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PubMed2025

Experimental Test of Evolutionary Safety of a CRISPR-Cas9 Gene-Drive Element.

CRISPR-Cas9 gene drives (CCGDs) are powerful tools for genetic control of wild populations, with applications from disease eradication to species conservation. However, Cas9 alone and in a complex with gRNA can cause double-stranded DNA breaks at off-target sites, which could increase the mutational load and lead to unintended loss-of-heterozygosity (LOH) events. These undesired effects raise potential concerns about the long-term evolutionary safety of CCGDs, but the magnitude of these effects is unknown. To measure how the presence of a CCGD or a Cas9 alone in the genome affects the rates of LOH events and de novo mutations, we carried out a mutation accumulation experiment in yeast Saccharomyces cerevisiae. We found no detectable effects on the genome-wide rates of mutations or LOH events. Our power calculations suggest that CCGD or Cas9 affect these rates by less than 30%, which is much less than natural variation for these traits in yeast. A more detailed examination shows that CCGD or Cas9 may alter the lengths and genomic distributions of LOH events, but the statistical support for these effects is weak. Thus, our results demonstrate that CCGDs impose at most a weak additional mutational burden in the yeast model. Although mutagenic effects of gene drives need to be further evaluated in other systems, our results add credence to the proposition that the evolutionary risks posed by well designed gene drives are likely acceptable.

Journal Article↗

PubMed1995

Mutagenesis and human genetic disease: dominant mutation frequencies and a characterization of mutational events in mice and humans.

Dominant deleterious traits are generally regarded to be the most relevant genetic endpoints when the expected increased mutational load of genetic diseases associated with exposure to mutagenic agents is considered in humans. At present, human risk estimation procedures rely on results from laboratory mammal germ-cell mutagenicity experiments as well as on data from human epidemiology and medical genetics. A comparison of the mouse and human data indicates that a small subset of loci, which when mutated result in a dominant phenotype, is contributing disproportionately to the observed mutation frequency. This is likely due to the fact that those loci with an observed high mutation frequency are inherently unstable, the function of such loci is critical, and/or the wild-type phenotype requires two copies of the normal gene (haploinsufficiency). The locus specificity of the observed spontaneous and induced mutation frequencies implies that efforts must be made to closely match those genetic endpoints screened in the mouse with the human genetic endpoints considered relevant in estimating the genetic risk after exposure to mutagenic agents. The contributions to our understanding of the organization, function, and stability of the mouse and human genomes provided by molecular biological techniques should make compliance with this restriction feasible.

Animals↗

PubMed2002

Selection, load and inbreeding depression in a large metapopulation.

The subdivision of a species into local populations causes its response to selection to change, even if selection is uniform across space. Population structure increases the frequency of homozygotes and therefore makes selection on homozygous effects more effective. However, population subdivision can increase the probability of competition among relatives, which may reduce the efficacy of selection. As a result, the response to selection can be either increased or decreased in a subdivided population relative to an undivided one, depending on the dominance coefficient F(ST) and whether selection is hard or soft. Realistic levels of population structure tend to reduce the mean frequency of deleterious alleles. The mutation load tends to be decreased in a subdivided population for recessive alleles, as does the expected inbreeding depression. The magnitude of the effects of population subdivision tends to be greatest in species with hard selection rather than soft selection. Population structure can play an important role in determining the mean fitness of populations at equilibrium between mutation and selection.

Animals↗

PubMed1999

High frequency of cryptic deleterious mutations in Caenorhabditis elegans.

Deleterious mutations with very small phenotypic effects could be important for several evolutionary phenomena, but the extent of their contribution has been unknown. Fitness effects of induced mutations in lines of Caenorhabditis elegans were measured using a system for which the number of deleterious point mutations in the DNA can be estimated. In fitness assays, only about 4 percent of the deleterious mutations fixed in each line were detectable. The remaining 96 percent, though cryptic, are significant for mutation load and, potentially, for the evolution of sex.

Animals↗

PubMed1998

Fetal origin of maturity-onset diabetes mellitus: genetic or environmental cause?

