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PubMed1996

[Evolution modes of eukaryote retrotransposons].

A number of general problems of molecular macroevolution of retroposons were examined, including the question of the ratio of the contributions of genomic replication and retrotransposition to mutational variability of retrotransposons, as well as that of the influence of stress-induced transpositional variability on the rate of evolution and the phylogenetic trees of retrotransposons. It is thought that the substitution fixation rate in genes of retrotransposons is determined by the transposition rate and the probability of mutation upon replication of copies of retransposons in the genome and upon retrotransposition, as well as by selection stabilizing the function of proteins of the retroreplicative mechanism. By means of molecular-evolutionary parameters, estimated for Drosophila retrotransposons and animal retroviruses, it was shown that spontaneous retrotransposition makes the dominant contribution to the frequency of mutation, and the expected fixation rate of nucleotide substations is on the order of 2 x 10(-8) per position per year. This version of evolution of retrotransposons agrees with the results of phylogenetic analysis of trees of macroevolution. Another version, associated with stress-induced transpositions, gives a very high rate of evolution, on the order 3 x 10(-6) fixations of nucleotide substitutions per position per year. This version seems improbable, as it leads to a significant hidden genetic load.

Animals↗
PubMed2006

Suffering in silence: why a developmental psychopathology perspective on selective mutism is needed.

A developmental psychopathology perspective is offered in an effort to organize the existing literature regarding the etiology of selective mutism (SM), a relatively rare disorder in which a child consistently fails to speak in 1 or more social settings (e.g., school) despite speaking normally in other settings (e.g., home). Following a brief description of the history, prevalence, and course of the disorder, multiple pathways to the development of SM are discussed, with a focus on the various genetic, temperamental, psychological, and social/environmental systems that may be important in conceptualizing this unusual childhood disorder. The authors propose that SM develops due to a series of complex interactions among the various systems reviewed (e.g., a strong genetic loading for anxiety interacts with an existing communication disorder, resulting in heightened sensitivity to verbal interactions and mutism in some settings). Suggestions are provided for future longitudinal, twin/adoption, molecular genetic, and neuroimaging studies that would be particularly helpful in testing the pathways perspective on SM.

Child↗
PubMed1993

[Genetic disorders in the pediatric population in Orava].

The study is focused on genetic characterization of the child population of the Orava region, where genetic isolates persisted as long as the middle of this century. Active screening for genetic pathology over a period of 5 years involved examination of 1058 children aged 0-14 years. Genetically determined pathological conditions were diagnosed in 757 children, which represents 1.67% of the child population of this region. Chromosomal aberrations were established in 55 children (0.12%), monogenic diseases in 193 children (0.43%), of these autosomal recessive conditions in 88 children (0.19%), and multifactorially determined conditions in 478 children (1.06%). Focal occurrence of an inherited disease was not recorded. Genetic load of the population studied was found to be comparable to that in panmictic populations. The occurrence of diseases inherited as autosomal recessive traits suggests that the influence of genetic isolates does no longer persist in Orava.

Adolescent↗
PubMed1997

About the origin of retroviruses and the co-evolution of the gypsy retrovirus with the Drosophila flamenco host gene.

The gypsy element of Drosophila melanogaster is the first retrovirus identified so far in invertebrates. According to phylogenetic data, gypsy belongs to the same group as the Ty3 class of LTR-retrotransposons, which suggests that retroviruses evolved from this kind of retroelements before the radiation of vertebrates. There are other invertebrate retroelements that are also likely to be endogenous retroviruses because they share with gypsy some structural and functional retroviral-like characteristics. Gypsy is controlled by a Drosophila gene called flamenco, the restrictive alleles of which maintain the retrovirus in a repressed state. In permissive strains, functional gypsy elements transpose at high frequency and produce infective particles. Defective gypsy proviruses located in pericentromeric heterochromatin of all strains seem to be very old components of the genome of Drosophila melanogaster, which indicates that gypsy invaded this species, or an ancestor, a long time ago. At that time, Drosophila melanogaster presumably contained permissive alleles of the flamenco gene. One can imagine that the species survived to the increase of genetic load caused by the retroviral invasion because restrictive alleles of flamenco were selected. The characterization of a retrovirus in Drosophila, one of the most advanced model organisms for molecular genetics, provides us with an exceptional clue to study how a species can resist a retroviral invasion.

