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PubMed1982

Chromosome interactions in Drosophila melanogaster. II. Total fitness.

In a large experiment, using nearly 200 population cages, we have measured the fitness of Drosophila melanogaster homozygous (1) for the second chromosome, (2) for the third chromosome, and (3) for both chromosomes. Twenty-four second chromosomes and 24 third chromosomes sampled from a natural population were tested. The mean fitness of the homozygous flies is 0.081 +/- 0.014 for the second chromosome, 0.080 +/- 0.017 for the third chromosome, and 0.079 +/- 0.024 for both chromosomes simultaneously. Assuming that fitnesses are multiplicative (the additive fitness model makes no sense in the present case because of the large selection coefficients involved), the expected mean fitness of the homozygotes for both chromosomes is 0.0066; their observed fitness is more than ten times greater. Thus, it appears that synergistic interactions between loci are considerable; and that, consequently, the fitness function substantially departs from linearity. Two models are tentatively suggested for the fitness function: a "threshold" model and a "synergistic" model.--The experiments reported here confirm previous results showing that the concealed genetic load present in natural populations of Drosophila is sufficient to account for the selective maintenance of numerous polymorphisms (of the order of 1000).

Animals↗
PubMed2002

Estimation of deleterious genomic mutation parameters in natural populations by accounting for variable mutation effects across loci.

The genomes of all organisms are subject to continuous bombardment of deleterious genomic mutations (DGM). Our ability to accurately estimate various parameters of DGM has profound significance in population and evolutionary genetics. The Deng-Lynch method can estimate the parameters of DGM in natural selfing and outcrossing populations. This method assumes constant fitness effects of DGM and hence is biased under variable fitness effects of DGM. Here, we develop a statistical method to estimate DGM parameters by considering variable mutation effects across loci. Under variable mutation effects, the mean fitness and genetic variance for fitness of parental and progeny generations across selfing/outcrossing in outcrossing/selfing populations and the covariance between mean fitness of parents and that of their progeny are functions of DGM parameters: the genomic mutation rate U, average homozygous effect s, average dominance coefficient h, and covariance of selection and dominance coefficients cov(h, s). The DGM parameters can be estimated by the algorithms we developed herein, which may yield improved estimation of DGM parameters over the Deng-Lynch method as demonstrated by our simulation studies. Importantly, this method is the first one to characterize cov(h, s) for DGM.

Animals↗
PubMed2004

On the rate and linearity of viability declines in Drosophila mutation-accumulation experiments: genomic mutation rates and synergistic epistasis revisited.

High rates of deleterious mutations could severely reduce the fitness of populations, even endangering their persistence; these effects would be mitigated if mutations synergize each others' effects. An experiment by Mukai in the 1960s gave evidence that in Drosophila melanogaster, viability-depressing mutations occur at the surprisingly high rate of around one per zygote and that the mutations interact synergistically. A later experiment by Ohnishi seemed to support the high mutation rate, but gave no evidence for synergistic epistasis. Both of these studies, however, were flawed by the lack of suitable controls for assessing viability declines of the mutation-accumulation (MA) lines. By comparing homozygous viability of the MA lines to simultaneously estimated heterozygous viability and using estimates of the dominance of mutations in the experiments, I estimate the viability declines relative to an appropriate control. This approach yields two unexpected conclusions. First, in Ohnishi's experiment as well as in Mukai's, MA lines showed faster-than-linear declines in viability, indicative of synergistic epistasis. Second, while Mukai's estimate of the genomic mutation rate is supported, that from Ohnishi's experiment is an order of magnitude lower. The different results of the experiments most likely resulted from differences in the starting genotypes; even within Mukai's experiment, a subset of MA lines, which I argue probably resulted from a contamination event, showed much slower viability declines than did the majority of lines. Because different genotypes may show very different mutational behavior, only studies using many founding genotypes can determine the average rate and distribution of effects of mutations relevant to natural populations.

Animals↗
PubMed1987

An epidemiologic approach to the evaluation of the effect of inbreeding on prereproductive mortality.

