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PubMed2003

Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers.

There is a critical need to understand why missense mutations are deleterious. The deleterious effects of missense mutations are commonly attributed to their impact on primary amino acid sequence and protein structure. However, several recent studies have shown that some missense mutations are deleterious because they disturb cis-acting splicing elements-so-called "exonic splicing enhancers" (ESEs). It is not clear whether the ESE-related deleterious effects of missense mutations are common. We have evaluated colocalization of pathogenic missense mutations (found in affected individuals) with high-score ESE motifs in the human mismatch-repair genes hMSH2 and hMLH1. We found that pathogenic missense mutations in the hMSH2 and hMLH1 genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a higher propensity for splicing defects. In contrast, nonpathogenic missense mutations (polymorphisms found in unaffected individuals) and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites shows that pathogenic effects of >/=20% of mutations in hMSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of >/=16% of missense mutations in the hMLH1 gene are ESE related. The colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related.

Adaptor Proteins, Signal Transducing↗

PubMed1990

Fitness of RNA virus decreased by Muller's ratchet.

Why sex exists remains an unsolved problem in biology. If mutations are on the average deleterious, a high mutation rate can account for the evolution of sex. One form of this mutational hypothesis is Muller's ratchet. If the mutation rate is high, mutation-free individuals become rare and they can be lost by genetic drift in small populations. In asexual populations, as Muller noted, the loss is irreversible and the load of deleterious mutations increases in a ratchet-like manner with the successive loss of the least-mutated individuals. Sex can be advantageous because it increases the fitness of sexual populations by re-creating mutation-free individuals from mutated individuals and stops (or slows) Muller's ratchet. Although Muller's ratchet is an appealing hypothesis, it has been investigated and documented experimentally in only one group of organisms--ciliated protozoa. I initiated a study to examine the role of Muller's ratchet on the evolution of sex in RNA viruses and report here a significant decrease in fitness due to Muller's ratchet in 20 lineages of the RNA bacteriophage phi 6. These results show that deleterious mutations are generated at a sufficiently high rate to advance Muller's ratchet in an RNA virus and that beneficial, backward and compensatory mutations cannot stop the ratchet in the observed range of fitness decrease.

Bacteriophages↗

PubMed2004

A primitive Y chromosome in papaya marks incipient sex chromosome evolution.

Many diverse systems for sex determination have evolved in plants and animals. One involves physically distinct (heteromorphic) sex chromosomes (X and Y, or Z and W) that are homozygous in one sex (usually female) and heterozygous in the other (usually male). Sex chromosome evolution is thought to involve suppression of recombination around the sex determination genes, rendering permanently heterozygous a chromosomal region that may then accumulate deleterious recessive mutations by Muller's ratchet, and fix deleterious mutations by hitchhiking as nearby favourable mutations are selected on the Y chromosome. Over time, these processes may cause the Y chromosome to degenerate and to diverge from the X chromosome over much of its length; for example, only 5% of the human Y chromosome still shows X-Y recombination. Here we show that papaya contains a primitive Y chromosome, with a male-specific region that accounts for only about 10% of the chromosome but has undergone severe recombination suppression and DNA sequence degeneration. This finding provides direct evidence for the origin of sex chromosomes from autosomes.

Alleles↗

PubMed2000

Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited cancer-prone syndrome. Here, we describe a novel and efficient approach for screening mutations of two major HNPCC susceptibility genes, hMSH2 and hMLH1. The system consists of RNA extraction from whole blood treated with the translation inhibitor, followed by long RT-PCR of the entire coding regions combined with direct sequencing. In analysis of 15 kindreds suspicious for HNPCC, 8 samples were subjected to analysis after puromycin treatment and 7 samples were analyzed without puromycin treatment. Three deleterious mutations were detected in the kindreds with puromycin treatment, while none were observed in those without puromycin. Signals from mutated alleles were enhanced after puromycin treatment and easily distinguished from the wild-type allele, achieved by suppression of nonsense-mediated mRNA decay. Furthermore, 12 other mutations were detected in 15 kindreds. The system is considered to be a reliable and useful approach for detecting germline mutations of hMSH2 and hMLH1 in HNPCC kindreds.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution.

