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PubMed1994

Selfish DNA as a method of pest control.

The inheritance of most genes is tightly controlled, governed by the rules of mendelian inheritance if nuclear or uniparental inheritance if cytoplasmic. A few notable genes and cytoplasmic genomes have escaped this regulation. Such genes may spread by increasing their own rate of transmission despite reducing host fitness and may be regarded as 'selfish'. Their population genetics are described and it appears they may impose a significant genetic load on the host population. Modern molecular techniques may enable similar loads to be imposed on pest species either by transferring selfish genes between species, or by linking deleterious genes to a selfish locus. Alternatively, 'modifier' genes that eliminate the virulent, or disease vectorial capacity, of the pest population may be introduced by linkage to a selfish locus. Selfish elements present in multiple copies may be preferable to single-copy elements as the former are capable of a larger reduction in host fitness. The practical application of these agents depends on five factors: (i) the rate of 'reversion' to a non-selfish form; (ii) the evolution of host repressor systems; (iii) their effect on host fitness, which determines their rate of invasion; (iv) the mechanism regulating host population size in the field; and (v) their ease of manipulation in the laboratory. The first two factors are the most uncertain in most systems, but should be amenable to experimental analysis. It is proposed that the development of such techniques may result in powerful new methods of population control which may be applied to both agricultural pests and disease vectors.

Alleles↗
PubMed2006

Restrictive flamenco alleles are maintained in Drosophila melanogaster population cages, despite the absence of their endogenous gypsy retroviral targets.

The flamenco (flam) locus, located at 20A1-3 in the centromeric heterochromatin of the Drosophila melanogaster X chromosome, is a major regulator of the gypsy/mdg4 endogenous retrovirus. In restrictive strains, functional flam alleles maintain gypsy proviruses in a repressed state. By contrast, in permissive strains, proviral amplification results from infection of the female germ line and subsequent insertions into the chromosomes of the progeny. A restrictive/permissive polymorphism prevails in natural and laboratory populations. This polymorphism was assumed to be maintained by the interplay of opposite selective forces; on one hand, the increase of genetic load caused by proviral insertions would favor restrictive flam alleles because they make flies resistant to these gypsy replicative transpositions and, on the other, a hypothetical resistance cost would select against such alleles in the absence of the retrovirus. However, the population cage data presented in this paper do not fit with this simple resistance cost hypothesis because restrictive alleles were not eliminated in the absence of functional gypsy proviruses; on the contrary, using 2 independent flam allelic pairs, the restrictive frequency rose to about 90% in every experimental population, whatever the pair of alleles and the allelic proportions in the initial inoculum. These data suggest that the flam polymorphism is maintained by some strong balancing selection, which would act either on flam itself, independently of the deleterious effect of gypsy, or on a hypothetical flanking gene, in linkage disequilibrium with flam. Alternatively, restrictive flam alleles might also be resistant to some other retroelements that would be still present in the cage populations, causing a positive selection for these alleles. Whatever selective forces that maintain high levels of restrictive alleles independently of gypsy, this unknown mechanism can set up an interesting kind of antiviral innate immunity, at the population level.

Alleles↗
PubMed2002

Improvement of the movement and host range properties of a plant virus vector through DNA shuffling.

Virus expression vectors based on the tobacco mosaic virus (TMV) genome are powerful tools for foreign gene expression in plants. However, the inclusion of increased genetic load in the form of foreign genes limits the speed of systemic plant invasion and host range of these vectors due to reduced replication and movement efficiencies. To improve these properties of TMV vectors, the gene encoding the 30-kDa movement protein was subjected to mutagenesis and DNA shuffling. A vector that expresses the green fluorescent protein was used to allow simple visual discrimination of mutants with enhanced movement phenotypes. An initial round of mutagenesis produced 53 clones with a faster local movement phenotype. Two subsequent rounds of DNA shuffling produced additional clones that showed further increased rates of cell-to-cell movement and degrees of systemic invasion in restrictive hosts. Surprisingly, sequence analysis of the best performing shuffled genes revealed alterations resulting in coding and silent changes in the movement protein gene. Separation of these coding and silent alterations into distinct gene backgrounds revealed that each contributes to improved movement protein function to differing degrees. The resulting vectors demonstrate that the complex activities of the movement protein genes of viruses can be evolved to have improved movement phenotypes, as evidenced by cell-to-cell and systemic invasion. The experiments produced improved vectors that will be of use both for in planta functional screening and for therapeutic protein production and demonstrated the power of shuffling for plant virus vector improvement.

