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PubMed2003

Opposites attract? Mate choice for parasite evasion and the evolutionary stability of sex.

If sex is naturally selected as a way to combat parasites, then sexual selection for disease resistance might increase the overall strength of selection for outcrossing. In the present study, we compared how two forms of mate choice affect the evolutionary stability of outcrossing in simultaneous hermaphrodites. In the first form, individuals preferred to mate with uninfected individuals (condition-dependent choice). In the second form, individuals preferred to mate with individuals that shared the least number of alleles in common at disease-resistance loci. The comparisons were made using individual-based computer simulations in which we varied parasite virulence, parasite transmission rate, and the rate of deleterious mutation at 500 viability loci. We found that alleles controlling both forms of mate choice spread when rare, but their effects on the evolutionary stability of sex were markedly different. Surprisingly, condition-dependent choice for uninfected mates had little effect on the evolutionary stability of sexual reproduction. In contrast, active choice for mates having different alleles at disease-resistance loci had a pronounced positive effect, especially under low rates of deleterious mutation. Based on these results, we suggest that mate choice that increases the genetic diversity of offspring can spread when rare in a randomly mating population, and, as an indirect consequence, increase the range of conditions under which sexual reproduction is evolutionarily stable.

Animals↗
PubMed2003

A naturally occurring substitution in human immunodeficiency virus Tat increases expression of the viral genome.

A natural amino acid substitution in the human immunodeficiency virus type 1 (HIV-1) transcriptional activator Tat increases its activity and compensates for deleterious mutations elsewhere in the Tat protein. Substitution of asparagine for threonine 23 increases Tat transactivation of the HIV-1 promoter and the binding of Tat to the cellular kinase positive transcription elongation factor b (P-TEFb). Of nine other position 23 mutations tested, only the serine substitution retained wild-type activity. Correspondingly, asparagine is the most frequent amino acid at this position in HIV-1 isolates, followed by threonine and serine. Asparagine is prevalent in Tat proteins of viruses in clades A, C, and D, which are major etiologic agents of AIDS. We suggest that selection for asparagine in position 23 confers an advantage to the virus, since it can compensate for deleterious mutations in Tat. It may also support the replication of otherwise less fit drug-resistant viruses and permit the emergence of virulent strains.

Amino Acid Sequence↗
PubMed2004

Error and repair catastrophes: A two-dimensional phase diagram in the quasispecies model.

This paper develops a two-gene, single fitness peak model for determining the equilibrium distribution of genotypes in a unicellular population which is capable of genetic damage repair. The first gene, denoted by sigma(via), yields a viable organism with first-order growth rate constant k>1 if it is equal to some target "master" sequence sigma(via,0). The second gene, denoted by sigma(rep), yields an organism capable of genetic repair if it is equal to some target "master" sequence sigma(rep,0). This model is analytically solvable in the limit of infinite sequence length, and gives an equilibrium distribution which depends on micro identical with Lepsilon, the product of sequence length and per base pair replication error probability, and epsilon(r), the probability of repair failure per base pair. The equilibrium distribution is shown to exist in one of the three possible "phases." In the first phase, the population is localized about the viability and repairing master sequences. As epsilon(r) exceeds the fraction of deleterious mutations, the population undergoes a "repair" catastrophe, in which the equilibrium distribution is still localized about the viability master sequence, but is spread ergodically over the sequence subspace defined by the repair gene. Below the repair catastrophe, the distribution undergoes the error catastrophe when micro exceeds ln k/epsilon(r), while above the repair catastrophe, the distribution undergoes the error catastrophe when micro exceeds ln k/f(del), where f(del) denotes the fraction of deleterious mutations.

Computer Simulation↗
PubMed2005

Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval 1-8) and 95% (95% confidence interval 91-99), respectively. In 97.9% of dominant cases, an IVS3-48C allele is co-inherited with the deleterious mutation. The frequency of the IVS3-48C allele differs widely in the Japanese (43%), southeast Asian (31%), white French (11%), North African (2.7%), and black West African (<1%) populations. These differences can be related to the prevalence of EPP in these populations and could account for the absence of EPP in black subjects. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yields an estimated age three to four times younger in the Japanese than in the white population, and this difference may be attributable either to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Finally, by calculating the KA/KS ratio in humans and chimpanzees, we show that the FECH protein sequence is subject to strong negative pressure. Overall, EPP looks like a Mendelian disorder, in which the prevalence of overt disease depends mainly on the frequency of a single common single-nucleotide polymorphism resulting from a unique mutational event that occurred 60,000 years ago.