Animals↗
PubMed1995

[Genetic analysis and elaboration of principles for predicting malignant tumors in families of patients with stomach cancer and primary multiple malignant neoplasms].

The results of familial population analysis of stomach cancer and multiple primary malignant tumors (MPMTs) are presented. The data obtained provide evidence for the multifactorial nature of stomach cancer. Hereditary factors accounted for 32% of the general predisposition of individuals to stomach cancer. The age-related character of stomach cancer was established. Genetic heterogeneity of this tumor is suggested by the data obtained. Significant genetic commonness in the inheritance of stomach, colon, Genetic Analysis and Prognosis for Malignant Tumors in breast, endometrial, and ovarian cancer in families of MPMT patients was demonstrated on the basis of the obtained genetic correlations between tumor types in MPMT patients and solitary tumors in members of their families. The greatest genetic load was shown for families of MPMT patients, as compared with families of patients with solitary tumors, the coefficient of MPMT inheritance being equal to 77.4%. The data on the genetic character of stomach cancer and MPMT formed the basis for the identification of criteria for developing methodological approaches to the screening of individuals from risk groups to facilitate early diagnosis and prevention of cancer.

Age Distribution↗
PubMed2026

The value of structural variants to conservation genomics in the pangenome era.

Structural variants (SVs) comprise an axis of genetic diversity with strong consequences for phenotype and fitness, making them a potentially important target for conservation genomics. Here, we review how and why SVs can play a role in conservation genomics; the different types of SVs and how they can affect phenotype; and how pangenomes and long-read sequencing are illuminating their evolution in populations, including small populations and those of conservation concern. SVs comprise multinucleotide mutations including insertions, deletions, transpositions, inversions, and other multinucleotide mutations, often overlapping genes and other functional genome regions. As a result, SVs often play important roles in phenotypic evolution and local adaptation and can contribute substantially to genetic load in inbred populations. However, our understanding of the factors influencing SV diversity in populations is still in its infancy and is complicated by the vast range of sizes, effects, and mechanisms of formation of these mutations. We argue that SVs are an important axis of genetic diversity which should be characterized alongside more traditional metrics of genetic diversity in conservation contexts. There are a number of analytical challenges to detecting and studying SVs, but analyses aimed at understanding the role of SVs in inbreeding load and population health are rapidly becoming realizable goals, accelerated by new technologies and analytical approaches. New tools, including population-scale long-read sequencing and pangenome approaches, are beginning to make SVs accessible in ways which can be readily applied in conservation settings.

Genomic Structural Variation↗
PubMed2006

Genetic structure at range edge: low diversity and high inbreeding in Southeast Asian mangrove (Avicennia marina) populations.

Understanding the genetic composition and mating systems of edge populations provides important insights into the environmental and demographic factors shaping species' distribution ranges. We analysed samples of the mangrove Avicennia marina from Vietnam, northern Philippines and Australia, with microsatellite markers. We compared genetic diversity and structure in edge (Southeast Asia, and Southern Australia) and core (North and Eastern Australia) populations, and also compared our results with previously published data from core and southern edge populations. Comparisons highlighted significantly reduced gene diversity and higher genetic structure in both margins compared to core populations, which can be attributed to very low effective population size, pollinator scarcity and high environmental pressure at distribution margins. The estimated level of inbreeding was significantly higher in northeastern populations compared to core and southern populations. This suggests that despite the high genetic load usually associated with inbreeding, inbreeding or even selfing may be advantageous in margin habitats due to the possible advantages of reproductive assurance, or local adaptation. The very high level of genetic structure and inbreeding show that populations of A. marina are functioning as independent evolutionary units more than as components of a metapopulation system connected by gene flow. The combinations of those characteristics make these peripheral populations likely to develop local adaptations and therefore to be of particular interest for conservation strategies as well as for adaptation to possible future environmental changes.

Australia↗
PubMed1989

Evolution of chromosome bands: molecular ecology of noncoding DNA.