DNA, Recombinant↗
PubMed2003

The Munich Vulnerability Study on Affective Disorders: risk factors for unipolarity versus bipolarity.

BACKGROUND: An individual with a high genetic load for psychiatric disorders is subject to a considerable risk factor for an affective illness. Family studies usually try to distinguish between bipolar and unipolar disorders since it was suggested that they might show different modes of inheritance. The aim of this study was to differentiate between healthy members of unipolar and bipolar families without a previous history of any psychiatric disorder according to the neurobiological and psychometric findings. METHODS: We first analysed the results obtained from neurobiological and psychometric measurements taken from 75 healthy subjects who had at least two close relatives with a unipolar and a bipolar disorder. In a second step we examined the subjects with a parental affective disorder; finally, we compared the members of 'pure' unipolar, bipolar and of mixed families to each other. RESULTS: The first-degree relatives of unipolar patients showed a significantly higher REM density and scored higher on scales of 'neuroticism' and 'vegetative lability' than the controls. No significant differences could be noticed between the relatives of unipolar and bipolar patients, either when considering the degree of relationship, or the parental type of affective disorder and the 'purity' of the respective families. CONCLUSIONS: We found some distinct neurobiological and psychometric differences between the relatives of unipolar patients and the control probands. No obvious differences, however, were ascertained between relatives of unipolar and bipolar patients. Therefore, we consider it to be possible that these findings represent potential vulnerability markers for affective disorders in general.

Adrenocorticotropic Hormone↗
PubMed1982

A molecular explanation of frequency-dependent selection in Drosophila.

Frequency-dependent selection provides a means for maintaining genetic variability within populations, without incurring a large genetic load. There is a wealth of experimental evidence for the existence of frequency-dependent changes in genotypic fitness among a wide variety of organisms. Examples of traits which have been shown to be subject to frequency-dependent selection include the self-incompatibility alleles of plants, chromosomal rearrangements in Drosophila, visible mutations, enzyme variants and rare-male mating advantage in Drosophila. These experiments have been interpreted in a number of different ways. Principally, frequency dependence of genotype fitness may result from intergenotype facilitation due to the production of biotic residues, or from the differential use of resources by the competing genotypes. However, it has proved extremely difficult to isolate and identify any biotic residue of importance or, alternatively, to understand the manner in which genotypes partition the environment. Thus, the difficulty in the interpretation of experiments which show frequency-dependent selective effects stems largely from our lack of understanding of the exact physiological mechanisms which produce these frequency-dependent effects. The principal aim of this study was to investigate the mechanisms associated with frequency-dependent selection at the amylase locus in Drosophila melanogaster. The excretion of catalytically active amylase enzyme and its effect on food medium composition were correlated with the outcome of intraspecific competition between amylase-deficient and amylase-producing genotypes. Amylase-producing genotypes were shown to excrete enzymatically active amylase protein into the food medium. The excreted amylase causes the external digestion of dietary starch; this accounts for the frequency-dependent increase in the viability of the amylase-deficient mutants in mixed cultures, maintained on a starch-rich diet.

Amylases↗
PubMed1984

Antimalarial red cells.

It is difficult to overestimate the evolutionary pressures exerted over the past few thousand years by endemic malaria. For most of hominid evolution, these parasites probably caused little morbidity and mortality. However, as Livingstone (1964, 1967, 1971) has pointed out, the advent of slash and burn horticulture and associated sedentary living patterns dramatically changed this situation. For many human populations, endemic malaria became an evolutionary emergency. In such pressing circumstances, genetic traits which ordinarily would carry with them an intolerable genetic load actually increase in frequency. Thus, although a few antimalarial red cell characteristics such as Duffy negativity are evidently innocuous, the majority of malaria-selected traits are not. Ovalocytosis, the abnormal hemoglobins and G-6-PD deficiencies are all quite deleterious in the homo- or hemizygote. This, more than anything else, bespeaks the extraordinary evolutionary pressures exerted by malaria. Needless to say, the mechanisms by which these various red cell traits protect are incompletely known. Although our discussion of such mechanisms has revolved about parasite/host cell relationships, the actual antimalarial effect may involve more distal interactions, especially of infected erythrocytes with the immune and reticuloendothelial systems. Protection exerted by modifications of such interactions would not be revealed by in vitro culture experiments upon which we rely for much of our information. For example, as normal red cells age and senesce, they express novel surface antigens which are recognized by specific immunoglobulins (Kay, 1983). Cells which have bound such antibodies are likely recognized and destroyed rapidly by the reticuloendothelial system. The expression of such senescence antigens may be hastened in already abnormal cells subject to the additional burden of an internal parasite. Therefore, it is quite possible that congenital defects of the red cell membrane, hemoglobin and metabolism may afford protection against malaria via immunologic mechanisms rather than by blocking penetration or predisposing the cell to spontaneous intravascular lysis. To be successful in the mammalian host, erythrocytic phase of malaria must recognize and attach to the host red cell, successfully penetrate, and replicate within. Remarkably, there are antimalarial red cells which impair each one of these individual steps. In this case, the ingenuity of natural selection has been almost--but not quite--a match for that of the malaria parasite.