Although many studies report deleterious effects of inbreeding on prereproductive mortality (death before age 20 years), such effects are usually measured in terms of genetic load, a concept much debated in the literature. To evaluate the public health impact of inbreeding on prereproductive mortality in terms of relative and attributable risks, the authors reviewed 31 studies with 294 observations comparing various stages of infant and child mortality in offspring of unrelated parents with offspring of first cousin, first cousin once removed, and second cousin marriages, respectively. Compared with offspring of unrelated parents, offspring of first cousin marriages have a higher risk of prereproductive mortality (median relative risk (RR) = 1.41, signed-rank test, p less than 0.01). Offspring of first cousin once removed and second cousin marriages had median relative risks of 1.16 and 1.26, respectively. Countries with relatively higher rates of consanguineous marriages (greater than 5%) had lower median relative risks than did countries with lower consanguinity rates. Also, the higher the mortality rate in the population, the lower the effect of consanguinity (median relative risk). Because of the rarity (less than 5%) and declining trends of consanguineous marriages in many places of the world, and because of their modest effect on prereproductive mortality (RR less than 2.0), it can be shown that the attributable risk of prereproductive mortality due to consanguineous marriages is less than 5%. Except for a few places with very high inbreeding levels, inbreeding has a minor impact on mortality in the prereproductive period.

Consanguinity↗
PubMed1987

Inbreeding and prereproductive mortality in the Old Order Amish. II. Genealogic epidemiology of prereproductive mortality.

The effects of offspring and parental inbreeding on prereproductive mortality (death before age 20 years) in the historical population of the Lancaster County, Pennsylvania, Old Order Amish were investigated using the Amish genealogic registry, which contains information on 42,465 births dating to the time of the pioneer migrants in the 1700s. Inbreeding coefficients for offspring and parents were computed using the path method of tracing common ancestors in the multigenerational pedigrees. In this population, prereproductive mortality declined from about 15% in the late 1800s to about 5% after 1930. Offspring inbreeding was found to be an independent predictor of prereproductive mortality after multivariate adjustment for demographic risk factors for mortality. Moreover, the higher the coefficient, the higher the relative risk of prereproductive death, and the higher the risk of multiple deaths in the same sibship. There was no evidence of declining inbreeding effects over 10 generations of continuous inbreeding, nor of any significant parental inbreeding effects. Because of the high levels of inbreeding, it could be shown that inbreeding accounts for about 40% of all prereproductive deaths in the present population. Genetic load analysis showed an average of about 1.7 lethal equivalents and a mostly mutational load.

Adult↗
PubMedDate not supplied

Effects of inbreeding on skeletal development of Rattus villosissimus.

In a species of Australian native rat, Rattus villosissimus, which experiences extreme population fluctuations and possibly episodes of local inbreeding in the wild, generations of inbreeding in a laboratory colony led to altered skull shape and increased fluctuating asymmetry in some skeletal characters. Although inbreeding was closely associated with the number of generations in captivity, the effect of inbreeding after controlling statistically for the generation number was to decrease skull length and width. The effect of generations in captivity after controlling for inbreeding was to increase skull length and width. The joint effect of these confounded determinants was to produce rats with increasingly broad and short skulls through generations of inbreeding. Developmental anomalies of the incisors and feet appeared in the population. The average effects of inbreeding on fluctuating asymmetry were not strong, as most inbred and noninbred rats were not detectably asymmetric. Asymmetry appeared to be a threshold phenomenon, as significantly asymmetric animals were more prevalent among the more highly inbred rats of later generations. We detected no trend for a lessening impact of inbreeding after many generations, as would have been expected if selection had been purging the population of its genetic load. Individual heterozygosity across five polymorphic allozyme loci was correlated with size and asymmetry metrics, but only in so far as could be accounted for by the correlation of sample heterozygosity with the level of inbreeding and the effect of inbreeding on size and asymmetry.

Animals↗
PubMed1976

Auto-immune disease.

Auto-immune disease may result from the interaction of the genetic load of the individual, modification of self-tissue antigens by environmental agents such as virus or drugs and abnormalities of the immunological system itself such as the loss of controlling or suppressor T cells with age. In the majority of people the outcome is tolerance, maintenance of normal tissue architecture and function. In the unfortunate few the outcome is auto-immune disease, that is, failure to recognize "self".

