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PubMed2000

Stronger association with HLA-Cw6 than with corneodesmosin (S-gene) polymorphisms in Swedish psoriasis patients.

Psoriasis vulgaris is strongly associated with certain human leukocyte antigens, especially in early onset. The purpose of this study was to study the HLA-Cw6 allele and its contribution to disease susceptibility in a set of 104 families with at least two affected siblings. A sequencing method was utilized to examine the two exons that build up the antigen binding site of the C locus receptor. DNA from patients homozygous for Cw6 based on haplotype information were sequenced. The results confirmed the identity of the Cw6 allele in affected individuals with the consensus sequence for Cw*0602. We screened the set of families for psoriasis patients homozygous for Cw6 and found 11 individuals with a mean age at onset of 16.1 years. The corresponding figure for the Cw6 heterozygotes was 18.45 years and for the Cw6-negatives 22.36 years. This is indicative of a gene dose effect. We performed a transmission disequilibrium test (TDT) on the Cw6 allele per se, used as a biallelic marker. The analysis resulted in a P-value of 5.3 x 10(-17) (t167/nt45). This greatly exceeds our previous results of a TDT in the region, including microsatellite markers and single nucleotide polymorphisms (SNPs) in the coding part of the S gene (corneodesmosin), which is a suggested candidate gene in the region. The maximum nonparametric linkage (NPL) value was also reached using HLA-C as a marker. We conclude that Cw6 is the allele which shows the highest degree of association with psoriasis in our set of families and we propose that it directly influences the age at onset of the disease rather than increasing the genetic load in accordance with a polygenic theory.

Alleles↗

PubMed1997

Brother-sister marriage in Roman Egypt.

According to official census returns from Roman Egypt (first to third centuries CE) preserved on papyrus, 23.5% of all documented marriages in the Arsinoites district in the Fayum (n = 102) were between brothers and sisters. In the second century CE, the rates were 37% in the city of Arsinoe and 18.9% in the surrounding villages. Documented pedigrees suggest a minimum mean level of inbreeding equivalent to a coefficient of inbreeding of 0.0975 in second century CE Arsinoe. Undocumented sources of inbreeding and an estimate based on the frequency of close-kin unions (corrected downwards to 30% for Arsinoe) indicate a mean coefficient of inbreeding of F = 0.15-0.20 in Arsinoe and of F = 0.10-0.15 in the villages at the end of the second century CE. These values are several times as high as any other documented levels of inbreeding. A schematic estimate of inbreeding depression in the offspring of full sibling couples indicates that fertility in these families had to be 20-50% above average to attain reproduction at replacement level. In the absence of information on the amount of genetic load in this population, this estimate may be too high.

Censuses↗

PubMed2001

Inbreeding depression in small populations of self-incompatible plants.

Self-incompatibility (SI) is a widespread mechanism that prevents inbreeding in flowering plants. In many species, SI is controlled by a single locus (the S locus) where numerous alleles are maintained by negative frequency-dependent selection. Inbreeding depression, the decline in fitness of selfed individuals compared to outcrossed ones, is an essential factor in the evolution of SI systems. Conversely, breeding systems influence levels of inbreeding depression. Little is known about the joint effect of SI and drift on inbreeding depression. Here we studied, using a two-locus model, the effect of SI (frequency-dependent selection) on a locus subject to recurrent deleterious mutations causing inbreeding depression. Simulations were performed to assess the effect of population size and linkage between the two loci on the level of inbreeding depression and genetic load. We show that the sheltering of deleterious alleles linked to the S locus strengthens inbreeding depression in small populations. We discuss the implications of our results for the evolution of SI systems.

Alleles↗

PubMed2004

Genetic epidemiology of alcohol-induced blackouts.