Adenosine Triphosphate↗
PubMed1987

Mania after brain injury. A controlled study of causative factors.

Eleven patients who developed manic syndromes after brain injury (secondary mania) were studied. Six patients had depressive episodes before mania and five had a definite or possible family history of affective disorder. Eight had lesions involving limbic areas, and nine had right hemisphere involvement. In addition to focal brain injury, mean values for bifrontal and third ventricle/brain ratios of manic patients were significantly increased when compared with non-manic patients who had lesions matched for cause, location, volume, and time since injury. Results indicate that the confluence of either anterior subcortical atrophy and a focal lesion of a limbic or limbic-connected region of the right hemisphere, or genetic loading and a limbic-connected right hemisphere lesion may account for the rare occurrence and specific factors necessary to produce secondary mania.

Bipolar Disorder↗
PubMed1975

Acute mania. Clinical and genetic study of responders and nonresponders to treatments.

We examined the relationships among family history of psychiatric illness, demographic and historical variables, clinical course and presentation, and treatment response for 58 patients satisfying research criteria for mania. Nearly two thirds of the group had excellent responses to somatic treatment, particularly lithium ion, while one third had poor responses to lithium carbonate, neuroleptics, or electric convulsive therapy. Responders frequently exhibited euphoric moods, grandiose delusions, and tended to have cyclothymic premorbid personalities. Nonresponders were rarely euphoric, frequently exhibited incomplete auditory hallucinations, and tended to hve formal thought disorder and depressive-withdrawn premorbid personalities. Responders tended (nonsignificant) to have greater genetic loading for affective illness and alcoholism. We could not distinguish the two groups by their age at illness onset, duration of illness, or number of illness episodes per ill patient year.

Acute Disease↗
PubMed1989

Age of alcoholism onset. I. Relationship to psychopathology.

Numerous attempts have been made to subdivide populations of alcoholics into homogeneous subgroups. Although no consensus has been reached about the characteristics of these subgroups, a number of classification schemes have identified a subgroup of patients with a high genetic loading for alcoholism, an early onset of alcoholism, a severe course, and coexisting psychiatric problems consisting of aggressive tendencies or criminality. In a recent typology proposed by Cloninger on the basis of adoption studies, this subgroup has been classified as type 2. Another group of patients who were found to differ in their mode of inheritance and clinical characteristics was classified as type 1. The identification of etiologically homogeneous subgroups is easier in studies of adoptees than in studies of individuals who were not adopted. In an attempt to divide alcoholics into two groups of individuals presenting type 1 and type 2 characteristics, we used as a criterion the age of alcoholism onset because type 2 alcoholics as well as their fathers had been found to abuse alcohol at a younger age than type 1 patients. Patients with an onset of alcoholism before their 20th birthday were found to have a significantly higher incidence of paternal alcoholism and were twice as likely to have been incarcerated for crimes involving physical violence. We also observed other features not previously described in this patient subgroup. Patients who started abusing alcohol in their teens were three times as likely to be depressed and four times as likely to have attempted suicide as patients with a later onset of alcohol abuse.

Adolescent↗
PubMed1995

In quest of identifying vulnerability markers for psychiatric disorders by all-night polysomnography.