Animals↗
PubMed1986

Season of birth: schizophrenia and bipolar disorder.

Studies investigating the association between the risk of schizophrenia and season of birth are reviewed and the association clearly established. This association cannot be explained on the basis of age-incidence or age-prevalence artifacts. Other studies suggest there may be an association between bipolar disorder and season of birth. The leading theory in explaining the season of birth phenomenon is that a seasonal factor (such as viral infection, malnutrition, vitamin deficiency, prenatal or obstetrical complications, or ambient temperature) can damage an infant's brain and thereby predispose the child to later development of psychosis. Evidence suggests that the seasonal effect is associated with a subgroup of schizophrenics who have early onset of psychosis, less genetic loading than other schizophrenics, and better prognosis. Case-control studies are needed comparing winterborn to nonwinter-born schizophrenics.

Adolescent↗
PubMed1987

Prognostic scale for chronic schizophrenia.

Although prognostic scales are available for schizophrenia, these focus on acute or subacute populations where premorbid functioning and established chronicity are the best predictors of outcome. Their usefulness in chronic schizophrenia is limited. The authors describe a simple and reliable 5-item, 12-point prognostic scale for chronic schizophrenia independent of chronicity. It measures prognosis as the product of a dynamic interplay between the highest level of adaptive occupational and social functioning ever achieved by the individual and the "invasiveness" of the Axis I disorder as manifest by genetic loading (family history of schizophrenia), erosion of reality testing (psychotic assaultiveness), and preservation of affect in psychopathology (depressed mood). Among chronic schizophrenic patients in the Chestnut Lodge Followup Study (n = 163), the prognostic score (based on history and admission clinical picture) allowed strong probabilistic statements to be made about long-term outcome. Tables present the conditional probability or risk of specific outcomes in the domains of institutionalization, work functioning, social relations, and global outcome for patients at varying levels along the prognostic spectrum. Close examination of these predictor-outcome relationships suggests that prognosis in chronic schizophrenia may be thought of as the variability (as opposed to fixedness) remaining in the individual's future life course, and poor outcome can be predicted with greater sensitivity than good outcome.

Adaptation, Psychological↗
PubMed1996

Smoking and vulnerability for schizophrenia.

In several countries, the prevalence of smoking among schizophrenia patients is extraordinarily high (70% or greater). A State hospital survey demonstrated that after correcting for other factors, inpatients who have schizophrenia are more likely to be smokers than are persons in the normal population or even other chronic psychiatric inpatients. These findings suggest that neuroleptic treatment and the hospital environment cannot completely explain the high prevalence of smoking. The relationship between smoking and schizophrenia may be explained by a combination of three factors. One factor is the great difficulty for schizophrenia patients to quit smoking. Another is late onset: some schizophrenia patients start to smoke after the onset of psychosis. A third is increased early onset: schizophrenia patients may start daily smoking in greater numbers during adolescence (before the onset of their psychosis) than do persons in the normal U.S. population. Daily smoking is usually considered a sign of nicotine addiction and is used by epidemiological surveys to define the prevalence of smokers (most smokers smoke daily and very few smokers do not smoke every day). The increased early onset suggests that familial factors may increase the prevalence of smoking even among patients who have not yet shown psychotic symptoms. It is hypothesized that smoking among family members in families with genetic loading for schizophrenia may be a marker for those at risk of developing schizophrenia.

Humans↗
PubMed1989

Childhood schizophrenia: theoretical and treatment issues.

Michael is an 8.5-year-old Caucasian male inpatient who presented at admission with severe agitation, suicidal impulses, and aggression toward his 18-month-old sister. He had been treated with stimulant medications before admission. Past history revealed bilateral genetic loading with two primary family members having a history of hallucinations and hospitalization, and two paternal aunts who were hospitalized since early childhood. Michael was raised in a chaotic, violent family environment where there was emotional, physical, and perhaps sexual abuse. Medical history included frequent staring spells. During residential treatment, more extensive interviews revealed a year's history of auditory hallucinations, inappropriate and labile affect, and a fixed delusional system. The patient was switched to neuroleptics and showed a slow response despite high doses.

