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PubMed2006

Mutation, selection and the future of human evolution.

Several recent analyses provide growing evidence of the influence of positive selection acting in the ancestors of modern humans. Additionally, the best way to explain current fluctuations in neutral variation across the genome is by including negative selection against a high rate of deleterious mutants. We suggest that explaining these predicted high deleterious mutation rates in humans could require the inclusion of additional factors, such as inbreeding and prezygotic selection, in addition to rank-order selection and fitness interactions among mutations. We also suggest that some forms of selection, rather than being relaxed in modern humans, are probably still acting and might intensify in the near future, and make some predictions about the next several millennia of human evolution.

Evolution, Molecular↗

PubMed2002

Establishing a control population to screen for the occurrence of nineteen unclassified variants in the BRCA1 gene by denaturing high-performance liquid chromatography.

Numerous missense mutations in BRCA1 and BRCA2 are detected during clinical screening of breast and ovarian cancer patients. Because of the lack of a functional protein assay to determine the functional consequence of these mutations, patients are often frustrated by inconclusive results due to unclassified variants (UV). To determine whether a reported UV is also present in a control collective and therefore more likely be a rare polymorphism than a deleterious mutation, we collected a control population consisting of 95 females and 25 males aged over 60 years (mean 73 years) without a family history of BRCA associated cancers. The age of the control group is beyond the median onset of breast and ovarian cancer with a hereditary background. These controls were analysed for the presence of 19 known UVs in BRCA1 with the DHPLC technique. Only four of the 19 variants (R496H, R866C, S1040N and M1652I) were detected and can be considered polymorphims. However, no firm conclusion can be drawn about the functional relevance of the other 15 variants.

Aged↗

PubMed1989

Analysis of mutations causing steroid 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency is the most frequent cause of congenital adrenal hyperplasia, an inherited inability to synthesize cortisol. Mutations causing this disorder have been characterized by hybridization analysis of patient DNA samples using cDNA and oligonucleotide probes, and by cloning and sequencing of mutant 21-hydroxylase (CYP21B) genes. About 20% of mutant alleles carry a 30 kilobasepair deletion that includes the 3' end of the CYP21A pseudogene, the C4B complement gene, and the 5' end of CYP21B, leaving behind a single CYP21A-like gene that is not functional. Non-deletional mutations include a nonsense mutation at codon 318 that is associated with severe disease and missense mutations at codons 172 (isoleucine to asparagine) and 281 (valine to leucine) that are respectively associated with intermediate and mild deficiency states. All of these alleles have apparently resulted from gene conversion events that have transferred deleterious mutations from the CYP21A pseudogene to CYP21B. Thus, recombinations between CYP21A and CYP21B probably account for the majority of 21-hydroxylase deficiency alleles.

Adrenal Hyperplasia, Congenital↗

PubMed1998

Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada.

Familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor (LDLR) gene and is usually associated with hypercholesterolemia, lipid deposition in tissues, and premature coronary artery disease (CAD). However, individuals with heterozygous FH in China exhibit a milder phenotype despite having deleterious mutations in the LDLR gene (X.-M. Sun et al, Arterioscler Thromb. 1994;14:85-94). Nineteen Chinese FH heterozygotes living in Canada were screened for the 11 mutations that had been described in FH patients living in China. One Chinese Canadian carried one of these mutations (Trp462Stop), 2 carried a previously unreported single-base substitution (Cysl63Arg), and 1 carried a mutation observed in French-Canadian patients (Glu207Lys). Twelve additional carriers of these mutations were identified in the families of the index patients. Significantly higher LDL cholesterol concentrations were observed in FH heterozygotes with defined mutations living in Canada (mean+/-SD, 7.46+/-1.29, n=16) than in those living in China (4.35+/-1.09, n=18; P<.0001). Six of the 16 FH heterozygotes residingin Canada had evidence of tendon xanthomata and 4 had a history of premature CAD, whereas none of those in China had tendon xanthomata or CAD. Complete segregation between hypercholesterolemia and inheritance of a mutant allele was observed in 3 Canadian Chinese FH families. Thus, Chinese FH heterozygotes living in Canada exhibit a phenotype similar to that of other FH patients in Western societies. The difference between patients living in Canada and those living in China could be ascribed to differences in dietary fat consumption, showing that environmental factors such as diet play a significant role in modulating the phenotype of heterozygous FH.