BACKGROUND: The persistence of a depressionlike sleep pattern in fully remitted depressed patients suggests that the pattern is a trait characteristic of sleep measurements. However, in the past, subjects have undergone investigation only after the onset of the disorder, and, therefore, the altered sleep pattern may merely represent a biological scar. METHODS: We polysomnographically investigated 54 healthy subjects who had no lifetime or current diagnosis of a psychiatric disorder but had at least one first-degree relative with major depression or a bipolar disorder and at least one further close relative with major depression, a bipolar disorder, or a schizophrenic disorder. Twenty unrelated control probands without a personal and family history of psychiatric disorders and 18 unrelated inpatients with major depression served as reference groups. Prior to investigation, all healthy subjects had been free of any prescription and nonprescription drug for at least 3 months. The depressed patients were free of drugs for at least 1 week. All subjects slept for 2 nights in the sleep research unit. The sleep of the second night was recorded and visually scored. RESULTS: Analysis of the individual sleep cycles in these subjects revealed both a reduced amount of slow wave sleep and increased rapid eye movement density in the first sleep cycle. Discriminant analysis showed that 10 subjects (18%) had sleep patterns similar to those of depressed patients. CONCLUSIONS: According to our observations, one fifth of the healthy subjects with a high genetic load for psychiatric disorders showed a conspicuous (depression-like) sleep pattern. The follow-up will determine whether this sleep pattern indeed represents a trait marker indicating vulnerability.

Adult↗
PubMed1999

Life cycle of the mammalian germ cell: implication for spontaneous mutation frequencies.

A brief history of the developmental life cycle of the mammalian germ cell, from fertilization to gametogenesis in the mature gonad, is presented. The differences between gametogenesis in the mature gonad of males and females are also described with regard to properties that may affect their susceptibilities to mutation. It is emphasized that any historical control background rate of necessity will include mutations that occur in germinal tissue at all stages of development and differentiation, although it is not always possible to determine at what stage of germline development a spontaneous mutation has occurred. Studies of induced mutations suggest that the impact on the molecular level and the distribution of mutations among the F1 and F2 progeny may be partly determined by the stage and sex of germ cells in which spontaneous mutations occur. In summary, historical control rates should only be considered the sum total of mutations that occur during the entire life of the individual and cannot represent the control values of any individual germ cell stage. Nonetheless, it is certainly important and valid to use historical control data for calculating human risk, because the primary use of the estimation of mutant frequencies is to access the potential impact of agents in increasing the genetic load in the human population.

Cell Cycle↗
PubMed1981

Historical note: the extraordinary handless and footless families of Brazil - 50 years of acheiropodia.

The history of acheiropodia is divided into 4 phases: discovery, exploration, modern studies, and contemporary knowledge. The discovery phase (1929-1930) is represented by the publication of the 1st family. For about 30 years, it remained the only family referred to in a number of textbooks of medicine, biology, and others. In the exploration phase (1956-1966), the first family was reanalyzed, other families were ascertained and analysed, and some radiologic aspects of the anomaly were published. The modern phase (1968-1972) is characterized by a large series of studies on the clinical aspects of acheiropodia, including laboratory and radiological examinations, psychological tests, status of vision, electrocardiograms, etc. In the contemporary phase (since 1974), genetic aspects prevailed, and studies were published on segregation analysis, selection pressure, genetic load, mutation rate, etc. Each one of these 4 phases is analyzed in detail.

Abnormalities, Multiple↗
PubMed2005

A family study of early-onset obsessive-compulsive disorder.

Results from family studies have suggested that obsessive-compulsive disorder (OCD) is a genetically heterogeneous disorder and have emphasized the importance of identifying valid subgroups of patients. The current study focused on early-onset OCD probands and examined the recurrence risks of OCD and tics among first-degree family members. One hundred six children and adolescents with OCD were recruited from a specialty clinic for OCD and 44 control individuals without OCD were identified by random-digit dialing. These 150 probands and their 465 first-degree relatives were assessed by trained interviewers, using standardized semi-structured interviews. Diagnoses were assigned according to DSM-IV criteria by two experts blind to the proband's diagnosis, through the best-estimate process. These data were analyzed using chi(2) tests, t-tests, logistic regression, and generalized estimating equations (GEE). Case probands had a mean age of onset of OC symptoms of 6.7 years (SD = 2.8), and high comorbid rates with Tourette syndrome (33%) and chronic tics (13.2%). Compared to control relatives, case relatives had higher age-corrected recurrence risks of OCD (22.7% vs. 0.9%, odds ratio (OR) = 32.5, 95% confidence interval (CI) = 4.5-230.8, P = 0.0005), and chronic tics (11.6% vs. 1.7%, OR = 7.9, 95% CI = 1.9-33.1, P = 0.005). A comorbid diagnosis of tics in the relatives was the best predictor of their diagnosis of OCD (OR = 7.35, 95% CI = 3.79-14.25, P < 0.0001). There was a significant correlation between the ages of onset of OCD in probands and their affected relatives. Childhood onset OCD is a highly familial disorder. Some early-onset cases may represent a valid subgroup, with higher genetic loading and shared vulnerability with chronic tic disorders.

