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PubMed2001

The influence of neighborhood size and habitat shape on the accumulation of deleterious mutations.

To examine the impact of genetic neighborhood size and habitat shape on genetic load and the accumulation of deleterious mutation, individual-based simulations were performed in continuously distributed habitats. The risk of extinction increased as both the area of the habitat and the neighborhood size decreased. When the neighborhood area became smaller than the habitat area, habitat shape also began to influence the risk of extinction by mutation loads, expected time to extinction being shorter in longer and narrower habitats than in a square habitat. Both the number of homozygous deleterious loci per individual and the mutation load in the population increased as the neighborhood size and total population size decreased. Neighborhood size and total population size both independently affected the average number of homozygous deleterious loci per individual. In addition, as the ratio of the long to the short side of the rectangle of a habitat increased, the average number of homozygous deleterious loci increased. When the areas of the habitats were held constant, the average number of homozygous loci and the mutation loads were smallest for a regular square and largest for the longest, narrowest habitat. These results suggest that the spatial genetic structure of an individual is an important factor in the accumulation of deleterious mutations and the risk of extinction by mutation meltdown.

Animals↗

PubMed2004

Ecologically relevant stress resistance: from microarrays and quantitative trait loci to candidate genes - a research plan and preliminary results using Drosophila as a model organism and climatic and genetic stress as model stresses.

We aim at studying adaptation to genetic and environmental stress and its evolutionary implications at different levels of biological organization. Stress influences cellular processes, individual physiology, genetic variation at the population level, and the process of natural selection. To investigate these highly connected levels of stress effects, it is advisable - if not critical - to integrate approaches from ecology, evolution, physiology, molecular biology and genetics. To investigate the mechanisms of stress resistance, how resistance evolves, and what factors contribute to and constrain its evolution, we use the well-defined model systems of Drosophila species, representing both cosmopolitan species such as D. melanogaster with a known genome map, and more specialized and ecologically well described species such as the cactophilic D. buzzatii. Various climate-related stresses are used as model stresses including desiccation, starvation, cold and heat. Genetic stress or genetic load is modelled by studying the consequences of inbreeding, the accumulation of (slightly) deleterious mutations, hybridization or the loss of genetic variability. We present here a research plan and preliminary results combining various approaches: molecular techniques such as microarrays, quantitative trait loci (QTL) analyses, quantitative PCR, ELISA or Western blotting are combined with population studies of resistance to climatic and genetic stress in natural populations collected across climatic gradients as well as in selection lines maintained in the laboratory.

Adaptation, Physiological↗

PubMed2004

Impact of founder population, drift and selection on the genetic diversity of a recently translocated tree population.

Recently established, temperate tree populations combine a high level of differentiation for adaptive traits, suggesting rapid genetic evolution, with a high level of genetic diversity within population, suggesting a limited impact of genetic drift and purifying selection. To study experimentally the evolutionary forces in a recently established population, we assessed the spatial and temporal patterns of genetic diversity within a disjunct population of Cedrus atlantica established 140 years ago in south-eastern France from a North African source. The population is expanding through natural regeneration. Three generations were sampled, including founder trees. We analysed 12 isozyme loci, three of which were previously found in tight association with selected genes, and quantitative traits. No bottleneck effect was detected in the founder generation, but a simple test of allelic association revealed an initial disequilibrium which disappeared in the following generations. The impact of genetic drift during secondary evolution was limited, as suggested by the weak temporal differentiation. The genetic load was not reduced after 3 generations, and the quantitative variation for adaptive traits did not change either. Thus, initial genetic changes first proceed from a rapid re-organisation of the diversity through mating and recombination, whereas genetic erosion through drift and selection is delayed due to temporal and spatial stochasticity. Two life-history traits of trees contribute to slowing down the processes of genetic erosion: perenniality and large spatial scale. Thus, one would expect recently established tree populations to have a higher diversity than older ones, which seems in accordance with experimental surveys.