Compensatory mutations, due to their ability to mask the deleterious effects of another mutation, are important for the adaptation and evolution of most organisms. Resistance to antibiotics, antivirals, antifungals, herbicides and insecticides is usually associated with a fitness cost. As a result of compensatory evolution, the initial fitness costs conferred by resistance mutations (or other deleterious mutations) can often be rapidly and efficiently reduced. Such compensatory evolution is potentially of importance for (i) the long-term persistence of drug resistance, (ii) reducing the rate of fitness loss associated with the accumulation of deleterious mutations in small asexual populations, and (iii) the evolution of complexity of cellular processes.

Amino Acid Sequence↗

PubMed2003

A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer.

A mutation analysis of the BRCA1 gene in 140 French families with a history of breast cancer or breast-ovarian cancer revealed several deleterious germline mutations, as well as rare sequence variants. The 19 genetics variants were of 15 different types, two of which had not been reported in the Breast cancer Information Core (BIC) database. Five distinct truncating mutations, leading to putative nonfunctional proteins, were identified out of 140 index cases (3.5%). One novel nonsense mutation, C4491T, was reported, whereas the four other BRCA1 deleterious mutations identified consisted of frequent frameshifts in the nucleotide sequence. One splice variant (331+3A>G) and thirteen missense variations leading to amino acid substitutions of unknown structural and functional importance were identified. Among these, two BRCA1 missense mutations, A120G and T243C could be considered as suspected deleterious. The first missense mutation modified the initiation codon (M1V) and the second (C39R) may have consequences on the structure and functioning of the BRCA1 protein by modifying cysteine ligands from the RING finger domain. As expected BRCA1 gene alteration, including missense mutations of unknown biological significance, were more frequent in families with a history of breast-ovarian-cancer (32%) than in breast-cancer-only families (12%).

Adult↗

PubMed1999

On the experimental design and data analysis of mutation accumulation experiments.

Characterizing deleterious genomic mutations is important. Most of the few current estimates come from the mutation-accumulation (M-A) approach, which has been extremely time- and labour-consuming. There is a resurgent interest in implementing this approach. However, its estimation properties under different experimental designs are poorly understood. By simulations we investigate these issues in detail. We found that many of the previous M-A experiments could have been more efficiently implemented with much less time and expense while still achieving the same estimation accuracy. If more than 100 lines are employed in M-A and if each line is replicated at least 10 times during each assay, an experiment of 10 M-A generations with two assays (at the beginning and at the end of M-A) may achieve at least the same estimation quality as a typical M-A experiment. The number of replicates per M-A line necessary for each assay largely depends on the magnitude of environmental variance. While 10 replicates are reasonable for assaying most fitness traits, many more are needed for viability, which has an exceptionally large environmental variance. The investigation is mainly carried out using Bateman-Mukai's method of moments for estimation. Estimation using Keightley's maximum likelihood is also investigated and discussed. These results should not only be useful for planning efficient M-A experiments, but also may help empiricists in deciding to adopt the M-A approach with manageable labour, time and resources.

Animals↗

PubMed2004

Mutational effects on the clonal interference phenomenon.

We study the process of fixation of beneficial mutations in an asexual population by means of a theoretical model. Particularly, we wish to investigate how the supply of deleterious and beneficial mutations influences the dynamics of the adaptive process of an evolving population. It is well known that the deleterious mutations drastically affect the fate of beneficial mutations. In addition, an increasing supply of favorable mutations, to compensate the decay of the fitness due to the accumulation of deleterious mutations, produces the clonal interference phenomenon where advantageous mutations in distinct lineages compete to reach fixation. This competition imposes a limit to the speed of adaptation of the population. Intuitively, we would expect that the interplay of the two mechanisms would conspire to ensure fixation of only large-effect beneficial mutations. Our results, however, show that beneficial mutations of small effect have an increased probability of fixation when both beneficial and deleterious mutations rates are increased.

