism and divergence data by an extension of the McDonald-Kreitman test. We have developed a maximum-likelihood method to do this and have applied our method to several data sets from three Drosophila species: D. melanogaster, D. simulans, and D. yakuba. The estimated number of adaptive substitutions per codon is not uniformly distributed among genes, but follows a leptokurtic distribution. However, the proportion of amino acid substitutions fixed by adaptive evolution seems to be remarkably constant across the genome (i.e., the proportion of amino acid substitutions that are adaptive appears to be the same in fast-evolving and slow-evolving genes; fast-evolving genes have higher numbers of both adaptive and neutral substitutions). Our estimates do not seem to be significantly biased by selection on synonymous codon use or by the assumption of independence among sites. Nevertheless, an accurate estimate is hampered by the existence of slightly deleterious mutations and variations in effective population size. The analysis of several Drosophila data sets suggests that approximately 25% +/- 20% of amino acid substitutions were driven by positive selection in the divergence between D. simulans and D. yakuba.

Adaptation, Biological↗

PubMed1993

The importance of downstream delta-factor binding elements for the activity of the rpL32 promoter.

A salient feature of mammalian ribosomal protein genes is the location of promoter elements downstream, as well as upstream, of the transcriptional start point. Previous functional studies of the mouse rpL32 gene (Chung and Perry, Mol. Cell. Biol. 9, 2075; 1989) indicated that the first intron of this gene contains such an element. We show here that this element encompasses a binding site for a zinc finger nuclear protein known as delta (YY-1, muE1, UCRBP). The intronic delta site (delta i) is located 32 bp downstream of another delta site in the first exon (delta e). Transfection experiments with genes containing deleterious mutations in one or both delta sites or having alterations in the spacing between the sites indicate that the two delta elements function independently and contribute additively to the overall strength of the rpL32 promoter. Moreover, the contribution of the delta i element is the same whether it is oriented parallel or antiparallel to the delta e element. Together, the two delta elements raise the expression level about 10-fold over that attained by the upstream and initiator portions of the promoter. The positive role of the delta factor in rpL32 expression contrasts strikingly with its repressive role in various other genes.

Animals↗

PubMed2004

RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult.

Cell cycle checkpoints induced by DNA damage play an integral role in preservation of genomic stability by allowing cells to limit the propagation of deleterious mutations. The retinoblastoma tumor suppressor (RB) is crucial for the maintenance of the DNA damage checkpoint function because it elicits cell cycle arrest in response to a variety of genotoxic stresses. Although sporadic loss of RB is characteristic of most cancers and results in the bypass of the DNA damage checkpoint, the consequence of RB loss upon chemotherapeutic responsiveness has been largely uninvestigated. Here, we employed a conditional knockout approach to ablate RB in adult fibroblasts. This system enabled us to examine the DNA damage response of adult cells following acute RB deletion. Using this system, we demonstrated that loss of RB disrupted the DNA damage checkpoint elicited by either cisplatin or camptothecin exposure. Strikingly, this bypass was not associated with enhanced repair, but rather the accumulation of phosphorylated H2AX (gammaH2AX) foci, which indicate DNA double-strand breaks. The formation of gammaH2AX foci was due to ongoing replication following chemotherapeutic treatment in the RB-deficient cells. Additionally, peak gammaH2AX accumulation occurred in S-phase cells undergoing DNA replication in the presence of damage, and these gammaH2AX foci co-localized with replication foci. These results demonstrate that acute RB loss abrogates DNA damage-induced cell cycle arrest to induce gammaH2AX foci formation. Thus, secondary genetic lesions induced by RB loss have implications for the chemotherapeutic response and the development of genetic instability.

Animals↗

PubMed2001

Elevated rates of nonsynonymous substitution in island birds.

Slightly deleterious mutations are expected to fix at relatively higher rates in small populations than in large populations. Support for this prediction of the nearly-neutral theory of molecular evolution comes from many cases in which lineages inferred to differ in long-term average population size have different rates of nonsynonymous substitution. However, in most of these cases, the lineages differ in many other ways as well, leaving open the possibility that some factor other than population size might have caused the difference in substitution rates. We compared synonymous and nonsynonymous substitutions in the mitochondrial cyt b and ND2 genes of nine closely related island and mainland lineages of ducks and doves. We assumed that island taxa had smaller average population sizes than those of their mainland sister taxa for most of the time since they were established. In all nine cases, more nonsynonymous substitutions occurred on the island branch, but synonymous substitutions showed no significant bias. As in previous comparisons of this kind, the lineages with smaller populations might differ in other respects that tend to increase rates of nonsynonymous substitution, but here such differences are expected to be slight owing to the relatively recent origins of the island taxa. An examination of changes to apparently "preferred" and "unpreferred" synonymous codons revealed no consistent difference between island and mainland lineages.