Base Sequence↗
PubMed2005

Recombination enhances protein adaptation in Drosophila melanogaster.

Evolutionary theory predicts that the rate and level of adaptation will be enhanced in sexual relative to asexual genomes because sexual recombination facilitates the elimination of deleterious mutations and the fixation of beneficial ones by natural selection. To date, the most compelling evidence for this prediction comes from experimental evolution studies and from loci completely lacking recombination, such as those on Y chromosomes, which often show reduced adaptation and even degeneration. Here, by analyzing replacement and silent DNA polymorphism and divergence at 98 loci, I show that recombination increases the efficacy of protein adaptation throughout the genome of the fruit fly Drosophila melanogaster. Genes residing in genomic regions with reduced recombination rates suffer a greater load of segregating, mildly deleterious mutations and fix fewer beneficial mutations than genes residing in regions with higher recombination rates. These findings suggest that the capacity to respond to natural selection varies with recombination rate across the genome, consistent with theory on the evolutionary advantages of sex and recombination.

Adaptation, Biological↗
PubMed2004

Gene relics in the genome of the yeast Saccharomyces cerevisiae.

There is increasing evidence that DNA duplication is a common and ongoing process that plays a major role in molecular evolution of genomes and that a large fraction of the duplicated gene copies becomes non-functional by accumulation of deleterious mutations. In order to describe this phenomenon, we systematically searched the 6404 intergenic regions (IRs) of the genome of Saccharomyces cerevisiae for traces of coding sequences presenting degenerated but still recognizable sequence similarity with active open reading frames (5823 annotated ORFs). We detected a total of 124 anciently coding regions, or "gene relics", showing similarity to a total of 149 distinct active ORFs. This set of relics shows a continuum of sequence degeneration from those whose sequence is slightly altered compared to the functional ORF (classically defined as pseudogenes), to those that contains so many deleterious mutations, as to reach the limit of recognition. Gene relics are more concentrated in the subtelomeric regions of the chromosomes, reflecting the high plasticity of these regions. The presence of relics also revealed ancestral duplication events of chromosomal segments that were previously undetected. Some of these segments are intermingled with the more easily recognizable ancestral blocks of duplication, indicating successive duplication events. We present a compilation of all the data available, leading to a total of 278 pseudogenes in the genome of S. cerevisiae.

Chromosomes, Fungal↗
PubMed1996

High nucleotide sequence variation in a region of low recombination in Drosophila simulans is consistent with the background selection model.

We surveyed nucleotide sequence variation at glucose dehydrogenase (Gld), in a region of low recombination on chromosome 3R, from a population sample of Drosophila simulans. The levels of nucleotide variation were surprisingly high. There was no departure from the expectation of a neutral model for the level of polymorphism, indicating no evidence of a selective sweep in this region. There was a significant deficiency of singleton polymorphisms according to the Fu and Li test, although Tajima and Hudson, Kreitman, and Aguade (HKA) tests do not provide evidence of a significant elevation of variation due to balancing selection. Genetic map data for the D. simulans third chromosome were used to calculate expected values of pi for Gld under a current model of background selection, varying the values for the parameter sh (selection coefficient against deleterious mutations). We show that the recombinational landscape of D. simulans is sufficiently different from that of D. melanogaster that we expect higher variation under the background selection model, even when effective population sizes are assumed to be equal. The data for Gld were tested against the predictions using computer simulations of the distribution of the number of segregating sites conditioned on pi. Background selection alone can explain our observations as long as sh is larger than 0.005 and species-level effective population size is assumed to be several-fold larger than in D. melanogaster. Alternatively, the deleterious mutation rate may be smaller in D. simulans, or balancing selection may be acting nearby, thereby reducing the effect of background selection.

Animals↗
PubMed1999

Evidence for genetic drift in endosymbionts (Buchnera): analyses of protein-coding genes.