Adult↗

PubMed2006

The distribution of fitness effects of new deleterious amino acid mutations in humans.

The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available. We apply the method to extensively sampled single-nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that >50% of mutations are likely to have mild effects, such that they reduce fitness by between one one-thousandth and one-tenth. We also infer that <15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a nonsynonymous mutation reduces fitness by a few percent and that the average strength of selection acting against a nonsynonymous polymorphism is approximately 9 x 10(-5). We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.

Alleles↗

PubMed2003

Restoration of Ig secretion: mutation of germline-encoded residues in T15L chains leads to secretion of free light chains and assembled antibody complexes bearing secretion-impaired heavy chains.

We previously described T15H chain mutants that were impaired in assembly with L chain and in ability to be secreted from the cell. The unmutated T15L chain is unusual in that it is secretion-impaired in the absence of assembly with H chain. The T15L chain preferentially pairs with T15H in vivo, suggesting that if we introduced mutations that would allow secretion of free T15L chain, they might also lead to the secretion of the complex with the defective H chain. We mutated four positions in the germline T15L that had amino acids infrequently found in other kappa-chains. Mutation to the most frequently occurring amino acid at three of the four positions allowed secretion of free L chain, while the combination of two secretion-restoring mutations was synergistic. Coexpression of secretion-restored mutant L chains with the secretion-defective mutant H chains rescued secretion of the assembled H(2)L(2) complex, suggesting that during somatic hypermutation in vivo, deleterious mutations at the H chain may be compensated by mutations on the L chain. To our knowledge, this is the first example of mutations in IgL chains that are able to restore secretion-defective H chains to secretion competence in mammalian cells.

Amino Acid Substitution↗

PubMed1993

Optimality, mutation and the evolution of ageing.

Evolutionary explanations of ageing fall into two classes. Organisms might have evolved the optimal life history, in which survival and fertility late in life are sacrificed for the sake of early reproduction and survival. Alternatively, the life history might be depressed below this optimal compromise by deleterious mutations: because selection against late-acting mutations is weaker, these will impose a greater load on late life. Evidence for the importance of both is emerging, and unravelling their relative importance presents experimentalists with a major challenge.

Adult↗

PubMed2005

Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis.

Juvenile polyposis syndrome is a hamartomatous intestinal polyposis associated with malignant changes in 20% of patients at an early age. Germline mutations mostly involve two genes, SMAD4 and BMPR1, with no strong evidence of phenotype-genotype correlation, which could be predictive of the specific long-term evolution. In contrast, PTEN mutations are more commonly associated with Cowden and related diseases. Forty-two unrelated patients affected by juvenile polyposis syndrome were analyzed for germline alterations in the BMPR1A and SMAD4 genes, and for clinical and histological features. Deleterious mutations were found in 14/42 (33%) patients: 5 in BMPR1A and 9 in SMAD4. Low-grade adenomas were present in both SMAD4 and BMPR1A mutation carriers; only patients with SMAD4 mutations harbored carcinoma lesions (5/9). Malformative vessels were present in all SMAD4 related polyps when the mutation involved codons prior to position 423. No gastric polyps were observed in BMPR1A mutation carriers. SMAD4 germline mutations are responsible for a more aggressive digestive phenotype in patients with juvenile polyposis. The presence of malformative vessels within the stromal component might be a useful tool to drive the subsequent genetic and clinical management.

Adolescent↗

PubMed2005

Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France.