Adolescent↗
PubMed2005

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin.

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-ras and p53 mutations. Four types of point mutation, GGC-->GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-ras codon 13; and one type of point mutation, GGA-->GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA-->GAA mutation at codon 12 or GGC-->GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G-->A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C-->T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin.

Animals↗
PubMed1998

Molecular genetics of mucopolysaccharidosis type I: mutation analysis among the patients of the former Soviet Union.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of the lysosomal protein alpha-l-iduronidase (IDUA). Patients present within a broad spectrum of phenotypes from severe (Hurler syndrome) to clinically less severe (Scheie syndrome). Since 1982 a special program for the diagnosis and prevention of lysosomal storage diseases has operated in the former Soviet Union (FSU). We report the genotypes of 25 MPS-I patients with different clinical severities from the FSU. All the patients were screened for two common mutations (W402X and Q70X) and four other mutations (P533R, R89Q, A327P, 474 2a-->g). W402X and Q70X alleles accounted for 4 and 44%, respectively. Using SSCP analysis and subsequent direct sequencing we also detected four novel mutations (P533L, Q63X, Y343X, and A75P) in the IDUA gene, together with two mutations (974ins12bp, 134del12bp) described elsewhere. All were found in the heterozygous form in MPS-I patients with different clinical severities. A total of 32 mutant alleles leading to MPS-I was identified with nine patients fully genotyped. Four patients were homozygous for Q70X while five others were genetic compounds. Besides the eight identified mutations, six known polymorphisms were found. The spectrum of mutant alleles discovered is highly specific and proves the peculiarity of genetic loads in the FSU. Our data suggest a closer relationship between the FSU and Scandinavian populations than with Western and Central European populations.

Alleles↗
PubMed2000

Possible benefits of kalilo plasmids to their Neurospora hosts.

Neurospora mitochondrial plasmids are ubiquitous in natural populations, yet many of them are lethal to their host strains or seem to impose a molecular genetic load. Five pairs of strains of Neurospora tetrasperma and N. crassa with and without kalilo-like plasmids were tested under a variety of situations. The purpose was to find possible beneficial effects of plasmids that might offset their disadvantages. We found that, in all cases tested, plasmids conferred an advantage to growth at temperatures close to the top of the range for this fungus. Also, the plasmids improved fertility, as measured by perithecial production. Negative results were obtained for heavy metal resistance and ascospore germination. The results generate the hypothesis that plasmids may have adaptive significance to their hosts.

Adaptation, Physiological↗
PubMed1994

Transgenerational, ultrastructural analysis on the antioxidative effects of tocopherol on early gametogenesis in Caenorhabditis elegans grown in 100% oxygen.

The random, free-radical-mediated oxidations of biological molecules result in membrane degradation leading to cellular deterioration (B. Halliwell, Free Radical Res. Commun. 9, 1-32, 1990). External oxygen, prooxidants, and internally produced oxygen free radicals (oxyradicals), interact and alter the nature of biomembranes. Antioxidants, e.g., tocopherol (Vitamin E), inhibit such oxidative damage of free radicals. In the present study, the nematode Caenorhabditis elegans was grown under hyperoxia (100% oxygen) with or without the addition of Vitamin E to the growth media. The nematodes were viable under such conditions for at least eight generations, although fecundity gradually decreased through successive generations, presumably due to genetic load. Vitamin E was also shown to have a protective effect against paraquat, which is a strong, intracellular, oxidizing agent. Ultrastructural observations of early meiosis showed that the formation of synaptonemal complexes was compromised and that the telomeres failed to attach to the nuclear envelope. Those nematodes grown in 100% oxygen with 200 micrograms/ml Vitamin E had normal meiotic structures and normal fecundity. Thus, the presence of enhanced levels of intracellular Vitamin E resulted in protection against oxidative stress during gametogenesis.

Animals↗
PubMed1979

Sex effect on the risk of mental retardation.

Risks of mental retardation were computed separately for the relatives of male and female probands. When compared, the risks for the relatives of females were always significantly higher than the risks for the relatives of males. These findings are consistent with the hypothesis of a differential genetic loading for males and females.

Female↗