Amino Acid Sequence↗

PubMed2001

Gene genealogies, cryptic species, and molecular evolution in the human pathogen Coccidioides immitis and relatives (Ascomycota, Onygenales).

Previous genealogical analyses of population structure in Coccidioides immitis revealed the presence of two cryptic and sexual species in this pathogenic fungus but did not clarify their origin and relationships with respect to other taxa. By combining the C. immitis data with those of two of its closest relatives, the free-living saprophytes Auxarthron zuffianum and Uncinocarpus reesii, we show that the C. immitis species complex is monophyletic, indicating a single origin of pathogenicity. Cryptic species also were found in both A. zuffianum and U. reesii, indicating that they can be found in both pathogenic and free-living fungi. Our study, together with a few others, indicates that the current list of known fungal species might be augmented by a factor of at least two. However, at least in the C. immitis, A. zuffianum, and U. reesii complexes, cryptic species represent subdivisions at the tips of deep monophyletic clades and thus well within the existing framework of generic classification. An analysis of silent and expressed divergence and polymorphism values between and within the taxa identified by genealogical concordance did not reveal faster evolution in C. immitis as a consequence of adaptation to the pathogenic habit, nor did it show positive Darwinian evolution in a region of a dioxygenase gene (tcrP gene coding for 4-HPPD) known to cause antigenic responses in humans. Instead, the data suggested relative stasis, indicative of purifying selection against mostly deleterious mutations. Two introns in the same gene fragment were considerably more divergent than exons and were unalignable between species complexes but had very low polymorphism within taxa.

4-Hydroxyphenylpyruvate Dioxygenase↗

PubMed2002

Asymmetric functional divergence of duplicate genes in yeast.

Most duplicate genes are eliminated from a genome shortly after duplication, but those that remain are an important source of biochemical diversity. Here, I present evidence from genome-scale protein-protein interaction data, microarray expression data, and large-scale gene knockout data that this diversification is often asymmetrical: one duplicate usually shows significantly more molecular or genetic interactions than the other. I propose a model that can explain this divergence pattern if asymmetrically diverging duplicate gene pairs show increased robustness to deleterious mutations.

Environment↗

PubMed1998

Preponderance of slightly deleterious polymorphism in mitochondrial DNA: nonsynonymous/synonymous rate ratio is much higher within species than between species.

We estimated synonymous (dN) and nonsynonymous (dS) substitution rates for protein-coding genes of the mitochondrial genome from two individuals each of the species human, chimpanzee, and gorilla. The genes were analyzed both separately and in a combined data set. Pairwise sequence comparisons suggest that the dN/dS rate ratios are about 5-10 times higher in within-species comparisons than in between-species comparisons. This result is confirmed by a more rigorous likelihood ratio test, which rejected the null hypothesis that the dN/dS rate ratios are identical within and between species. The likelihood models account for the genetic code structure, transition/transversion rate ratio, and codon usage bias and are expected to produce more reliable results than the commonly used contingency test. Separate analyses of different genes show that the dN/dS rate ratios are higher within species than between species for all 13 mitochondrial genes, with the difference being statistically significant for all except three small or slowly evolving genes. Furthermore, in conserved genes, nonsynonymous rates within species tend to be higher than the between-species rates by a greater proportion than in fast-changing genes. Our findings confirm and extend earlier results obtained from smaller data sets and suggest the operation of slightly deleterious mutations throughout the mitochondrial genome in the hominoids. Implications of the results for evolutionary studies and, in particular, for studies of the origin of modern humans, are discussed.

Adenosine Triphosphatases↗

PubMed1998

Improved tests for heterogeneity across a region of DNA sequence in the ratio of polymorphism to divergence.

The neutral theory of molecular evolution predicts that the ratio of polymorphisms to fixed differences should be fairly uniform across a region of DNA sequence. Significant heterogeneity in this ratio can indicate the effects of balancing selection, selective sweeps, mildly deleterious mutations, or background selection. Comparing an observed heterogeneity statistic with simulations of the heterogeneity resulting from random phylogenetic and sampling variation provides a test of the statistical significance of the observed pattern. When simulated data sets containing heterogeneity in the polymorphism-to-divergence ratio are examined, different statistics are most powerful for detecting different patterns of heterogeneity. The number of runs is most powerful for detecting patterns containing several peaks of polymorphism; the Kolmogorov-Smirnov statistic is most powerful for detecting patterns in which one end of the gene has high polymorphism and the other end has low polymorphism; and a newly developed statistic, the mean sliding G statistic, is most powerful for detecting patterns containing one or two peaks of polymorphism with reduced polymorphism on either side. Nine out of 27 genes from the Drosophila melanogaster subgroup exhibit heterogeneity that is significant under at least one of these three tests, with five of the nine remaining significant after a correction for multiple comparisons, suggesting that detectable evidence for the effects of some kind of selection is fairly common.