Biological Evolution↗

PubMed2006

Early onset bipolar disorder: possible linkage to chromosome 9q34.

OBJECTIVES: Bipolar disorder (BD) is characterized by manic and depressive states that onset at various times in life. Research shows that early onset forms of BD are associated with a stronger genetic loading for the illness. We hypothesized that using age at onset to look at subsets of BD families in a genetic linkage analysis would prove useful in separating etiologically homogeneous BD sub-groups and subsequently identifying genetic susceptibility regions. METHODS: We used the wave-I National Institute of Mental Health (NIMH) Genetics Initiative BD sample, which includes 540 individuals from 97 families with BD, in an ordered-subsets linkage analysis with age at onset of mania as the subset-identifying covariate. This analysis was performed using GENEHUNTER-PLUS followed by the ordered-subsets analysis program. This program generates empirical p-values for the subset with the largest LOD score to determine whether this value was significantly higher than the baseline LOD score using all families. RESULTS: Three chromosomal regions resulted in LOD scores above 2.0: 2.21 (6q25), 3.21 (9q34), and 2.16 (20q11). The largest increase in LOD score was observed on chromosome 9q34 between markers D9S290 and D9S915 in the subset of 58 families that had mania onset before age 20. Families with a minimal mania onset less than 20 years had a significantly greater number of psychiatric comorbidities (p = 0.02) and a marginal increase in depressive symptoms (p = 0.10). CONCLUSIONS: Further investigation into chromosomal region 9q34 is necessary to determine whether this region may harbor a gene specific to families with a minimal age at onset of less than 20.

Age Factors↗

PubMed2002

The first large population based twin study of coeliac disease.

BACKGROUND AND AIMS: The genetic load in coeliac disease has hitherto been inferred from case series or anecdotally referred twin pairs. We have evaluated the genetic component in coeliac disease by estimating the concordance rate for the disease among twin pairs in a large population based study. METHODS: The Italian Twin Registry was matched with the membership lists of a patient support group. Forty seven twin pairs were recruited and screened for antiendomysial (EMA) and antihuman-tissue transglutaminase (anti-tTG) antibodies; zygosity was verified by DNA fingerprinting and twins were typed for HLA class II DRB1 and DQB1 molecules. RESULTS: Concordance rates for coeliac disease differ significantly between monozygotic (MZ) (0.86 probandwise and 0.75 pairwise) and dizygotic (DZ) (0.20 probandwise and 0.11 pairwise) twins. This is the highest concordance so far reported for a multifactorial disease. A logistic regression model, adjusted for age, sex, number of shared HLA haplotypes, and zygosity, showed that genotypes DQA1*0501/DQB1*0201 and DQA1*0301/DQB1*0302 (encoding for heterodimers DQ2 and DQ8, respectively) conferred to the non-index twin a risk of contracting the disease of 3.3 and 1.4, respectively. The risk of being concordant for coeliac disease estimated for the non-index twin of MZ pairs was 17 (95% confidence interval 2.1-134), independent of the DQ at risk genotype. CONCLUSION: This study provides substantial evidence for a very strong genetic component in coeliac disease, which is only partially due to the HLA region.

Adolescent↗

PubMed1981

Platelet monoamine oxidase values and genetic heterogeneity in schizophrenia research.

Platelet monoamine oxidase (MAO) activity is significantly reduced in chronic schizophrenics with family history of schizophrenia. The degree of reduction is related to the extent of genetic load. Schizophrenics with no affected relatives do not differ from control subjects. These findings are consistent with the hypothesis of genetic heterogeneity in schizophrenia. Discrepancies among previously reported data sets can thus be explained by overrepresentation of nongenetic phenocopies with normal MAO levels. The implications for biologic and genetic research in schizophrenia are discussed.

Blood Platelets↗

PubMed2006

Good genes sexual selection in nature.