The prevalence of BRCA1/2 germ-line mutations was assessed in a prospective population-based series of early-onset breast cancer (BC) patients in France, and the usefulness of a clinical assessment of hereditary BC risk, based on multiple criteria including pedigree structure, was evaluated. Through the Rhone region BC registry, 232 women diagnosed with BC before 46 years of age were included. They were tested for BRCA1/2 mutations an average of 10 months after diagnosis. All the women were classified according to their family history of cancer: high risk of hereditary breast cancer (HBC), low risk of HBC, isolated BC, and unknown HBC risk. Deleterious mutations were observed in 21 women (9.1%): 15 (6.5%) BRCA1 and 6 (2.6%) BRCA2. Mutations were more prevalent in women who developed BC before age 41 than in women who developed BC between ages 41 and 45 (12.8% versus 5.2%, respectively, P = 0.04). A high prevalence of BRCA1/2 mutations was found among women in the high-risk category with particular family features (i.e., small family size, predominantly male pedigree, specific cancers; 23.5%) and among women with isolated BC before age 41 and with five or fewer close adult female relatives (16.6%). According to the 10% probability level recommended by the American Society of Clinical Oncology guidelines for genetic testing of cancer, BRCA1/2 mutation screening should be considered for all women diagnosed before age 41, except for those with isolated BC in a large pedigree including multiple unaffected female relatives. The clinical assessment of HBC risk that we have developed should help in the decision to perform genetic testing.

Adolescent↗

PubMedDate not supplied

The Wilhelmine E. Key 1994 invitational Lecture. Plant genetic diversity and the struggle to measure selection.

The fundamental research program of population genetics has been to seek a quantitative assessment of the role of the various forces of evolution in shaping patterns of genetic variation. This goal has been pursued on both empirical and theoretical fronts. The introduction of biochemical and molecular techniques into population genetics more than 25 years ago revealed vast stores of genetic variation within populations. This level of genetic diversity is difficult to reconcile with balancing selection, and as a consequence, recent thinking has emphasized the role of mutation and genetic random drift as the primary determinants of genetic diversity. The resulting neutral theory of molecular evolution has dominated population genetic thought for more than 20 years. Nonadaptive theories have also emphasized the role of deleterious mutations in driving evolutionary change. New insights into the relative importance of selection and genetic random drift can now be obtained from samples of DNA sequences of genes drawn from within species. The elaboration of coalescence theory, together with the accumulation of data on gene genealogies, permits an integration over relatively long periods of evolutionary time. The ability to integrate over long periods of evolutionary time permits the detection of small selection intensities and it reveals some information about the mode of selection. When the genealogy is consistent with a neutral process, the effective population size can be estimated, as can the age of the coalescent, thus providing new empirical approaches to the estimation of these important parameters. Applications of these approaches in plant population genetics are still in their infancy, but they have already provided new insights into effective population sizes and they are beginning to illustrate how selection for domestication has affected plant genomes.

Chromosome Mapping↗

PubMedDate not supplied

Mutations of the BRCA1 gene in hereditary breast and ovarian cancer in the Czech Republic.

OBJECTIVE: Mutations in the BRCA1 gene confer a high risk for the development of breast or ovarian cancer. The aim of this study was to establish the frequency and spectrum of BRCA1 mutations in Czech breast or ovarian cancer families. SUBJECTS AND METHODS: We have screened 28 patients with early-onset cancer and 54 patients from risk families for germ-line mutations in BRCA1. All coding exons were analyzed by the protein truncation test (PTT) and the reverse transcription polymerase chain reaction (RT-PCR). Detected variants were characterized by direct sequencing of PCR products. RESULTS: Five distinct deleterious mutations have been identified in six families. All the mutations led to the premature termination of translation. One mutation was detected in a group of 11 (9.1%) patients with early-onset breast cancer. Two mutations were observed in 32 (6.3%) families with a history of breast cancer only. Three mutations were found in 22 (13.6%) families with both breast and ovarian cancer. The 5382insC mutation was the only abnormality detected twice. In addition, two variant transcripts, the loss of exon 5 and in-frame 3-bp deletion at the beginning of exon 8, were identified only at the cDNA level. Their biological significance remains unknown. CONCLUSION: PTT analysis enables examination of long PCR products. The technique is useful for rapid detection of mutations in hereditary breast cancer.