Giemsa dark bands, G-bands, are a derived chromatin character that evolved along the chromosomes of early chordates. They are facultative heterochromatin reflecting acquisition of a late replication mechanism to repress tissue-specific genes. Subsequently, R-bands, the primitive chromatin state, became directionally GC rich as evidenced by Q-banding of mammalian and avian chromosomes. Contrary to predictions from the neutral mutation theory, noncoding DNA is positionally constrained along the banding pattern with short interspersed repeats in R-bands and long interspersed repeats in G-bands. Chromosomes seem dynamically stable: the banding pattern and gene arrangement along several human and murine autosomes has remained constant for 100 million years, whereas much of the noncoding DNA, especially retroposons, has changed. Several coding sequence attributes and probably mutation rates are determined more by where a gene lives than by what it does. R-band exons in homeotherms but not G-band exons have directionally acquired GC-rich wobble bases and the corresponding codon usage: CpG islands in mammals are specific to R-band exons, exons not facultatively heterochromatinized, and are independent of the tissue expression pattern of the gene. The dynamic organization of noncoding DNA suggests a feedback loop that could influence codon usage and stabilize the chromosome's chromatin pattern: DNA sequences determine affinities of----proteins that together form----a chromatin that modulates----rate constants for DNA modification that determine----DNA sequences. Theories of hierarchical selection and molecular ecology show how selection can act on Darwinian units of noncoding DNA at the genome level thus creating positionally constrained DNA and contributing minimal genetic load at the individual level.

Base Sequence↗
PubMed1978

Inbreeding effects: evidence for a genetic system which regulates viability in Drosophila melanogaster populations.

Mating studies on individual couples of Drosophila melanogaster allowed the structure of inbred populations in terms of egg hatchability and egg-to-adult survival to be elucidated. The comparison between inbred (from brother-sister matings) and control (randomly crossed) populations distinguished between couples sensitive and insensitive to inbreeding. Mendelian ratios were observed for this "phenotypic trait" in the progeny of single couples. These ratios and a double mating experiment indicated that a gene or gene complex implicated in morphogenetic events blocked development during embryonic and larvo-pupal stages. The expression of this lethal gene in homozygous embryos depended on the genetic makeup of both parental flies, i.e., on male and female factors which act as regulatory components. Homozygous embryos which survived the first critical phase (from fertilization to hatching) continued to develop normally until the larvo-pupal period, when they died. Lethality was also modulated by the cytoplasmic composition of the parental eggs, as shown by taxonomic analysis and the double mating experiment. The results account for lethality throughout development due to inbreeding. They lead to an estimated genetic load from laying to adult stage of one "lethal equivalent".

Animals↗
PubMed2025

Sexual selection, genomic evolution and population fitness in Drosophila pseudoobscura.

Sexual selection shapes the genome in unique ways. It is also likely to have significant fitness consequences, such as purging deleterious mutations from the genome or conversely maintaining genetic load in a population via sexual conflict. Here, we examined what the influence of sexual selection has on genomic variation potentially underlying population fitness using experimentally evolved Drosophila pseudoobscura populations. Sexual selection was manipulated by keeping replicate lines in elevated polyandry or strict monogamy for approximately 200 generations followed by individual-based sequencing. Using pi (π), fixation index (Fst)and recombination rate measures, we confirmed signatures of selection were not dispersed but mainly localized to the third and X chromosome. Overall mutational load was similar between lines but our analysis of the distribution of fitness effects revealed considerable variation between lines and chromosomes. Furthermore, we found that the distribution of transposable elements differs between the lines, with a higher load in monogamous lines. Our results suggest that complex interactions between purifying selection and sexual conflict are shaping the genome, particularly on chromosome 3 and the sex chromosome; sexual selection influences divergence across chromosomes but in a more complex way than proposed by simple 'purging' of deleterious loci.

Animals↗
PubMed2001

[Daltonism and the genetics of aging].

In order to test whether mutations giving rise to color vision deficiencies are more frequently inherited from older fathers, an exhaustive screening of births in the Namur region has allowed to isolate a sample of 225 descending sons of maternal grandfathers who were older than 45 years at their daughter's birth. The incidence of color vision defects was compared between this set of cases and three control groups totalling 959 boys from independent families. While these comparisons were not conclusive, we propose new hypotheses concerning the population dynamics of color vision deficiencies. Neomutations in X-linked pigment genes may be a marker of the overall genetic load borne by the X chromosome. Selection against such loaded X chromosomes may occur in the second generation, either in the course of embryogenesis, or during female gametogenesis. The future assessment of these novel hypotheses relies on the arbitration of molecular genetics.