Low birthweight is a risk factor for a number of diseases of adult life including non-insulin-dependent diabetes mellitus (NIDDM). This implies that either genetic constitution or factors operating during intrauterine development have a causal role in NIDDM. One reason for rejecting a genetic cause, however, is that there is a rapidly changing prevalence of NIDDM with the onset and establishment of affluence, which does not fit with conventional models of multifactorial genetic disease. But in this article a new model of genetic disease based on the concept of redundancy is explored. The idea is that mutant genes interact synergistically in highly redundant systems to degrade performance and increase the risk of disease. The mutational load is in turn determined by the pre-conceptual environment. This model can explain a rapidly changing prevalence of NIDDM.

Age of Onset↗

PubMed2000

Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene.

AIMS: To clarify the phenotype-genotype relation associated with the A3243G mitochondrial DNA mutation. METHODS: Five unrelated probands harbouring the A3243G mutation but presenting different clinical phenotype were analysed. Probands include Leigh syndrome (LS(3243)), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS(3243)), progressive external ophthalmoplegia (PEO(3243)), and mitochondrial diabetes mellitus (MDM(3243)). Extensive clinical, histological, biochemical, and molecular genetic studies were performed on five families. RESULTS: All patients showed ragged red fibres (RRF), and focal cytochrome c oxidase (COX) deficiency except for the patient with MDM(3243). The mutation load was highest in the proband with LS(3243) (>90%), who also presented the highest proportion of RRF (68%) and COX negative fibres (10%), and severe complex I plus IV deficiency. These proportions were lower in the probands with PEO(3243) and with MDM(3243). CONCLUSION: The most severe clinical phenotype, LS(3243), was associated with the highest proportion of the A3243G mutation as well as the most prominent histological and biochemical abnormalities.

Adolescent↗

PubMed2003

The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients.

Impaired skeletal muscle oxidative phosphorylation in patients with severe mitochondrial respiratory chain defects results in disabling exercise intolerance that is associated with a markedly blunted capacity of muscle to increase oxygen utilization in relation to circulatory and ventilatory responses that increase oxygen delivery to muscle during exercise. The range of oxidative limitation and the relationship between the severity of oxidative defects and physiological responses to exercise among a broader spectrum of mitochondrial respiratory chain defects has not been defined. We evaluated oxidative capacity and circulatory and ventilatory responses to maximal cycle exercise in 40 patients with biochemically and/or molecularly defined mitochondrial myopathy (MM) associated with varying levels of exercise tolerance, and compared responses with those in healthy sedentary individuals. In the MM patients, mean peak work capacity (0.88 +/- 0.6 W/kg) and oxygen uptake (VO(2), 16 +/- 8 ml/kg/min) were significantly lower (P < 0.01) than in controls (mean work capacity = 2.2 +/- 0.7 W/kg; VO(2) = 32 +/- 7 ml/kg/min), but the patient range was broad (0.17-3.2 W/kg; 6-47 ml/kg/min). Oxidative capacity in patients was limited by the ability of muscle to extract available oxygen from blood [mean peak systemic arteriovenous O(2) difference (a-vO(2)); patients = 7.7 +/- 3.5, range 2.7-17.6 ml/dl, controls = 15.2 +/- 2.1 ml/dl], as indicated by a linear correlation between peak VO(2) and peak systemic a-vO(2) difference (r(2) = 0.69). In the patients, the increase in cardiac output relative to VO(2) (mean DeltaQ/DeltaVO(2) = 15.0 +/- 13.6; range 3.3-73) and ventilation (mean peak VE/VO(2) = 65 +/- 24; range 21-104) were exaggerated compared with controls (mean DeltaQ/DeltaVO(2) = 5.1 +/- 0.7; VE/VO(2) = 41.2 +/- 7.4, P < 0.01). There was a negative exponential relationship between DeltaQ/DeltaVO(2) and peak systemic a-vO(2) difference (r(2) = 0.92) and between peak VE/VO(2) and systemic a-vO(2) difference (r(2) = 0.53). In patients with heteroplasmic mtDNA mutations, we found an inverse relationship between the proportion of skeletal muscle mutant mtDNA and peak extraction of available oxygen during exercise (r(2) = 0.70). We conclude that the degree of exercise intolerance in MM correlates directly with the severity of impaired muscle oxidative phosphorylation as indicated by the peak capacity for muscle oxygen extraction. Exaggerated circulatory and ventilatory responses to exercise are direct consequences of the level of impaired muscle oxidative phosphorylation and increase exponentially in relation to an increasing severity of oxidative impairment. In patients with mtDNA mutations, muscle mutation load governs mitochondrial capacity for oxidative phosphorylation and determines exercise capacity.