Adult↗

PubMed2003

Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers.

BACKGROUND: BRCA1 and BRCA2 alterations are associated with an increased risk of developing breast carcinoma. The authors hypothesized that the progression of breast neoplasia may differ between patients with hereditary disease and patients with nonhereditary disease and that this difference in progression may be visualized by studying the prevalence of precursor lesions and neoplastic lesions. METHODS: The authors developed two case cohorts of high-risk patients with a strong family history of breast carcinoma who underwent prophylactic mastectomy. The first cohort was comprised of women who underwent therapeutic mastectomy and contralateral prophylactic mastectomy, and the second cohort was comprised of women who underwent bilateral prophylactic mastectomy. Patients without a family history of breast carcinoma who underwent unilateral or bilateral prophylactic mastectomy were selected as a control group. DNA from peripheral blood leukocytes was screened for BRCA1 and BRCA2 mutations. The available pathologic materials were reviewed independently by two pathologists, and all neoplastic and precursor lesions were identified and classified. Proliferation activity was assessed using MIB-1 immunohistochemistry on all available lesions from the unilateral mastectomy cohort. RESULTS: The 28 women from the unilateral cohort with deleterious BRCA1/2 mutations had a lower prevalence of proliferative fibrocystic changes (PFC) (7%) compared with their matched control group (25%) (P = 0.075) and with patients who had a family history but no BRCA1/2 mutation (22-33%). None of the 11 deleterious mutation carriers from the bilateral cohort (0%) had PFC compared with 36% of women in the matched control group (P = 0.03). There was no major difference in the prevalence of other precursor lesions (including in situ carcinoma) in either cohort. Invasive carcinomas from the deleterious mutation carriers in the unilateral cohort were of higher grade compared with the control group (P = 0.003) and patients without a mutation (P < 0.0001) but were of similar grade compared with carriers of unclassified variant BRCA1/2 alterations (P = 0.20). Neoplastic lesions from the deleterious mutation carriers in the unilateral cohort had higher MIB-1 proliferation indices compared with other patients with and without a family history of breast carcinoma. CONCLUSIONS: The current data suggest that the progression rate of breast neoplasia is accelerated in women who carry BRCA1/2 deleterious mutations compared with other patients who have breast carcinoma with or without a family history. This increased progression rate should be taken into account when considering the surveillance of asymptomatic women.

Adenocarcinoma↗

PubMed1984

Evolutionary constraints and the neutral theory.

The neutral theory of molecular evolution postulates that nucleotide substitutions inherently take place in DNA as a result of point mutations followed by random genetic drift. In the absence of selective constraints, the substitution rate reaches the maximum value set by the mutation rate. The rate in globin pseudogenes is about 5 X 10(-9) substitutions per site per year in mammals. Rates slower than this indicate the presence of constraints imposed by negative (natural) selection, which rejects and discards deleterious mutations.

Animals↗

PubMed2005

Roles of E. coli double-strand-break-repair proteins in stress-induced mutation.

Special mechanisms of mutation are induced during growth-limiting stress and can generate adaptive mutations that permit growth. These mechanisms may provide improved models for mutagenesis in antibiotic resistance, evolution of pathogens, cancer progression and chemotherapy resistance. Stress-induced reversion of an Escherichia coli episomal lac frameshift allele specifically requires DNA double-strand-break-repair (DSBR) proteins, the SOS DNA-damage response and its error-prone DNA polymerase, DinB. We distinguished two possible roles for the DSBR proteins. Each might act solely upstream of SOS, to create single-strand DNA that induces SOS. This could upregulate DinB and enhance mutation globally. Or any or all of them might function other than or in addition to SOS promotion, for example, directly in error-prone DSBR. We report that in cells with SOS genes derepressed constitutively, RecA, RuvA, RuvB, RuvC, RecF, and TraI remain required for stress-induced mutation, demonstrating that these proteins act other than via SOS induction. RecA and TraI also act by promoting SOS. These and additional results with hyper-mutating recD and recG mutants support roles for these proteins via error-prone DSBR. Such mechanisms could localize stress-induced mutagenesis to small genomic regions, a potentially important strategy for adaptive evolution, both for reducing additional deleterious mutations in rare adaptive mutants and for concerted evolution of genes.