Buchnera, the bacterial endosymbionts of aphids, undergo severe population bottlenecks during maternal transmission through their hosts. Previous studies suggest an increased effect of drift within these strictly asexual, small populations, resulting in an increased fixation of slightly deleterious mutations. This study further explores sequence evolution in Buchnera using three approaches. First, patterns of codon usage were compared across several homologous Escherichia coli and Buchnera loci, in order to test the prediction that selection for the use of optimal codons is less effective in small populations. A chi 2-based measure of codon bias was developed to adjust for the overall A + T richness of silent positions in the endosymbionts. In contrast to E. coli homologues, adaptive codon bias across Buchnera loci is markedly low, and patterns of codon usage lack a strong relationship with gene expression level. These data suggest that codon usage in Buchnera has been shaped largely by mutational pressure and drift rather than by selection for translational efficiency. One exception to the overall lack of bias is groEL, which is known to be constitutively overexpressed in Buchnera and other endosymbionts. Second, relative-rate tests show elevated rates of sequence evolution of numerous protein-coding loci across Buchnera, compared to E. coli. Finally, consistently higher ratios of nonsynonymous to synonymous substitutions in Buchnera loci relative to the enteric bacteria strongly suggest the accumulation of nonsynonymous substitutions in endosymbiont lineages. Combined, these results suggest a decreased effectiveness of purifying selection in purging endosymbiont populations of slightly deleterious mutations, particularly those affecting codon usage and amino acid identity.

Animals↗
PubMed2003

The conservation of redundancy in genetic systems: effects of sexual and asexual reproduction.

The relationship between probability of survival and the number of deleterious mutations in the genome is investigated using three different models of highly redundant systems that interact with a threatening environment. Model one is a system that counters a potentially lethal infection; it has multiple identical components that act in sequence and in parallel. Model two has many different overlapping components that provide threefold coverage of a large number of vital functions. The third model is based on statistical decision theory: an ideal detector, following an optimum decision strategy, makes crucial decisions in an uncertain world. The probability of a fatal error is reduced by a redundant sampling system, but the chance of error rises as the system is impaired by deleterious mutations. In all three cases the survival profile shows a synergistic pattern in that the probability of survival falls slowly and then more rapidly. This is different than the multiplicative or independent survival profile that is often used in mathematical models. It is suggested that a synergistic profile is a property of redundant systems. Model one is then used to study the conservation of redundancy during sexual and asexual reproduction. A unicellular haploid organism reproducing asexually retains redundancy when the mutation rate is very low (0.001 per cell division), but tends to lose high levels of redundancy if the mutation rate is increased (0.01 to 0.1 per cell division). If a similar unicellular haploid organism has a sexual phase then redundancy is retained for mutation rates between 0.001 and 0.1 per cell division. The sexual organism outgrows the asexual organism when the above mutation rates apply. If they compete for finite resources the asexual organism will be extinguished. Variants of the sexual organism with increased redundancy will outgrow those with lower levels of redundancy and the sexual process facilitates the evolution of more complex forms. There is a limit to the extent that complexity can be increased by increasing the size of the genome and in asexual organisms this leads to progressive accumulation of mutations with loss of redundancy and eventual extinction. If complexity is increased by using genes in new combinations, the asexual form can reach a stable equilibrium, although it is associated with some loss of redundancy. The sexual form, by comparison, can survive, with retention of redundancy, even if the mutation rate is above one per generation. The conservation and evolution of redundancy, which is essential for complexity, depends on the sexual process of reproduction.

Genome↗
PubMed2006

Cell divisions are required for L1 retrotransposition.

LINE-1 (L1) retrotransposons comprise a large fraction of genomic DNAs of many organisms. Many L1 elements are active and may generate potentially deleterious mutations by inserting into genes, yet little is known about the control of retrotransposition by the host. Here we examined whether retrotransposition depends on the cell cycle by using a retrotransposition assay with cultured human cells. We show that in both cancer cells and primary human fibroblasts, retrotransposition was strongly inhibited in the cells arrested in the G(1), S, G(2), or M stage of the cell cycle. Retrotransposition was also inhibited during cellular senescence in primary human fibroblasts. The levels of L1 transcripts were strongly reduced in arrested cells, suggesting that the reduction in L1 transcript abundance limits retrotransposition in nondividing cells. We hypothesize that inhibition of retrotransposition in nondividing cells protects somatic tissues from accumulation of deleterious mutations caused by L1 elements.

