Estimation of deleterious genomic mutation parameters in natural populations by accounting for variable mutation effects across loci. (1/46)

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.  (+info)

Clinical variables and genetic loading for schizophrenia: analysis of published Danish adoption study data. (2/46)

Schizophrenia shows considerable clinical variation, but the relationship between clinical variables and degree of genetic loading for schizophrenia is unclear. We investigated this by analyzing published data from the adoption study of Kety et al. (1994) in Denmark. We sought to determine which clinical variables in proband adoptees with chronic schizophrenia predicted risk of schizophrenia in their biological relatives, using logistic regression analysis. We found that risk of chronic schizophrenia in relatives was predicted by the presence of pervasive negative symptoms (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 1.98-45.01) and absence of pervasive positive symptoms (OR = 0.09, 95% CI = 0.01-0.78) in probands. Pervasive negative symptoms were defined by the presence of all of the symptoms: social withdrawal, autistic behavior, poverty of thought/speech, and flat affect. Pervasive positive symptoms were defined by the presence of all of the symptoms: suspiciousness/ideas of reference, delusions, auditory hallucinations, and other hallucinations. These clinical variables may be useful for refining phenotypic definitions of schizophrenia in molecular genetic studies.  (+info)

Genetic loading in familial migraine with aura. (3/46)

Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi(2)=6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi(2)=9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.  (+info)

Familial versus mass selection in small populations. (4/46)

We used diffusion approximations and a Markov-chain approach to investigate the consequences of familial selection on the viability of small populations both in the short and in the long term. The outcome of familial selection was compared to the case of a random mating population under mass selection. In small populations, the higher effective size, associated with familial selection, resulted in higher fitness for slightly deleterious and/or highly recessive alleles. Conversely, because familial selection leads to a lower rate of directional selection, a lower fitness was observed for more detrimental genes that are not highly recessive, and with high population sizes. However, in the long term, genetic load was almost identical for both mass and familial selection for populations of up to 200 individuals. In terms of mean time to extinction, familial selection did not have any negative effect at least for small populations (N< or =50). Overall, familial selection could be proposed for use in management programs of small populations since it increases genetic variability and short-term viability without impairing the overall persistence times.  (+info)

Sheltered load associated with S-alleles in Solanum carolinense. (5/46)

Bud pollinations allowed me to examine the effects of homozygosity at loci in the area of suppressed recombination around the S-locus in Solanum carolinense, whose S-alleles show surprisingly low diversification rates. The total number of seeds produced was lower for incompatible than compatible pollinations, revealing that self-incompatibility was only somewhat overcome by bud pollination. However, low seed set in incompatible crosses was not due solely to the incompatibility response; crosses between distinct plants sharing the same alleles at the S-locus led to dramatically high seed abortion, nearly equal to that found upon selfing. An excess of heterozygotes in the surviving progeny supports the supposition that these high abortion rates are due to sheltered load, that is, previously unexpressed load accumulated due to enforced heterozygosity and recombination suppression around the S-locus. Of the seven alleles examined in total, two showed evidence of severe load and five did not. The magnitude of load was consistent with terminal branch length in some, but not all, cases.  (+info)

A review and new report of medial temporal lobe dysfunction as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric family study of the parahippocampal gyrus. (6/46)

A central question in schizophrenia research is which brain abnormalities are independent of psychosis and which evolve before and after psychosis begins. This question can be addressed by longitudinal neuroimaging studies beginning in the prodrome, but at present there is only one published study. We reviewed the literature on structural brain imaging in persons with chronic and first episode schizophrenia, nonpsychotic persons at genetic high risk, and persons thought to be at risk for imminent psychosis ("prodromal" persons). Medial temporal lobe (MTL), especially hippocampal, volume alterations are among the most robust brain vulnerabilities for schizophrenia. Because verbal declarative memory (VDM) deficits are prominent and the parahippocampal gyrus (PHG) is considered to be centrally involved with the hippocampus in VDM processing, we analyzed PHG data from a family study of schizophrenia. Patients with schizophrenia and nonpsychotic relatives from "multiplex" families (families with multiple persons with schizophrenia) had significantly smaller right parahippocampal anterior (PHa) volumes than controls. Marginally significant findings were observed for the left PHa. Unexpectedly, relatives from "simplex" families (families with only one person with schizophrenia) had significantly larger PH posterior volumes than controls and did not differ from controls on PHa. Results provide some support for the hypothesis that the vulnerability to schizophrenia includes abnormal volumes of the PHG. These data provide additional support for the hypothesis that some MTL abnormalities in schizophrenia are independent of psychosis, at least in families with presumably high genetic loading. Implications of genetic risk studies for prodromal research are discussed.  (+info)

The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. (7/46)

A T8993G point mutation in the mtDNA results in a Leu156Arg substitution in the MTATP6 subunit of the mitochondrial F1F0-ATPase. The T8993G mutation causes impaired oxidative phosphorylation (OXPHOS) in two mitochondrial disorders, NARP (neuropathy, ataxia and retinitis pigmentosa) and MILS (maternally inherited Leigh's syndrome). It has been reported, in some studies, that the T8993G mutation results in loss of assembled F1F0-ATPase. Others reported that the mutation causes impairment of proton flow through F0. In addition, it was shown that fibroblasts from NARP subjects have a tendency to undergo apoptotic cell death, perhaps as a result of increased free radical production. Here, we show that the T8993G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. We suggest that free radical-mediated inhibition of OXPHOS contributes to the loss of ATP synthesis. Importantly, we show that antioxidants restore respiration and partially rescue ATP synthesis in cells harboring the T8993G mutation. Our results indicate that free radicals might play an important role in the pathogenesis of NARP/MILS and that this can be prevented by antioxidants. The effectiveness of antioxidant agents in cultured NARP/MILS cells suggests that they might have a potential beneficial role in the treatment of patients with NARP.  (+info)

On the rate and linearity of viability declines in Drosophila mutation-accumulation experiments: genomic mutation rates and synergistic epistasis revisited. (8/46)

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.  (+info)