Child↗
PubMed2003

Apomixis in flowering plants: an overview.

Apomixis is a common feature of perennial plants, which occurs in ca. 60% of the British flora, but has been largely ignored by reproductive theoreticians. Successful individuals may cover huge areas, and live to great ages, favoured by 'symmetrical' selection. Apomixis is favoured by colonizing modes, for instance post-glacially. Despite its theoretical advantages, apomixis usually coexists with sexuality, suggesting 'hidden' disadvantages. Agamospermy (apomixis by seed) is relatively uncommon, but gains from the attributes of the seed. It pays agamospermy genes, which discourage recombination, to form co-adapted linkage groups, so that they become targets for disadvantageous recessive mutant accumulation. Consequently, agamospermy genes cannot succeed in diploids and agamosperms are hybrid and highly heterotic. Agamospermous endosperm may suffer from genomic imbalance, so that nutritious ovules, which can support embryos without endosperm, may be preadapted for agamospermy. When primary endosperm nucleus fertilization ('pseudogamy') continues as a requirement for many aposporous agamosperms, selfing sex becomes preadaptive and archesporial sex remains an option. Apomictic populations can be quite variable although apomictic families are much less variable than sexuals. Only in some diplosporous species does sex disappear completely, and in those species some release of variability may persist through somatic recombination. The search for an agamospermy gene suitable for genetic modification should target fertile sexuals with a single localized agamospermy (A) gene, which therefore lack a genetic load. The A gene should coexist alongside sexuality, so that it would be easy to select seedlings of sexual and asexual origins. Plants with sporophytic agamospermy provide all these attributes.

Magnoliopsida↗
PubMed2003

Sensory gating impairment associated with schizophrenia persists into REM sleep.

Physiological measures of sensory gating are increasingly used to study biological factors associated with attentional dysfunction in psychiatric and neurologic patient populations. The present study was designed to assess sensory gating during rapid eye movement (REM) sleep in patients with schizophrenia, a population bearing a genetic load for gating impairment. Auditory event-related potentials (ERPs) were recorded in response to paired clicks during separate waking and overnight sleep recording sessions in controls and schizophrenia patients. Suppression of ERP component P50 was significantly impaired in the patient group during both waking and REM sleep, whereas the difference between groups for N100 gating was dependent on state. These results suggest that REM sleep is an appropriate state during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in other clinical populations.

Acoustic Stimulation↗
PubMed2002

Deleterious mutation and the evolution of eusociality.

Certain arguments concerning the evolution of eusociality form a classic example of the application of the principles of kin selection. These arguments center on the different degrees of relatedness of potential beneficiaries of an individual's efforts, for example a female's higher relatedness to her sisters than to her daughters in a haplodiploid system. This type of reasoning is insufficicnt to account for the evolution and maintainence of sexual reproduction, because parthenogenic females produce offspring that are more closely related to them than are offspring produced sexually. Among the forces invoked to explain sexual reproduction is deleterious mutation. This factor can be shown to favor eusociality as well, because siblings produced by helping carry fewer deleterious alleles on average than would offspring. The strength of this effect depends on the genomewide deleterious mutation rate, U, and on the selection coefficient, s, associated with deleterious alleles. For small s, the effect depends approximately on the product Us. This phenomenon illustrates that an assumption implicit in some analyses-that the relatedness of an individual to an actor is all that matters to its value to that actor-can fail for the evolution of eusociality as it does for the evolution of sex.

Animals↗
PubMed2006

Pollinator limitation and inbreeding depression in orchid species with and without nectar rewards.