Cell Division↗
PubMed2002

Reduced adaptation of a non-recombining neo-Y chromosome.

Sex chromosomes are generally believed to have descended from a pair of homologous autosomes. Suppression of recombination between the ancestral sex chromosomes led to the genetic degeneration of the Y chromosome. In response, the X chromosome may become dosage-compensated. Most proposed mechanisms for the degeneration of Y chromosomes involve the rapid fixation of deleterious mutations on the Y. Alternatively, Y-chromosome degeneration might be a response to a slower rate of adaptive evolution, caused by its lack of recombination. Here we report patterns of DNA polymorphism and divergence at four genes located on the neo-sex chromosomes of Drosophila miranda. We show that a higher rate of protein sequence evolution of the neo-X-linked copy of Cyclin B relative to the neo-Y copy is driven by positive selection, which is consistent with the adaptive hypothesis for the evolution of the Y chromosome. In contrast, the neo-Y-linked copies of even-skipped and roundabout show an elevated rate of protein evolution relative to their neo-X homologues, probably reflecting the reduced effectiveness of selection against deleterious mutations in a non-recombining genome. Our results provide evidence for the importance of sexual recombination for increasing and maintaining the level of adaptation of a population.

Adaptation, Biological↗
PubMed2005

Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.

INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.

Adult↗
PubMed1998

Required buried alpha-helical structure in the bilirubin UDP-glucuronosyltransferase, UGT1A1, contains a nonreplaceable phenylalanine.

A conserved hydrophobic region in the bilirubin-type UDP-glucuronosyltransferase isozyme was first uncovered as a consequence of a deleterious mutation in the UGT1A1 (HUG-Br1) isozyme of a Crigler-Najjar (CN) Type I patient. According to analysis by the RAOARGOS computer program, this hydrophobic region in UGT1A1 is located between residues 159-177 and defines a buried helix centered over position 169-172 with a positive factor of 1.22. Further analysis showed that the planar phenol-type UGT1A6 (HLUG P1) isoform, unlike the steroid-type UGT2B7 (UDPGTh2) isozyme, has a similar conserved hydrophobic region and that the positive factor for its buried helix is 1.14 compared to the threshold of 1.13 for such a structure. The analysis detected the typical membrane-insertion-signal sequence and a membrane-anchoring domain in each isoform. The different amino acid sequence patterns between positions 168-172 for the three types of isoforms and the deleterious mutations in this microregion (MRA) of UGT1A1 in CN-I patients are evidence of a critical and descriminating role for MRA. With the recombinant UGT1A1 enzyme and its mutants, P167G, F170del, F170L, F170I, F170V, F170A, F170Y, F170E, F171L, F171I, F171V, F171A, F171Y, or L175Q, expressed in COS-1 cells, bilirubin glucuronidating activity at both pH 6.4 and 7.6 demonstrated that Phe-170 is not replaceable, whereas Phe-171 can be replaced by Leu without any loss of activity. The less hydrophobic buried helix in the phenolic-type UGT1A6 has a Tyr/Leu at position 170/171; this isoform glucuronidated bilirubin at 1/10 the level of that by UGT1A1 with a Km (bilirubin) of 25 microM compared to that for UGT1A1 of 5. 0 microM.

Amino Acid Sequence↗
PubMed1989

Evolution of the major histocompatibility complex: independent origin of nonclassical class I genes in different groups of mammals.