Adolescent↗

PubMed2005

Exercise and training in mitochondrial myopathies.

The intriguing concept of exercise training as therapy for mitochondrial disease is currently unsettled: in the unique setting of mitochondrial heteroplasmy, what are the effects of chronic exercise on skeletal muscle containing a mixture of mutated and wild-type mitochondrial DNA (mtDNA)? Furthermore, what are the consequences of habitual physical inactivity on mitochondrial heteroplasmy? In patients with mtDNA defects, deleterious effects of limited physical activity likely magnify the mitochondrial oxidative impairment contributing to varying degrees of exercise intolerance. Normal adaptive responses to endurance training offer the potential to increase levels of functional mitochondria, improving exercise tolerance. The few clinical studies assessing such training effects in patients with mtDNA defects have unequivocally demonstrated physiologic and biochemical adaptations that improve exercise tolerance and quality of life. Uncertain, however, is the training effect on mitochondrial heteroplasmy. To determine therapeutic advisability of endurance training, it remains imperative to establish whether: reported increases in mutant mtDNA levels can be offset by increases in absolute wild-type mtDNA levels; and chronic physical inactivity leads to a selective down-regulation of wild-type mtDNA. Resistance exercise training offers an alternate, innovative therapeutic approach in patients with sporadic mtDNA mutations; exercise-induced transfer of normal mtDNA templates from muscle satellite cells to mature myofibers, thereby lowering mutation load (increasing functional mitochondrial load). Efficacy and safety of this approach needs to be replicated in a larger group of patients. Currently, appropriate recommendation (either in support or against) exercise training in mitochondrial disease is lacking, which is frustrating for physicians and disheartening for patients. Although considerable progress has been made, an immediate urgency exists to resolve the effects of chronic exercise on skeletal muscle in patients with heteroplasmic mtDNA mutations.

DNA, Mitochondrial↗

PubMed1998

Mutation-selection balance with multiple alleles.

Human genetic disorders provide an extraordinary richness of data on the diversity of defective alleles. Well over 100 defective alleles for each of several human genetic disorders have been identified, including breast cancer (BRCA1), cystic fibrosis (CFTR), muscular dystrophy (DZM), and phenylketonuria (PAH). These observations raise the classical question of balance between the action of mutation generating new defective alleles and selection removing those alleles from the population. The problem of multiple-allele, mutation-selection balance was considered by Crow and Kimura, who obtained some approximate results showing that the level of dominance and degrees of interallelic complementation are important in determining the equilibrium allele frequencies. Here those deterministic results are reviewed and extended, showing that there are conditions yielding surprisingly high equilibrium frequencies of defective alleles. Just as the equilibrium mutation load is independent of the level of dominance, it is also independent of the number of defective alleles.

Alleles↗

PubMed2003

The mitochondrial theory of aging: dead or alive?

The mitochondrial theory of aging is based around the idea of a vicious cycle, in which somatic mutation of mtDNA engenders respiratory chain dysfunction, enhancing the production of DNA-damaging oxygen radicals. In turn, this is proposed to result in the accumulation of further mtDNA mutations. Finally, a bioenergetic crisis leads to overt tissue dysfunction and degeneration. A substantial body of circumstantial evidence seems to support this idea. However, the extent of detectable mtDNA mutation is far less than can easily be reconciled to this hypothesis, unless it is assumed that a subset of cells with much higher than average mtDNA mutation load is systematically lost by apoptosis. A rigorous test of the hypothesis remains to be undertaken, but would require a direct manipulation of the rate of mtDNA mutagenesis, to test whether this could alter the kinetics of aging.

Aging↗

PubMed1975

Human genetic studies in areas of high natural radiation. VIII. Genetic load not related to radiation.