BACKGROUND: Alcohol-induced blackouts (ie, periods of anterograde amnesia) have received limited recent research attention. OBJECTIVE: To examine the genetic epidemiology of lifetime blackouts and having had 3 or more blackouts in a year, including analyses controlling for the frequency of intoxication. DESIGN, SETTING, AND PARTICIPANTS: Members of the young adult Australian Twin Register, a volunteer twin panel born between January 1, 1964, and December 31, 1971, were initially registered with the panel as children by their parents between 1980 and 1982. They underwent structured psychiatric telephone interviews from February 1996 through September 2000. The current sample contains 2324 monozygotic and dizygotic twin pairs (mean [SD] age 29.9 [2.5] years) for whom both twins' responses were coded for blackout questions and for frequency of intoxication. MAIN OUTCOME MEASURE: Outcome Measure Data on lifetime blackouts and having had 3 or more blackouts in a year were collected within an examination of the genetic epidemiology of alcoholism. RESULTS: A lifetime history of blackouts was reported by 39.3% of women and 52.4% of men; 11.4% of women and 20.9% of men reported having had 3 or more blackouts in a year. The heritability of lifetime blackouts was 52.5% and that of having had 3 or more blackouts in a year was 57.8%. Models that controlled for frequency of intoxication found evidence of substantial genetic contribution unique to risk for the blackouts and a significant component of genetic risk shared with frequency of intoxication. CONCLUSIONS: The finding of a substantial genetic contribution to liability for alcohol-induced blackouts including a component of genetic loading shared with frequency of intoxication may offer important additional avenues to investigate susceptibility to alcohol-related problems.

Adult↗

PubMedDate not supplied

Synthesis and properties of a double translocation heterozygote involving a stable ring-of-six interchange in the German cockroach.

The synthesis and properties of a new double translocation heterozygote in B germanica, combining T (8;9) with the progressive interchange T (4;5;10), are described. Competitiveness and sterility data indicate that males are promising candidates for a "field" experiment in genetic control of a cockroach. Sterility from genetic load and embryonic trapping is complete. Disjunction properties of the parental interchanges are similar to those found in cells of the double males, but chiasma frequency of the interchanged chromosomes is increased. Evidence of a possible relationship between chiasma formation and disjunction type is discussed.

Animals↗

PubMed1990

Some consideration on diversifying selection.

The diversifying selection due to genotype-environment interaction can increase the genetic variation in natural populations. It is known, however, that the conditions for stable genetic polymorphism or marginal overdominance are quite restricted in this selection model. In this paper a simple model of diversifying selection was examined, and the following results were obtained: (1) Even when the conditions for marginal overdominance are not satisfied, if the diversifying selection is operating, the frequency of mutants can be higher than that in the case of simple mutation-selection balance. (2) This selection model causes a large amount of genetic load (environment load), even when the conditions for marginal overdominance are not satisfied, namely even when the equilibrium frequency of mutant is very low. From these results it can be concluded that the number of loci on which this type of diversifying selection is operating is very small, if any.

Animals↗

PubMed1979

Trenimon: biochemical, physiological and genetic effects on cells and organisms.

The trifunctional alkylating mutagen Trenimon interferes with the genetic material of a variety of organisms and test systems with respect to the induction of point and chromosomal mutations, sister-chromatid exchanges, recombination phenomena and phage induction. Beneath these mutagenic effects several biochemical and cell physiological aspects have been investigated. In this review we discuss chemical and cell physiological effects of Trenimon, aspects of cancer therapy with Trenimon and genetic effects induced by Trenimon. The available data on mutagenic effects of Trenimon are presented according to organisms or test systems. A short discussion on a possible genetic load by therapy with Trenimon in man concludes this review. DNA damage, especially the induction of cross-linkings, seems to represent the common reason for most of the described effects of Trenimon on cells and organisms.

Animals↗

PubMed2000

P300 in family studies of schizophrenia: review and critique.

The published studies using P300 event-related potential (ERP) as a vulnerability marker in schizophrenia have been summarized and reviewed. Several factors across sibling, offspring, and familial studies appear to contribute to the variegated findings with respect to the utility of P300 as a vulnerability marker for schizophrenia. These include how subject samples are defined in terms of their genetic loading for schizophrenia, sample size, ERP methodology, and the relationship of P300 measures to neuropsychological test outcomes. It was concluded that the P300 holds promise as a vulnerability marker for schizophrenia, if used in conjunction with other neuroimaging and neuropsychological testing methods.