Alleles↗

PubMed1991

A test of Fisher's theory of dominance.

One of the first patterns noticed by geneticists was that mutations are almost always recessive to their wild-type alleles. Several explanations of this striking pattern have been offered. The two most influential are Fisher's theory--which argues that dominance results from natural selection against recurring deleterious mutations--and Wright's theory--which argues that dominance results from the physiology of gene action. The debate over which of these theories is correct represents one of the most protracted controversies in the history of evolutionary biology. Here I test Fisher's theory by assessing the dominance of mutations in an organism that is typically haploid, the alga Chlamydomonas reinhardtii. The results show that mutations are recessive just as often among haploid as among diploid species. This result falsifies Fisher's theory of dominance and provides strong support for the alternative physiological theory.

Alleles↗

PubMed1997

Neutral and nonneutral mutations: the creative mix--evolution of complexity in gene interaction systems.

Random drift, while indifferent to the functionality of the molecular features on which it acts, may nevertheless affect evolving molecular mechanisms. It can lead to functional novelty in either gene structure or regulation. In particular, a nearly neutral (in the sense of Ohta), somewhat deleterious mutation can result in a loss of efficiency in gene regulation, and this loss is expected at times to be compensated by a selected event of a particular type: the use of an additional regulatory factor. An accumulation of additional regulatory factors, implying a combination of events of drift and selection, can permit regulatory systems to achieve an increase in both specificity and complexity as mere byproducts of a particular repair process. Nearly neutral mutations thus may, at times, constitute a required pathway for increases in gene interaction complexity. The process seems to point to an inbuilt drive-built into the gene interaction system itself-toward the evolution of higher organisms. This is a matter worthy of experimental exploration, since the general foundations for the evolution of "higher" from "lower" organisms seems so far to have largely eluded analysis.

Animals↗

PubMed2000

BRCA1 mutation analysis in breast/ovarian cancer families from Greece.

Germline mutations in BRCA1 gene account for varying proportions of breast/ovarian cancer families, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations the entire coding sequence of BRCA1 in 30 breast/ovarian cancer women with family history of two or more cases of breast cancer under age 50 and/or ovarian cancer at any age. Genomic DNA from patient was initially analyzed for truncating mutations in exon 11 with PTT followed by DNA sequencing. In the cases where no frameshift mutation was observed in exon 11, all other exons were screened with direct sequencing. Two novel (3099delT, 3277insG) and three already described (3741insA, 1623del5-TTAAA, 5382insC-twice) truncating mutations were identified. In addition, 6 point mutations (L771L, P871L, E1038G, K1183R, S1436S, S1613G) which are already classified as polymorphisms were identified. Three unclassified intronic variants (IVS16-68 G>A, IVS16-92 G>A, IVS18+65G>A) were also detected. These results show that BRCA1 deleterious mutations are present in a fraction (20%) of Greek breast/ovarian cancer families similar to other European countries. Mutations were detected in high- (>/=3 members) as well as in moderate-risk (2 members) families. This is the first report of BRCA1 mutation analysis in Greece.

Adult↗

PubMed2005

Lethal mutagenesis of HIV.

HIV-1 and other retroviruses exhibit mutation rates that are 1,000,000-fold greater than their host organisms. Error-prone viral replication may place retroviruses and other RNA viruses near the threshold of "error catastrophe" or extinction due to an intolerable load of deleterious mutations. Strategies designed to drive viruses to error catastrophe have been applied to HIV-1 and a number of RNA viruses. Here, we review the concept of extinguishing HIV infection by "lethal mutagenesis" and consider the utility of this new approach in combination with conventional antiretroviral strategies.

APOBEC-3G Deaminase↗