Adaptation, Biological↗

PubMed1992

Deleterious mitochondrial DNA mutations accumulate in aging human tissues.

This paper reviews the current state of knowledge of the contribution of mitochondrial DNA (mtDNA) mutations to the phenotype of aging. Its major focus is on the discovery of deletions of mtDNA which previously were thought to occur only in individuals with neuromuscular disease. One particular deletion (mtDNA4977) accumulates with age primarily in non-dividing cells such as muscle and brain of normal individuals. The level of the deletion rises with age by more than 1000 fold in heart and brain and to a lesser extent in other tissues. In the brain, different regions have substantially different levels of the deletion. High levels of accumulation of the deletion in tissues are correlated with high oxygen consumption. We speculate that oxidative damage to mtDNA may be 'catastrophic'; mutations affecting mitochondrially encoded polypeptides involved in electron transport could increase free radical generation leading to more mtDNA damage.

Aging↗

PubMed2005

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

CONTEXT: The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used. OBJECTIVE: To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing. RESULTS: Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone. CONCLUSIONS: The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Breast cancer genetics in African Americans.

BACKGROUND: An overview of the state of genetic testing for BRCA1 and BRCA2 genes was presented at the Summit Meeting on Breast Cancer Among African American women. METHODS: An exhaustive literature search was performed using PubMed and abstracts published from meetings of the American Association for Cancer Research, the American Society of Human Genetics, and the American Society of Clinical Oncology. The Breast Cancer Information Core was also searched for information regarding sequence variants in which the ethnicity of the individual tested was known. RESULTS: Of the 26 distinct BRCA1 pathogenic mutations (protein-truncating, disease-associated missense, and splice variants) detected in Africans or African Americans, 15 (58%) have not been previously reported. In addition, 18 deleterious BRCA2 mutations have been identified and 10 (56%) of these are unique to the group. Only two pathogenic BRCA1 mutations (943ins10 and M1775R) have been detected in three or more unrelated families. However, seven additional BRCA1 or BRCA2 deleterious mutations have been reported in at least two unrelated families. Three of these recurrent BRCA1 mutations (943ins10, 1832del5, and 5296del4) have been characterized by haplotype studies and each likely arose from a common ancestor, including one ancestor that could be traced to the Ivory Coast in West Africa. Although only a few African-American families have been tested for BRCA1 and BRCA2 mutations, the probability of finding a mutation is invariably dependent on the age of onset and the number of breast and/or ovarian cancer cases in the family. The psychosocial implications of genetic testing for African Americans have not been well studied, so that high-risk African Americans may underestimate their risks of breast and ovarian cancer. CONCLUSIONS: Deleterious BRCA1 and BRCA2 mutations have been identified in African-American and African families. A number of unique mutations have been described, but recurrent mutations are widely dispersed and are not readily identifiable in the few families that have been tested. Access to genetic counseling and testing in a culturally sensitive research setting must remain a high priority before genetic testing can be disseminated in the community.

Black People↗

PubMed1990

Multiple domains of U1 snRNA, including U1 specific protein binding sites, are required for splicing.

Domains of U1 snRNA which are functionally important have been identified using a splicing complementation assay in Xenopus oocytes. Mutations in, and deletions of, all three of the hairpin loop structures near the 5' end of the RNA are strongly deleterious. Similarly, mutation of the Sm binding site abolishes complementation activity. Analysis of the protein binding properties of the mutant U1 snRNAs reveals that three of the functionally important domains, the first two hairpin loops and the Sm binding site, are required for interaction with U1 snRNP proteins. The fourth functionally important domain does not detectably affect snRNP protein binding and is not evolutionarily conserved. All of the deleterious mutations are shown to have similar effects on in vivo splicing complex formation.

Animals↗

PubMed2005

Strong biases in the transmission of sex chromosomes in the aphid Rhopalosiphum padi.