Whether the mate sampling and choice performed by females in nature influences offspring performance is a controversial issue in theory and an open empirical question. Pronghorn (Antilocapra americana) females engage in an obvious and energetically expensive mate sampling process to identify vigorous males. Although individual females sample independently, their choices converge on a small proportion of males that sire most young. Offspring of attractive males were more likely to survive to weaning and to age classes as late as 5 years, resulting in a selection differential, calculated by expected differences in lifetime number of offspring weaned, of 0.32 against random mating. Enhanced survival to weaning appeared to be accomplished by faster growth rates. Females compensated for matings with a less attractive mate by elevating rates of milk delivery to their young. Because pronghorn males do not have costly ornaments, we conclude that female choice for good genes can exist in the absence of ornaments. Furthermore, female choice may be important and unrecognized as a force that can lower population genetic load.

Animals↗

PubMed1990

Childhood onset (age less than 10) obesity has high familial risk.

We assessed risk for obesity in 1743 first-degree relatives (parents and siblings) of 566 obese patients at three sites in the USA and one in Argentina. Onset of obesity prior to adulthood, and especially by age 10, significantly increased relative risk (2.14) for obesity in adult first-degree relatives. This increase in risk was consistent across four different patient samples from two different countries. Higher levels of obesity in patients were also associated with increased familial risk. Age of onset of obesity may be used to select obese adults with high genetic loading--an approach that should facilitate the identification of specific genes for human obesity. The enhanced ability to identify persons at high genetic risk for obesity provided by this study should increase the effectiveness of efforts to prevent obesity.

Adolescent↗

PubMedDate not supplied

Evidence of variation in segregation patterns within a Cedrus population.

We used horizontal starch-gel electrophoresis for a genetic analysis of isozymes within one French Cedrus atlantica stand. Eleven to 29 megagametophytes per tree from 186 trees were assayed. Among the 33 enzyme systems tested, 15 correctly resolved and 8 appeared variable in at least one zone of activity: ACP, GOT, IDH, LAP, MDH, MNR, PGI, and SKDH. They were coded by at least 12 polymorphic loci which were described and tested for Mendelian segregation and linkage. Segregation patterns and linkage relationships were variable in the population. We detected homogeneous segregation distortion for loci Idh, Acp-c, and Got-a over the whole set of segregating progeny. We also found segregation distortions in a significant proportion of progeny for loci Got-b, Mdh-c, Pgi-b, and SKDH: The Acp-c and Got-b loci were linked with an overall map distance of 17 cM, but distance varied drastically among progeny. Both segregation distortions and heterogeneity of recombination frequencies indicate the occurrence of a genetic load in this population.

Chromosome Segregation↗

PubMed2006

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.

Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.

Adolescent↗

PubMed2005

Pest control by genetic manipulation of sex ratio.

We model the release of insects carrying an allele at multiple loci that shifts sex ratios in favor of males. We model two approaches to sex ratio alteration. In the first (denoted SD), meiotic segregation (or sperm fertility) is distorted in favor of gametes carrying the male-determining genetic element (e.g., Y-chromosome). It is assumed that any male carrying at least one copy of the SD allele produces only genotypically male offspring. In the second approach (denoted PM), the inserted allele alters sex ratio by causing genetically female individuals to become phenotypically male. It is assumed that any insect carrying at least one copy of the PM allele is phenotypically male. Both approaches reduce future population growth by reducing the number of phenotypic females. The models allow variation in the number of loci used in the release, the size of the release, and the negative fitness effect caused by insertion of each sex ratio altering allele. We show that such releases may be at least 2 orders of magnitude more effective than sterile male releases (SIT) in terms of numbers of surviving insects. For example, a single SD release with two released insects for every wild insect and a 5% fitness cost per inserted allele could reduce the target population to 1/1000th of the no-release population size, whereas a similar-sized SIT release would only reduce the population to one-fifth of its original size. We also compare these two sex ratio alteration approaches to a female-killing (FK) system and the sterile male technique when there are repeated releases over a number of generations. In these comparisons, the SD approach is the most efficient with equivalent pest suppression achieved by release of approximately 1 SD, 1.5-20 PM, 2-70 FK, and 16-3,000 SIT insects, depending on conditions. We also calculate the optimal number of SD and PM allele insertions to be used under various conditions, assuming that there is an additional genetic load incurred for each allelic insertion.