The genetic load disclosed by inbreeding has been analyzed in a multiple regression model for a population involving several localities in the state of Espírito Santo, Brazil. The inbreeding load has been estimated for number of pregnancies, abortions, stillbirths, children born alive, anomalies in general, sex ratio, infant mortality, post-infant mortality, and sterility and infertility of the couple. There was no evidence of either maternal or paternal inbreeding effects on the variables analyzed. The effect of inbreeding of the zygote was significant only for anomalies in general (B = 2.29 +/- 0.45) and infant mortality (B = 3.19 +/- 1.39). The latter result must be accepted with caution because of the many environmental causes affecting infant mortality. The B/A ratio suggested a predominantly mutational load for anomalies in general (B/A = 25), but with respect to infant mortality (B/A = 6), the ratio is regarded as an underestimate because of the environmental contribution to A and therefore not supportive of the segregational interpretation.

Abnormalities, Radiation-Induced↗

PubMed2001

Sexual selection and the maintenance of sex.

Sex is expensive. A population of females that reproduce asexually should prima facie have twice the growth rate of an otherwise equivalent anisogamous sexual population lacking paternal care, or a population with modes of paternal care that can be co-opted by parthenogenetic females. The two leading theories for the maintenance of sex require either synergistic interactions between deleterious mutations, or antagonistic epistasis between beneficial mutations. Current evidence is equivocal as to whether the required levels of epistasis exist. Here I show that a third factor, differential male mating success (or, more generally, higher variance in male than in female fitness), can drastically reduce mutational load in sexual populations with or without any form of epistasis. Differential mating success has the further advantage of being ubiquitous, and is likely to have preceded or evolved concurrently with anisogamy.

Animals↗

PubMed2007

Characteristics, causes and evolutionary consequences of male-biased mutation.

Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, alpham, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, alpham is estimated at approximately 4-6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in alpham. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex.

Cell Division↗

PubMed2003

Delineating the requirements for spontaneous DNA damage resistance pathways in genome maintenance and viability in Saccharomyces cerevisiae.

Cellular metabolic processes constantly generate reactive species that damage DNA. To counteract this relentless assault, cells have developed multiple pathways to resist damage. The base excision repair (BER) and nucleotide excision repair (NER) pathways remove damage whereas the recombination (REC) and postreplication repair (PRR) pathways bypass the damage, allowing deferred removal. Genetic studies in yeast indicate that these pathways can process a common spontaneous lesion(s), with mutational inactivation of any pathway increasing the burden on the remaining pathways. In this study, we examine the consequences of simultaneously compromising three or more of these pathways. Although the presence of a functional BER pathway alone is able to support haploid growth, retention of the NER, REC, or PRR pathway alone is not, indicating that BER is the key damage resistance pathway in yeast and may be responsible for the removal of the majority of either spontaneous DNA damage or specifically those lesions that are potentially lethal. In the diploid state, functional BER, NER, or REC alone can support growth, while PRR alone is insufficient for growth. In diploids, the presence of PRR alone may confer a lethal mutation load or, alternatively, PRR alone may be insufficient to deal with potentially lethal, replication-blocking lesions.

Alleles↗

PubMed2004

Monomelic amyotrophy associated with the 7472insC mutation in the mtDNA tRNASer(UCN) gene.

We describe a 49-year-old male patient who experienced progressive amyotrophy with no sensorial abnormality in the left arm since 45 years of age. The neuromuscular syndrome was identical to that known as Hirayama disease, a rare form of focal lower motor neuron disease affecting the C7-C8-T1 metamers of the spinal cord. Asymmetric neurosensorial hearing loss was present since age 35 in the patient, and was also documented in an elder sister and in the mother. A muscle biopsy showed cytochrome c oxidase (COX) negative fibers but no ragged-red fibers, and mild reduction of COX was confirmed biochemically. The patient was found to have high levels of a known pathogenic mutation of mtDNA, the 7472insC in the gene encoding the tRNA(Ser(UCN)). Investigation on several family members showed a correlation between mutation load and clinical severity. This is the second report documenting the association of lower motor neurone involvement with a specific mtDNA.