Aging↗
PubMed2004

Multigenic control of hepatic iron loading in a murine model of hemochromatosis.

BACKGROUND & AIMS: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. METHODS: To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. RESULTS: We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. CONCLUSIONS: Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.

Animals↗
PubMedDate not supplied

Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees.

Concordance to antidepressant response in members of the same family is a common observation in clinical practice. However, few published data support this view; moreover families with affected members responder to the same antidepressant have been poorly studied. We have analyzed 45 pairs consisting of one mood disorder fluvoxamine double-responder proband and one first-degree relative with known outcome to fluvoxamine treatment. Among 45 pairs 30 (67%) were concordant for good response to fluvoxamine. In family pedigrees of concordant pairs we found a significantly higher distribution of bipolar forms in secondary cases than in families of non concordant pairs (14.9% vs 3.9% P = 0.039) suggesting that concordance to antidepressant therapy could select families with higher genetic loading.

Adult↗
PubMed1972

Mutation rate and dominance of genes affecting viability in Drosophila melanogaster.

Spontaneous mutations were allowed to accumulate in a second chromosome that was transmitted only through heterozygous males for 40 generations. At 10-generation intervals the chromosomes were assayed for homozygous effects of the accumulated mutants. From the regression of homozygous viability on the number of generations of mutant accumulation and from the increase in genetic variance between replicate chromosomes it is possible to estimate the mutation rate and average effect of the individual mutants. Lethal mutations arose at a rate of 0.0060 per chromosome per generation. The mutants having small effects on viability are estimated to arise with a frequency at least 10 times as high as lethals, more likely 20 times as high, and possibly many more times as high if there is a large class of very nearly neutral mutations.-The dominance of such mutants was measured for chromosomes extracted from a natural population. This was determined from the regression of heterozygous viability on that of the sum of the two constituent homozygotes. The average dominance for minor viability genes in an equilibrium population was estimated to be 0.21. This is lower than the value for new mutants, as expected since those with the greatest heterozygous effect are most quickly eliminated from the population. That these mutants have a disproportionately large heterozygous effect on total fitness (as well as on the viability component thereof) is shown by the low ratio of the genetic load in equilibrium homozygotes to that of new mutant homozygotes.

Crosses, Genetic↗
PubMed2006

Dose-response relationship between number of comorbid anxiety disorders in adolescent bipolar/unipolar disorders, and psychosis, suicidality, substance abuse and familiality.

OBJECTIVES: To ascertain rates of panic, obsessive-compulsive (OCD) and social phobic disorders among adolescents with bipolar disorder (BP), unipolar major depressive disorder (MDD) and psychiatric comparison patients, to assess their relationships to suicidality, psychosis, comorbidity patterns and familiality. METHODS: The first author (SCD) interviewed 313 Latino adolescents using a structured interview based on the SCID. Family history was ascertained by live interview or interview by proxy. Patients were classified as BP, MDD, or non-affectively ill comparison controls (CC). Data regarding suicidality and psychosis were collected. Regression analysis was used to test associations and control for confounding effects. Positive likelihood ratios were used to measure the dose-response relationships between number of anxiety disorders and measures of severity of illness and familial loading for affective illness. RESULTS: Of the total sample, 36.7% were BP, 44.7% MDD and 18.5% CC. In BP vs. MDD the odds of panic disorder were 4.4, of OCD 5.1, and of social phobia 3.3. MDD, in turn, were more likely to have these disorders than CC. BP (but not MDD) with panic disorder and social phobia, were more likely to have suicidal ideation; among the anxiety disorders, only social phobia was associated with having greater odds of suicide attempts. Among BP and MDD, patients with all three anxiety disorders were more likely to be psychotic. Presence of any mood disorder among first-degree relatives substantially increased the odds of having panic disorder and social phobia. The presence of one comorbid anxiety disorder increased the odds of having another. Finally, there were dose-response relationships between number of anxiety disorders and measures of severity of illness and familial loading for affective illness. LIMITATIONS: Single interviewer using the SCID; cross sectional exploratory study. CONCLUSIONS: BP adolescents have a greater anxiety disorder burden than their MDD counterparts. The results are compatible with the hypothesis that heavy familial-genetic loading for affective illness in juveniles is associated with bipolarity, cumulative anxiety disorder comorbidity, suicidality and psychosis. These observations are in line with pioneering psychopathologic observation in the early 1900s by two French psychiatrists, Gilbert Ballet and Pierre Kahn, who saw common ground between what until then had been considered the distinct categories of the neuroses and cyclothymic (circular) psychoses. This perspective has much in common with current complex genetic models of anxious diatheses in bipolar disorder.