Many orchids produce no nectar rewards. Foraging pollinators should visit more flowers per inflorescence in species with nectar, which could increase geitonogamous self-fertilization. If a history of selfing decreases genetic load, then nectar-producing orchids should harbour lower inbreeding depression than nectarless species. Here, I tested this hypothesis by quantifying inbreeding depression and pollinator limitation in populations of three closely related orchid species, one of which provides nectar. I also compared inbreeding depression for nectarless and nectar-producing species of orchids using published studies. All field populations expressed pollinator limitation, but the nectar-providing species was intermediate to the two nectarless species. All populations expressed inbreeding depression, and levels increased in later life-history stages. There was no tendency for nectarless species to express higher inbreeding depression either in experiments or published studies. Nectarless orchids may not express higher levels of inbreeding depression because pollinators fail to visit more flowers in nectar-bearing species, because such visitations do not result in greater selfing, and/or because higher selfing may be ineffective in purging the mutations that cause load.

Ecosystem↗
PubMed2006

Inbreeding effects on progeny sex ratio and gender variation in the gynodioecious Silene vulgaris (Caryophyllaceae).

In gynodioecious species, sex expression is generally determined through cytoplasmic male sterility genes interacting with nuclear restorers of the male function. With dominant restorers, there may be an excess of females in the progeny of self-fertilized compared with cross-fertilized hermaphrodites. Moreover, the effect of inbreeding on late stages of the life cycle remains poorly explored. Here, we used hermaphrodites of the gynodioecious Silene vulgaris originating from three populations located in different valleys in the Alps to investigate the effects of two generations of self- and cross-fertilization on sex ratio and gender variation. We detected an increase in females in the progeny of selfed compared with outcrossed hermaphrodites and inbreeding depression for female and male fertility. Male fertility correlated positively with sex ratio differences between outbred and inbred progeny, suggesting that dominant restorers are likely to influence male fertility qualitatively and quantitatively in S. vulgaris. We argue that the excess of females in the progeny of selfed compared with outcrossed hermaphrodites and inbreeding depression for gamete production may contribute to the maintenance of females in gynodioecious populations of S. vulgaris because purging of the genetic load is less likely to occur.

Disorders of Sex Development↗
PubMed2006

Relative contribution of inbreeding depression and eroded adaptive diversity to extinction risk in small populations of shore campion.

To study the relative importance of inbreeding depression and the loss of adaptive diversity in determining the extinction risk of small populations, we carried out an experiment in which we crossed and self-fertilized founder plants from a single, large population of shore campion (Silene littorea Brot.). We used the seeds these plants produced to colonize 18 new locations within the distribution area of the species. The reintroduced populations were of three kinds: inbred and genetically homogeneous, each made up of selfed seed from a single plant; inbred and mixed, made up of a mixture of selfed seeds from all founder plants; and outbred and mixed, made up of a mixture of seeds obtained in outcrosses between the founders. We compared the inbred homogeneous populations with the inbred mixed to measure the effect of genetic diversity among individuals and the inbred mixed with the outbred mixed to measure the effect of inbreeding. Reintroduction success was seriously limited by inbreeding, whereas it was not affected by genetic diversity. This observation and the nonsignificant interaction between family and reintroduction location for individual plant characters suggest that the fixation of overall deleterious genes causing inbreeding depression posed a more serious threat to the short-term survival of the populations than the loss of genes involved in genotype and environment interactions. Thus, reintroduction success was related to adaptive diversity. Preventing such fixation might be the most important consideration in the genetic management and conservation of shore campion populations.

Adaptation, Physiological↗
PubMed1987

Family history of alcoholism does not predict neuropsychological performance in alcoholics.

We examined the relationship of history of alcoholism in first-degree relatives to neuropsychological performance of alcoholics abstinent from several weeks to several years. Eighty-four men were assigned to four groups based on "strength" of family history of alcoholism. The groups were: (1) "strong history," a parent plus another first-degree relative positive; (2) "moderate," parent only positive; (3) "weak," nonparent first-degree relative only positive; and (4) "negative," no first-degree relative positive. There were no significant between-group differences in NP performance. In other analyses there were no NP differences between alcoholics classified positive or negative purely on basis of paternal alcoholism, and no differences between subjects who had multigenerational versus unigenerational versus negative familial histories of alcoholism. It is concluded that genetic loading for alcoholism does not significantly affect the NP status of abstinent alcoholic groups equated for education, drinking history, and medical risk.

Adult↗