The class I major histocompatibility complex genes are composed of classical and nonclassical genes, the latter being largely nonfunctional. To understand the evolutionary relationships of the two groups of class I genes, a phylogenetic analysis of DNA sequences was conducted using 45 genes from six mammalian and one avian species. The results indicate that nonclassical genes in one species are more closely related to classical genes from the same species than to nonclassical genes from a species belonging to a different order or family. This indicates that the differentiation of classical and nonclassical genes occurs rather rapidly in the genome. Classical genes are apparently duplicated with a high frequency in the evolutionary process, and many of the duplicated genes seem to degenerate into nonclassical genes as a result of deleterious mutation. The nonclassical Qa genes in the mouse have sequences homologous to regulatory sequences involved in the universal expression of classical class I genes, but they have accumulated numerous nucleotide substitutions in these sequences. The pattern of nucleotide substitution in nonclassical genes is different from that in classical genes. In nonclassical genes, the rate of nonsynonymous substitution is higher in the antigen recognition site than in other gene regions, as is true of classical genes. However, unlike the case of classical genes, the nonsynonymous rate does not always exceed the synonymous rate in the antigen recognition site. Nonclassical proteins further differ from classical proteins in having amino acid replacements in conserved antigen recognition site positions. These observations are consistent with the hypothesis that nonclassical genes have originated from classical genes but have lost classical class I function because of deleterious mutation.

Animals↗
PubMed2002

Lack of deleterious somatic mutations in the CD95 gene of plasmablasts from systemic lupus erythematosus patients and autoantibody-producing cell lines.

The interaction of CD95 with its ligand CD95L is important for negative selection of B cells during the germinal center (GC) reaction. Recently, mutations conferring resistance to CD95-induced apoptosis have been described for human GC B cells. Hence, as has been demonstrated for CD95-deficient mice, also GC-derived autoreactive B cells carrying somatic CD95 gene mutations may potentially service negative selection and participate in the development of autoimmune diseases. Here, single plasmablasts (PB) which are implicated in the production of autoantibodies in systemic lupus erythematosus (SLE) patients as well as ten human B cell lines producing autoantibodies were analyzed for destructive somatic CD95 gene mutations. However, inactivating CD95 gene mutations were very rare in PB and not detected in the cell lines. Sequence analysis of V gene rearrangements amplified from single PB confirmed that the cells are (post) GC B cells and additionally demonstrated massive clonal expansion of these cells in two of four SLE patients. We conclude that CD95 gene mutations play little if any role in the generation of the pool of PB in SLE patients and that mutations in the CD95 gene are rare among autoantibody-producing B cells in SLE and rheumatoid arthritis.

Autoantibodies↗
PubMed2002

Natural selection at linked sites in humans.

Theoretical and empirical work indicates that patterns of neutral polymorphism can be affected by linked, selected mutations. Under background selection, deleterious mutations removed from a population by purifying selection cause a reduction in linked neutral diversity. Under genetic hitchhiking, the rise in frequency and fixation of beneficial mutations also reduces the level of linked neutral polymorphism. Here we review the evidence that levels of neutral polymorphism in humans are affected by selection at linked sites. We then discuss four approaches for distinguishing between background selection and genetic hitchhiking based on (i) the relationship between polymorphism level and recombination rate for neutral loci with high mutation rates, (ii) relative levels of variation on the X chromosome and the autosomes, (iii) the frequency distribution of neutral polymorphisms, and (iv) population-specific patterns of genetic variation. Although the evidence for selection at linked sites in humans is clear, current methods and data do not allow us to clearly assess the relative importance of background selection and genetic hitchhiking in humans. These results contrast with those obtained for Drosophila, where the signals of positive selection are stronger.

Africa↗
PubMed1999

Identification of the gene responsible for gelatinous drop-like corneal dystrophy.

Gelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness, with an incidence of 1 in 300,000 in Japan. Our previous genetic linkage study localized the gene responsible to a 2.6-cM interval on chromosome 1p. Clinical manifestations, which appear in the first decade of life, include blurred vision, photophobia and foreign-body sensation. By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients. Here we report DNA sequencing, cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S170X) in M1S1 (formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-associated antigen. The Q118X mutation was the most common alteration in the GDLD patients examined, accounting for 33 of 40 (82.5%) disease alleles in our panel of families. Protein expression analysis revealed aggregation of the mutated, truncated protein in the perinuclear region, whereas the normal protein was distributed diffusely in the cytoplasm with a homogenous or fine granular pattern. Our successful identification of the gene that is defective in GDLD should facilitate genetic diagnosis and potentially treatment of the disease, and enhance general understanding of the mechanisms of amyloidosis.

Amyloidosis↗