Adolescent↗

PubMed2002

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.

Adult↗

PubMed2003

Spatial working memory as an endophenotype for schizophrenia.

BACKGROUND: Spatial working memory impairments are among the neurocognitive deficits that may mark genetic predisposition toward schizophrenia. We previously reported that impairment on the spatial span subtask of the Wechsler Adult Intelligence Scale-Revised increased in a dose-dependent manner with increasing genetic predisposition toward schizophrenia in a sample of discordant twins; however, it remains to be determined whether these deficits reflect difficulties with encoding, maintenance, manipulation, time-tagging of visual spatial information, storage capacity, or complex motor response. METHODS: We developed a spatial delayed response task in which memory set size was parametrically varied, holding constant manipulation and decision processes. We then reassessed 80 of the previously studied twins (17 probands with 8 monozygotic co-twins and 13 dizygotic co-twins, and 42 healthy twins). RESULTS: The spatial delayed response task was sensitive to genetic loading for schizophrenia but did not provide evidence for capacity limitations in probands or their co-twins. CONCLUSIONS: The findings suggest that deficits in the encoding or storage aspects of short-term spatial mnemonic processing may be an effective endophenotypic marker for schizophrenia.

Female↗

PubMed1975

A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities.

Data from a chromosome examination of 14,069 consecutive newborn infants is presented. Successful karyotypes were obtained on 13,939 babies using short-term blood cultures and conventional staining methods. Of those, 13,645 babies had normal chromosomes; 64 (0.46%) had a major chromosome abnormality; and 230 (1.65%) had a marker chromosome; giving a total of 294 (2.11%) babies with a major chromosome abnormality or distinctive marker chromosomes. Six male babies with sex chromosome abnormalities had a 47,XXY and four a 47,XYY karyotype, and three were mixoploids. Five female babies had a 47,XXX karytotype and two were mixoploids. There were three babies with ambiguous external genitalia, all with normal karyotypes. Fourteen babies had 21-trisomy; there were three 18-trisomics and one 13-trisomic. The mother of one 18-trisomy baby had a balanced (18;21) translocation. Twenty-four infants had a balanced chromosome rearrangement. Eleven of these were reciprocal and thirteen were Robertsonian translocations. One baby had an unbalanced derivative chromosome resulting from an 18;11 insertion. Two infants with additional unidentified fragments were detected. Two hundred and thirty babies (1:60) carying distinctive chromosome variants were detected. The commonest variant was the Yq+ among males (0.89%). Other common variants involved the short arms of the D and G groups (0.32% and 0.57%, respectively) 16q+ (0.09%), and 1q+ (0.04%). The results of the present study when combined with five other comparable studies, thus comprising a total of 46,150 newborn infants, indicates that the frequency of major chromosome abnormalities is between 1:150 and 1:200 live-born babies. This represents a small proportion of all conceptuses with chromosome abnormalities, which has been estimated as being approximately 1:20. It is thus clear that chromosome abnormalities form a major part of the genetic load carried by the human population. The development of chromosome banding techniques already has increased, and with further increase, the complexities of human cytogenetics and may reveal many additional rearrangements undetectable by conventional methods.

Canada↗

PubMed2003

Severity of obstetric complications and risk of adult schizophrenia in male patients: a case-control study.

OBJECTIVE: Obstetric complications may be an etiologically important factor in the development of schizophrenia. The aim of this study was to evaluate whether the risk for developing schizophrenia in adult life is increased in individuals with more severe obstetric complications at birth. METHODS: To this end, mothers were interviewed to gather data about obstetric complications. The 'midwife protocol' of Parnas and colleagues was used to quantify the presence and entity of obstetric complications. We studied the frequency distribution and the severity of obstetric complications in 64 male DSM IV schizophrenic patients. The genetic load was reduced by using 81 brothers who were not psychiatric patients as controls. Odds ratios for the effects of obstetric complications, maternal age, birth order and birth weight were calculated using conditional logistic regression. RESULTS: The only factor found to have a significant effect on the risk of schizophrenia was the overall measure of obstetric complications at birth. The history of obstetric complications was higher in schizophrenic patients than in their siblings. CONCLUSION: The results seem to confirm the hypothesis that obstetric complications may contribute to increased vulnerability to the disease, in addition to genetic risk factors.