Alleles↗

PubMed1989

[Increased recombination in a multi-locus system during environmental fluctuations].

The role of variability of environment as a factor of recombination evolution is studied. It was shown that selection in multilocus system under cyclic or random fluctuations of external conditions results in rapid increase in recombination frequency, even under free recombination between the rec-modificator and the selected system (SS). If so, pair-vise linkage disequilibrium coefficients have unchanged signs and are negative, and the advantage of rec+ alleles is provided by changes in signs of disequilibriums of higher order. The low frequency environmental fluctuations maintain recombination as it is, while high frequency ones induce the substitution of the low level by high. It was established that the recombination promoting mechanism of crossing-over maintenance, due to elimination of non-optimal allelic combinations of SS loci under temporal optimum variations, may be accomplished by smaller genetic load, than under elimination of deleterious mutations.

Environment↗

PubMed1981

Genetic analysis of Tourette syndrome suggesting major gene effect.

Data on Gilles de la Tourette syndrome are analyzed by multiple threshold models in inheritance that incorporate sex effect. The polygenic-multifactorial model is rejected. Single major locus inheritance can account for the data, although many of the occurrences of Tourette are due to nongenetic phenocopies. In both models, males and females share a common genetic environmental liability, but the less prevalent sex, that is, females, has a higher genetic loading for the disorder. The predicted population prevalences in the single major locus model are 2.3% for males and 0.8% for females. The implications for genetic and biological research in Tourette syndrome are discussed.

Female↗

PubMed1997

[Comparative study of genetic adaptation of the Caucasian highlanders to historic and to the new urban environments].

Marriage structure and female reproductive characteristics in a highland isolate and an urban population from Dagestan were compared. The studied urban population could be divided into three groups according to ethnic, genetic, and demographic parameters. In the native, highland population, a steady selection occurred due to a high, uncontrolled birthrate and a high prereproductive mortality. The genetic structure of the urban population still remained at the stage of formation. Different ethnic groups of the female urban population differed both in the rate and directions of selection. The migration of highlanders to the city mainly affected their mortality and morbidity, but not fecundity. The subpopulation of migrants from the highlands who retained a traditional endogamous and inbred marriage structure exhibited a high infant mortality comparable to that in the highland population. The migrant subpopulation in which interpopulation and interethnic marriages were contracted exhibited an increased genetic load expressed as high pre- and perinatal mortalities. The results obtained are discussed in terms of the hypotheses on the adaptive gene complex and the genetic and physiological mechanisms of differential adaptation of highland isolates to environmental changes due to migration or environmental pollution.

Adaptation, Physiological↗

PubMed2006

Ecological-genetic feedback in DNA repair in wild barley, Hordeum spontaneum.

Regulation of genetic variation in natural populations is a problem of primary importance to evolutionary biology. In the reported study, the repair efficiency of double strand DNA breaks was compared in six wild barley accessions from Israeli natural populations of H. spontaneum: three from mesic populations (one from Maalot and two from Mount Meron, Upper Galilee) and three from xeric populations (one from Wadi Quilt in the Judean Desert and two from Sede Boqer, in the northern Negev Desert). Pulsed field gel electrophoresis was used to score double-strand breaks of DNA (DSBs) caused by methyl methanesulphonate (MMS) treatment. All six accessions were also tested for heat tolerance: four of these, three xeric and one mesic (from Maalot population), were scored as heat tolerant whereas both accessions from Mount Meron population displayed heat sensitivity. MMS caused a significant increase in the level of DSBs relative to the control in all accessions. The major questions were whether and how the efficiency of DNA repair after mutagenic treatment is affected by the environmental conditions and accession's adaptation to these conditions. Differences were found among the accessions in the repair pattern. Plants of two out of the four heat tolerant accessions did not manage to repair DNA neither at 25 degrees Celsius nor at 37 degrees Celsius. The remaining two heat tolerant accessions significantly repaired the breaks at 37 degrees Celsius, but not at 25 degrees Celsius. By contrast, plants of the two heat susceptible accessions significantly lowered the level of DSBs at 25 degrees Celsius but not at 37 degrees Celsius. Therefore, the accessions that proved capable to repair the induced damages in DNA at one of the two temperatures displayed a pattern that may imply the existence of a negative feedback mechanism in regulation of genetic variation. Such a dependence of DNA integrity on environment and genotype may serve an important factor for maintaining relatively high level of mutability without increasing the genetic load.