The typical life cycle of aphids involves several parthenogenetic generations followed by a single sexual one in autumn, i.e. cyclical parthenogenesis. Sexual females are genetically identical to their parthenogenetic mothers and carry two sex chromosomes (XX). Male production involves the elimination of one sex chromosome (to produce X0) that could give rise to genetic conflicts between X-chromosomes. In addition, deleterious recessive mutations could accumulate on sex chromosomes during the parthenogenetic phase and affect males differentially depending on the X-chromosome they inherit. Genetic conflicts and deleterious mutations thus may induce transmission bias that could be exaggerated in males. Here, the transmission of X-chromosomes has been studied in the laboratory in two cyclically parthenogenetic lineages of the bird cherry-oat aphid Rhopalosiphum padi . X-chromosome transmission was followed, using X-linked microsatellite loci, at male production in the two lineages and in their hybrids deriving from reciprocal crosses. Genetic analyses revealed non-Mendelian inheritance of X-chromosomes in both parental and hybrid lineages at different steps of male function. Putative mechanisms and evolutionary consequences of non-Mendelian transmission of X-chromosomes to males are discussed.

Animals↗

PubMed2004

Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis.

Mutations in mitochondrial DNA (mtDNA) cause excessive production of mitochondrial reactive oxygen species (ROS) and shorten animal life span. We examined the mechanisms responsible for removal of mitochondria with deleterious mtDNA mutations by autophagy. Incubation of primary cells and cell lines in the absence of serum promotes autophagy of mitochondria with deleterious mtDNA mutations but spares their normal counterparts. The effect of serum withdrawal on the autophagy of dysfunctional mitochondria is prevented by the addition of IGF-1. As a result of the elimination of mitochondria with deleterious mutations, excessive ROS production, characteristic of dysfunctional mitochondria, is greatly reduced. Mitochondrial autophagy shares a common mechanism with mitochondrial-induced cell apoptosis, including mitochondrial transition pore formation and increased ROS production.

Apoptosis↗

PubMed2004

Characterization of two novel BRCA1 germ-line mutations involving splice donor sites.

Deleterious BRCA1 mutations have significant clinical implications for the patients that carry them. Point mutations in critical functional domains and frameshift mutations that lead to early termination of protein translation are associated with a 60-80% risk of breast cancer and a 20-40% risk of ovarian cancer. In contrast, the significance of mutations located in intronic regions of BRCA1, even in the setting of a family history of breast and ovarian cancer, is not always clear. Some of these mutations occur in splice donor/acceptor consensus sites. These mutations can affect heteronuclear RNA (hnRNA) processing, leading to the loss of functional BRCA1 protein and thus may be disease-associated. However, it is important to verify the effect of these mutations, because splicing alterations cannot be predicted from genomic sequence alone. We report here the characterization of two novel BRCA1 mutations identified in families seen in our cancer risk evaluation clinic that alter splice donor sites of BRCA1. We show that both mutations alter transcript splicing and result in truncated BRCA1. IVS17 + 1G --> T leads to inclusion of part of intron 17 after the coding sequence of exon 17, resulting in early termination of BRCA1 protein following codon 1692. 252del5insT abolishes the splice donor site in exon 3, leading to the skipping of exon 5 and BRCA1 protein truncation following codon 45. Thus, both mutations result in loss of BRCA1 function, and carriers of these mutations should be counseled in the same manner as carriers of other truncating BRCA1 mutations.

BRCA1 Protein↗

PubMed1991

A study on a nearly neutral mutation model in finite populations.