Adolescent↗
PubMed2025

Conservation Arks: Genomic Erosion and Inbreeding in an Abundant Island Population of Koalas.

The persistence of many threatened species depends on isolated habitat patches such as conservation parks, fenced reserves, and islands. While these 'conservation arks' provide refuge from many contemporary threats, they can also pose risks of genetic diversity loss and inbreeding depression, further exacerbating extinction risk. A pertinent example is the Kangaroo Island koala population in South Australia that originated from a few translocated founding individuals in the 1920s but now sustains a large population with a low prevalence of infectious disease. We investigated the extent and consequences of founder effects on genomic diversity, inbreeding, and adaptive potential in Kangaroo Island koalas by comparing them with mainland Australian populations using high-coverage whole genomes. Our findings support sharp, recent declines in effective population sizes (Ne) in both mainland and Kangaroo Island populations. However, Kangaroo Island koalas had much lower individual and population-level diversity. Together with longer and more numerous runs of homozygosity and an increased proportion of homozygous genetic load, these results support the hypothesis that a severe bottleneck has contributed to inbreeding and maladaptation in Kangaroo Island koalas. While Kangaroo Island has the potential to conserve a viable population of koalas, we recommend genetic rescue to restore diversity and mitigate inbreeding depression in this isolated population. Our results emphasise the need for longitudinal genomic monitoring and genetic management to maintain long-term viability and resilience in potential conservation arks. Understanding the demographic history of such populations will help inform future conservation aimed at preventing genetic erosion and preserving biodiversity.

Animals↗
PubMed2006

Familial aggregation of eye-tracking endophenotypes in families of schizophrenic patients.

BACKGROUND: Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility. OBJECTIVE: To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain. DESIGN: Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients. SETTING: Outpatient clinics. PARTICIPANTS: Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited. MAIN OUTCOME MEASURES: Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain. RESULTS: The sibling intraclass correlation coefficient of the predictive pursuit gain (r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain (r = 0.02-0.20) (P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P<.001) but relatively low heritability in the traditional maintenance pursuit measure (heritability = 0.27, SE = 0.21; P = .08). CONCLUSION: These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.

Adult↗
PubMed2006

Association of Huntington's disease and schizophrenia-like psychosis in a Huntington's disease pedigree.

BACKGROUND: Huntington's disease (HD) is a dominantly inherited, neurodegenerative disorder due to expansion of a polymorphic trinucleotide repeat in the short arm of chromosome 4. Clinical manifestations consist of a triad of choreic movements, cognitive decline and psychiatric syndromes starting in the fourth to fifth decade. Psychiatric manifestations vary and may precede motor and cognitive changes. Personality changes and depression occur most commonly. Paranoid schizophrenia-like symptoms occur in 6% to 25% of cases. CASE REPORT: We describe a 55 year-old woman with an 8 yearlong history of behavioural changes, multi-thematic delusions and auditory hallucinations. History and mental state examination were suggestive of paranoid schizophrenia. Neurological examination revealed discrete, involuntary movements affecting her arms and trunk. Genotyping detected an expanded allele (43 trinucleotide repeats). A three-generation-long family history of chorea and schizophrenia-like psychosis was found. CONCLUSION: HD-families have been reported in which schizophrenia-like syndromes emerged in all or most HD-affected members long before they developed extra-pyramidal or cognitive changes. This has been attributed to more than mere coincidence. We hypothesise that in these families the HD gene is transmitted along with a low load of small-effect "psychosis genes" which, in the presence of the severe cognitive changes of HD, manifest as a schizophrenia-like phenotype. Further research is needed in order to clarify the links between genetic loading and the emergence of psychotic symptoms in Huntington's disease.

Journal Article↗