DNA, Mitochondrial↗

PubMed2003

No slave to sex.

Fully asexual lineages cannot purge accumulating mutations from their genome through recombination. In ancient asexuals that have persisted without sex for millions of years, this should lead to high allelic divergences (the 'Meselson effect') as has been shown for bdelloid rotifers. Homogenizing mechanisms can counter this effect, resulting in low genetic diversity within and between individuals. Here, we show that the ancient asexual ostracod species Darwinula stevensoni has very low nucleotide sequence divergence in three nuclear regions. Differences in genetic diversity between embryos and adults furthermore indicate that up to half of the observed genetic changes in adults can be caused by somatic mutations. Likelihood permutation tests confirm the presence of gene conversion in the multi-copy internal transcribed spacer sequence, but reject rare or cryptic forms of sex as a general explanation for the low genetic diversity in D. stevensoni. Other special mechanisms (such as highly efficient DNA repair) might have been selected for in this ancient asexual to overcome the mutational load and Muller's ratchet. In this case, our data support these hypotheses on the prevalence of sex, even if the two extant ancient asexual groups (bdelloids and darwinulids) seem to follow opposite evolutionary strategies.

Animals↗

PubMed2006

Microdissection genotyping analysis of the effect of intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland adenoid cystic carcinoma.

PURPOSE: To investigate the feasibility of integrating molecular analysis into standard histopathology for lacrimal gland adenoid cystic carcinoma (ACC), and to gain insights into the molecular pathogenesis of this tumor and its response to intraarterial cytoreductive chemotherapy (IACC) that is of clinical use. DESIGN: A retrospective, comparative case series. METHODS: setting: Institutional. patient population: Nine consecutive patients with lacrimal gland ACC were treated with IACC, followed by orbital exenteration and chemoradiotherapy. This case series was compared with a series of seven patients treated by conventional local therapies. intervention procedure: Gene analysis was performed on microdissected tissue samples. Mutational allelotyping targeting nine genomic loci was performed with 15 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes serving as markers for the presence of gene deletion. main outcome measure: A fractional mutation index was used to compare the acquired mutational load between different tumors having nonidentical patterns of microsatellite informativeness. RESULTS: Allelic imbalance (loss of heterozygosity [LOH]) for microsatellite markers at 1p36 was the single most common site affected by imbalance in this series, followed by LOH in temporal sequence involving 9p21, 22q12, 10q23, and 9q22. CONCLUSIONS: Microdissection genotyping holds promise as a clinical tool in integrating molecular analysis into standard histopathology to advance the understanding of lacrimal gland ACC tumorigenesis. A unique time course for temporal mutation acquisition in ACC is proposed, consisting of 1p36 loss first. Allelic loss for microsatellite markers at 1p36 may be a common as well as an early event in ACC formation and progression.

Adult↗

PubMed2002

In situ analysis of the variable heavy chain gene of an IgM/IgG-expressing follicular lymphoma: evidence for interfollicular trafficking of tumor cells.

It is generally assumed that follicular lymphomas (FL) not only morphologically resemble normal germinal centers but have retained some functional characteristics of their non-neoplastic counterparts as well. Recent IgV gene analyses on a panel of FLs however, strongly suggested that FLs do not retain the capacity of somatic hypermutation and are not being selected on basis of the quality of their mIgV regions. To extend these findings, we investigated the follicular organization and class switching in a FL that consisted of both IgM- and IgG-expressing tumor cells with a high somatic mutation load and significant intraclonal V(H) gene diversity. V(H)-C(mu) and V(H)-Cgamma gene transcripts were amplified and sequenced from samples of approximately 50 tumor cells, isolated from frozen tissue sections by laser microdissection. We identified many different subclones and obtained limited evidence of subclone dominance in individual follicles. Remarkably, several subclones were found scattered over different follicles. All samples contained IgM- and IgG-expressing tumor cells with, in general, non-identical mutation patterns, which is not in support of ongoing class switching. Accordingly, no switch circle recombination products were found. The findings indicate that the neoplastic follicles lack the organization and functions typical of reactive germinal centers.

Cell Movement↗