As a nearly neutral mutation model, the house-of-cards model is studied in finite populations using computer simulations. The distribution of the mutant effect is assumed to be normal. The behavior is mainly determined by the product of the population size, N, and the standard deviation, sigma, of the distribution of the mutant effect. If 4N sigma is large compared to one, a few advantageous mutants are quickly fixed in early generations. Then most mutation becomes deleterious and very slow increase of the average selection coefficient follows. It takes very long for the population to reach the equilibrium state. Substitutions of alleles occur very infrequently in the later stage. If 4N sigma is the order of one or less, the behavior is qualitatively similar to that of the strict neutral case. Gradual increase of the average selection coefficient occurs and in generations of several times the inverse of the mutation rate the population almost reaches the equilibrium state. Both advantageous and neutral (including slightly deleterious) mutations are fixed. Except in the early stage, an increase of the standard deviation of the distribution of the mutant effect decreases the average heterozygosity. The substitution rate is reduced as 4N sigma is increased. Three tests of neutrality, one using the relationship between the average and the variance of heterozygosity, another using the relationship between the average heterozygosity and the average number of substitutions and Watterson's homozygosity test are applied to the consequences of the present model. It is found that deviation from the neutral expectation becomes apparent only when 4N sigma is more than two. Also a simple approximation for the model is developed which works well when the mutation rate is very small.

Computer Simulation↗

PubMed2001

Albinism and phenotype of barn swallows (Hirundo rustica) from Chernobyl.

The effects of mutation on phenotypic expression are supposed to be mainly deleterious because mutations disrupt the expression of genes that function relatively well under current environmental conditions. Thus, mutations are assumed to give rise to deviant phenotypes that are generally selected against. Radioactive contamination in the Chernobyl region of Ukraine is associated with a significant increase by a factor two to 10 in mutation rate in microsatellite markers of the barn swallow, Hirundo rustica. Barn swallows from Chernobyl had a temporally constant, elevated frequency of partial albinism compared to the situation before radioactive contamination and compared to birds from a control area. Albinism disproportionately affected the carotenoid-based plumage of the head, suggesting that carotenoid metabolism is particularly susceptible to the effects of radiation. Individuals with partially albinistic plumage had, on average, lower mean phenotypic values than other birds, and this was particularly the case for males. Furthermore, differences in phenotypic variation, as determined using Levene's test, were significantly larger in partial albinos compared to nonalbinos in males, but not in females, even though the null expectation would be the opposite due to the lower mean phenotypic values of partial albinos. Although small phenotypes were commonly associated with germline mutations, there was no general decrease in overall body size during the period 1991-2000, implying that small individuals were selected against. Because partial albinism is disfavored by natural selection, the effects of mutations are deleterious, giving rise to a balance between mutation and selection.

Albinism↗

PubMed1999

Evolutionary feedback: a new mechanism for stasis and punctuated evolutionary change based on integration of the organism.

This paper argues that organisms are integrated, holistic systems whose phenotypic traits and genes interact with each other and natural selection. More than this, organisms are feedback systems. I introduce the term integration of the organism to refer to this idea that organisms are such interacting systems. Integration of the organisms is a major reason why most mutations are deleterious, and why the larger a mutation's effect, the greater the probability that a mutation will be deleterious. Yet, it is also why macromutations can occasionally be adaptive. Such adaptive mutations of large effect, an example of which is neoteny, must be coordinated with the generic system and ontogeny of the organism. Integration of the organism and the ability of both the phenotype and genotype to influence and interact with natural selection means a species can undergo sequential evolution, a term I coin in this paper to refer to a change in a trait causing a change in selection on a second trait, which leads to a change in the second trait, which in turn causes a change in selection on a third trait, changing it, and so on. Sequential evolution can sometimes result in closed feedback loops, in which a trait farther down the sequence affects a trait earlier in the sequence of traits. I call this process evolutionary feedback. Both sequential evolution and evolutionary feedback can sometimes cause punctuated evolutionary change. Evolutionary feedback can also act as a mechanism for stasis. Hence, evolutionary feedback is a mechanism for punctuated equilibrium. I propose that species to a large extent influence, even drive, their own evolution. This, of course, is not to suggest they do so willfully or consciously. It is proposed that there are three mechanisms for punctuated evolutionary change; these are described. Examples of and evidence for sequential evolution and punctuated evolution by evolutionary feedback are presented.

Adaptation, Physiological↗