Adaptation, Biological↗

PubMed2004

Mating within the meiotic tetrad and the maintenance of genomic heterozygosity.

Mating among the products of a single meiosis (automixis or meiotic parthenogenesis) is found in diverse groups of plant, animal, and fungal taxa. Restoration of the diploid stage is often strictly controlled and brings together products separated at the first meiotic division. Despite apparent similarities to diploid selfing, the theoretical prediction is that heterozygosity should be maintained on all chromosomes when it is linked to the centromeres and thus also segregates at the first meiotic division. Using the fungus Microbotryum, we directly test this prediction by linear tetrad analysis. The patterns of meiotic segregation for chromosome size variation (electrophoretic karyotypes) and PCR products (AFLP procedures) were determined for Microbotryum lineages native to North America and Europe. Our data reveal a surprisingly dynamic genome that is rich in heterozygosity and where size-dimorphic autosomes are common. The genetic variation agrees with the prediction of centromere-linked heterozygosity. This was observed to the greatest extent in the lineage of Microbotryum native to North America where there was consistent first-division segregation and independent assortment of multiple linkage groups. The data also show properties that distinguish the fungal sex chromosomes from the autosomes in both lineages of Microbotryum. We describe a scenario where the mating system of automixis with first-division restitution is the result of feedback mechanisms to control exposure of genetic load.

Basidiomycota↗

PubMed1993

A note on the reduction of the dynamics of multilocus diploid genetic systems with multiplicative fitness.

The dynamics of any diploid multilocus genetic system with two alleles and uniform dynamics per locus can be deduced from that of the corresponding single-locus system by trinomial sampling to produce the frequencies of the different mutant classes, provided that fitness is multiplicative, and there is linkage equilibrium (allowing for physical linkage, however). The component processes that can be considered are mutation, gene conversion, gamete production (with recombination) and random mating, and selection. If mutations occur according to Bernoulli trials, outcrossing sexual systems have a genetic load exactly deducible from that of the single-locus system.

Animals↗

PubMed1991

Screening for fetal and genetic abnormalities.

Screening for genetic abnormalities is an integral part of obstetrics. Prior to initiating screening, however, several prerequisites must be met: (i) capacity to alter clinical management, (ii) cost effectiveness, (iii) reliable means (usually assays) of assessment, and (iv) capacity to handle problems. In all pregnancies one should determine in systematic fashion whether family history places a pregnant woman at increased risk over the background risk of 2-3% congenital anomalies. All women over age 35 years at delivery should be offered prenatal cytogenetic testing, and women of all ages should be offered maternal serum alpha-fetoprotein screening for neural tube defects. Screening ostensibly normal populations is appropriate in certain ethnic groups to determine heterozygosity for selected disorders: Blacks for sickle-cell anaemia, Mediterranean people for beta-thalassaemia, Southeast Asians and Filipinos for alpha-thalassaemia, Ashkenazi Jews and perhaps French-Canadians for Tay-Sachs disease. Cystic fibrosis screening (delta F508 mutations) is not currently recommended for the general populations, but should be offered to relatives of an individual having delta F508 cystic fibrosis. Irrespective of the extent of screening programmes for Mendelian traits, the mutant allele will remain in the general population because by far the greatest genetic load lies in clinically normal heterozygotes, affected contributing far less to the load despite the obvious clinical effect.

Abortion, Legal↗