Adult↗

PubMed1987

A model of evolution for accumulating genetic information.

By taking into account recent knowledge of multigene families and other repetitive DNA sequences, a model of evolution by gene duplication for accumulating genetic information is studied. Genetic information is defined as the sum of distinct functions that the gene family can perform. A coefficient, "genetic diversity" is defined and used in this study, that is highly correlated with genetic information. Initially, a multigene family with a few gene copies is assumed, and natural selection starts to work on this gene family to increase genetic diversity contained in the gene family. As an important mechanism, unequal crossing-over is incorporated. Together with mutation, it is responsible for supplying genetic variability among individuals for selection to work. A specific model, in which individuals with less genetic diversity are selectively disadvantageous, has been studied in detail. Through approximate theoretical analysis and extensive Monte Carlo studies, it has been shown that the system is an extremely efficient way to accumulate genetic information. For attaining one gene, the genetic load is much smaller under this model than under the traditional model of natural selection. The model may be applied to the process of origin of multigene families with diverse copy members such as those of immunoglobulin or cytochrome P450. In general, the process of creating new genes by duplication might be somewhere between the present and the traditional models.

Biological Evolution↗

PubMed1998

Ionizing radiation and genetic risks. VIII. The concept of mutation component and its use in risk estimation for multifactorial diseases.

Multifactorial diseases, which include the common congenital abnormalities (incidence: 6%) and chronic diseases with onset predominantly in adults (population prevalence: 65%), contribute substantially to human morbidity and mortality. Their transmission patterns do not conform to Mendelian expectations. The model most frequently used to explain their inheritance and to estimate risks to relatives is a Multifactorial Threshold Model (MTM) of disease liability. The MTM assumes that: (i) the disease is due to the joint action of a large number of genetic and environmental factors, each of which contributing a small amount of liability, (ii) the distribution of liability in the population is Gaussian and (iii) individuals whose liability exceeds a certain threshold value are affected by the disease. For most of these diseases, the number of genes involved or the environmental factors are not fully known. In the context of radiation exposures of the population, the question of the extent to which induced mutations will cause an increase in the frequencies of these diseases has remained unanswered. In this paper, we address this problem by using a modified version of MTM which incorporates mutation and selection as two additional parameters. The model assumes a finite number of gene loci and threshold of liability (hence, the designation, Finite-Locus Threshold Model or FLTM). The FLTM permits one to examine the relationship between broad-sense heritability of disease liability and mutation component (MC), the responsiveness of the disease to a change in mutation rate. Through the use of a computer program (in which mutation rate, selection, threshold, recombination rate and environmental variance are input parameters and MC and heritability of liability are output estimates), we studied the MC-heritability relationship for (i) a permanent increase in mutation rate (e.g., when the population sustains radiation exposure in every generation) and (ii) a one-time increase in mutation rate. Our investigation shows that, for a permanent increase in mutation rate of 15%, MC in the first few generations is of the order of 1-2%. This conclusion holds over a broad range of heritability values above about 30%. At equilibrium, however, MC reaches 100%. For a one-time increase in mutation rate, MC reaches its maximum value (of 1-2%) in the first generation, followed by a decline to zero in subsequent generations. These conclusions hold for so many combinations of parameter values (i.e., threshold, selection coefficient, number of loci, environmental variance, spontaneous mutation rate, increases in mutation rate, levels of 'interaction' between genes and recombination rates) that it can be considered to be relatively robust. We also investigated the biological validity of the FLTM in terms of the minimum number of loci, their mutation rates and selection coefficients needed to explain the incidence of multifactorial diseases using the theory of genetic loads. We argue that for common multifactorial diseases, selection coefficients are small in present-day human populations. Consequently, with mutation rates of the order known for Mendelian genes, the FLTM with a few loci and weak selection provides a good approximation for studying the responsiveness of multifactorial diseases to radiation exposures.