Animals↗

PubMed1994

Molecular evolution in the gnd locus of Salmonella enterica.

The gnd gene, the structural gene for 6-phosphogluconate dehydrogenase, was sequenced and analyzed in 34 isolates from different serovars of the seven subspecies of Salmonella enterica to provide comparative information on the evolution in this gene, which has been studied extensively in Escherichia coli. The gene tree obtained by the neighbor-joining method in general gave separate branches for each subspecies, with the few exceptions readily explained by recombination. There is evidence of recombination involving transfer of long (more than 400 bp) and short (30-150 bp) segments of DNA. Four of the six long-segment transfers detected are at the 5' end of the gene, and in all four cases a variant of the chi sequence is located close to the recombination junction and appears to have mediated the recombination events. We suggest that in these four cases and in a fifth case with intersubspecies transfer of the whole gnd gene, the adjacent rfb (O antigen) locus may have been transferred in the same event. The estimates of the number of synonymous substitutions per synonymous site, KS, and the number of nonsynonymous substitutions per nonsynonymous site, KA, within the E. coli and S. enterica gnd genes, and also between the two species show an interesting distribution, with KS being lower toward the ends of the gene and KA in particular being lower in the first than in the second domain. In S. enterica, synonymous sites also seem to be subjected to negative selection. The ratio of KA to KS was higher within S. enterica and E. coli than between them, which may indicate that intraspecies variation is essentially between clones and that mildly deleterious mutations can be fixed within clones, which would thus raise KA within species.

Amino Acid Sequence↗

PubMed2005

CD3 deficiencies.

PURPOSE OF REVIEW: The molecular characterization of inherited T-cell immunodeficiencies has contributed to delineating key factors in human T-cell development. This review reports on the recent description of deleterious mutations in the genes encoding CD3 subunits expressed at the T-lymphocyte membrane in association with the T-cell receptor. RECENT FINDINGS: Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype. Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes. These results contrast with the partial T-cell immunodeficiency caused by a deficiency in CD3G. SUMMARY: Two new severe combined immunodeficiency conditions have been reported as a consequence of either CD3D or CD3E deficiency. The distinct phenotype of CD3G deficiency sheds light on the differential roles of CD3 subunits in T-lymphocyte development.

CD3 Complex↗

PubMed1994

Sib competition and sperm competitiveness: an answer to 'why so many sperms?' and the recombination/sperm number correlation.

Sperm, or inter-ejaculate, competition leads to the evolution of many sperm per ejaculate. However, sperm competition theory does not predict the correlation between sperm number and chiasma, or that between sperm number and haploid chromosome number. Firstly, we show that phylogenetic inertia cannot account for at least the latter relation, and secondly, a model is presented which incorporates sib competition (intra-ejaculate competition) and sperm competitiveness to explain the relation between sperm numbers and recombination and the question 'Why so many sperms?'. It is argued that if there are deleterious mutations which affect sperm competitiveness this will lead to sib or intra-ejaculate competition. If inter-ejaculate competition also exists, then there will be selection for increased recombination. A chiasmate male heterozygous for n mutations which reduce sperm competitiveness can produce gametes with 0...n mutations. The proportion of gametes with 0 mutations per ejaculate is s = 0.5n, which is a small fraction. This means that to ensure on average one sperm with 0 mutations per ejaculate, a chiasmate male must produce 1/s sperm. We may therefore expect that 1/s will be positively correlated with sperm numbers. If inter-ejaculate competition leads to an optimum sperm number of x, then the optimum number of sperm per ejaculate is x/s. Sperm numbers will be increased by: (i) the number of loci which affect sperm competitiveness in the haploid state; (ii) the mutation rate; and (iii) the recombination rate. A correlation between recombination rates and sperm numbers is therefore to be expected.

Animals↗

PubMed2000

Heterosis increases the effective migration rate.

Individuals coming from the same subpopulation are more likely to share deleterious mutations at any given locus than hybrids formed between parents from different populations. Offspring of migrants therefore may experience heterosis and have higher fitness than resident individuals. This will, in turn, result in the immigrant alleles being present in higher frequencies than predicted from neutral expectations and thus a higher effective migration rate. In this paper we derive a formula to calculate the effective migration rate in the presence of heterosis. It is shown that the effect of heterosis on the migration rate can be substantial when fitness reduction within local populations is severe. The effect will be more pronounced in species with relatively short map lengths. Furthermore the heterosis effect will be highly variable throughout the genome, with the largest effect seen near selected genes and in regions of high gene density.

Emigration and Immigration↗