Adult↗

PubMed2026

Runs of Homozygosity Predict Inbreeding Depression Across Taxa: A Systematic Review and Meta-Analysis.

Measuring inbreeding via runs of homozygosity (ROH) captures realized autozygosity and can infer inbreeding timing through ROH length. A growing body of literature links the proportion of the genome in ROH (FROH) to fitness outcomes across taxa, yet systematic synthesis has been lacking. Here, we conduct a systematic review and meta-analysis to quantify FROH-fitness associations, identify drivers of variation and derive conservation-relevant recommendations. Narrative synthesis of 44 studies revealed that inbreeding depression operates through multiple interconnected pathways (survival, maternal effects, disease susceptibility, reproduction). Critically, purging cannot be relied upon to eliminate inbreeding depression as substantial fitness costs persist even in historically small populations. Meta-analysis of 62 effect sizes revealed a significant negative association between genomic inbreeding and fitness across taxa (Fisher's z = -0.103, r = -0.10, p < 0.0001). Study group, whether wildlife, livestock or humans, explained 22.5% of variance, with wildlife showing strongest effects (6-fold stronger than humans). Survival traits showed the greatest sensitivity to the effects of ROH (r = -0.22). Additionally, ROH detection methodology significantly influenced effect sizes: comprehensive approaches (all ROH lengths) detected stronger depression (r = -0.18) than long-ROH-only analyses (r = -0.08, p = 0.008), indicating cumulative genetic load matters. Overall, results indicate significant but variable fitness associations with ROH, with effect magnitude depending on biological context and methodological approach. Comprehensive ROH-based approaches show promise as conservation monitoring tools, but limited wildlife studies, particularly for non-mammalian taxa, highlight an urgent need for standardized protocols and expanded empirical research.

Animals↗

PubMed2006

Chromosomal basis of viability differences in Tigriopus californicus interpopulation hybrids.

Crosses between populations of Tigriopus californicus result in backcross and F2 hybrid breakdown for a variety of fitness related measures. The magnitude of this hybrid breakdown is correlated with evolutionary divergence. We assessed the chromosomal basis of viability differences in nonrecombinant backcross hybrids using markers mapped to individual chromosomes. To assess effects of evolutionary divergence we crossed one population to three different populations: two distantly related (approximately 18% mitochondrial COI sequence divergence) and one closely related (approximately 1% mitochondrial COI sequence divergence). We found that all three interpopulation crosses resulted in significant deviations from expected Mendelian ratios at a majority of the loci studied. In all but one case, deviations were due to a deficit of parental homozygotes. This pattern implies that populations of T. californicus carry a significant genetic load, and that a combination of beneficial dominance and deleterious homozygote-heterozygote interactions significantly affects hybrid viability. Pairwise tests of linkage disequilibrium detected relatively few significant interactions. For the two divergent crosses, effects of individual chromosomes were highly concordant. These two crosses also showed higher heterozygote excess in females than males across the vast majority of chromosomes.

Animals↗

PubMed1999

Neutral evolution of mutational robustness.

We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population's limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network's adjacency matrix. Moreover, the average number of neutral mutant neighbors per individual is given by the matrix spectral radius. These results quantify the extent to which populations evolve mutational robustness-the insensitivity of the phenotype to mutations-and thus reduce genetic load. Because the average neutrality is independent of evolutionary parameters-such as mutation rate, population size, and selective advantage-one can infer global statistics of neutral network topology by using simple population data available from in vitro or in vivo evolution. Populations evolving on neutral networks of RNA secondary structures show excellent agreement with our theoretical predictions.

Evolution, Molecular↗

PubMed2004

FAMMM syndrome: pathogenesis and management.

Familial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Pathogenesis of this syndrome has not been fully investigated. Across multiple studies, germline mutations in the INK4a antioncogene encoding p16 protein were found on average in approximately 40% of the FAMMM syndrome. Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer. Melanoma can develop from numerous atypical moles as well as de novo. A proper diagnosis of the syndrome and early application of prophylactics decreases the risk of neoplastic transformation of melanocytes.

Cell Transformation, Neoplastic↗