Models of multifactorial inheritance: II, the covariance structure for a scalar phenotype under selective assortative mating and sex-dependent symmetric parental-transmission

This study concentrates on a scalar trait for a two-sex population entailing symmetric sex-dependent parent-offspring transmission, a nonlinear (selective) assortative mating pattern, and random perturbation factors. A number of qualitative and comparative properties of the equilibrium covariance structure are set forth. In particular, it is shown that the phenotype variance generally increases under attenuated assortative mating tendencies and for an increased level of parent-offspring transmission. Moreover, with more contrasting sex-dependent transmission the sibling covariances diverge from the parent-offspring covariance. Also, shared residual-environmental covariance enhances the sibling covariances. The absolute product moment of the deviation of a child phenotype from the separate parental phenotypes exhibits a minimum for a mixed assortative random mating scheme rather than under extreme assortative mating or pure random mating. We establish that the equilibrium variance of a married individual is reduced compared to the variance of the population at large. Interpretations and implications are discussed.     

Models of multifactorial inheritance: I, multivariate formulations and basic convergence results

A multivariate dynamic model of a vector phenotype trait under the influence of a selective mating pattern, a hierarchy of parental-offspring transmission rules, and random environmental effects is developed. The formulation can incorporate age class effects, geographical variation, asymmetric maternal and paternal contributions, sex-differentiated offspring expression, selective family adoption procedures, and classes of family and pedigree influences. The mating, transmissible, and environmental aspects of family structure parameters can vary systematically or randomly in time. Cultural and biological variables are handled in one framework. Results on the dynamic and equilibrium behavior of these multivariate processes are set forth and interpreted.     

Models of multifactorial inheritance: III, calculation of covariance of relatives under selective assortative mating

A hierarchy of kinship covariance calculations is elaborated within a framework of an extended selective mating mechanism. These include explicit determinations for first- through third-degree family relationships and correlations of adopted with natural children. A critique of several explicit and implicit assumptions in the classical procedures is contained in Section 2.     

Heterogeneity between populations for multifactorial inheritance of plasma lipids

A general linear model was described for multifactorial inheritance of the two plasma lipids, total cholesterol (CH), and triglyceride (TG). Analyses of two separate studies, the Honolulu Heart Study (HHS) and the Cincinnati Lipid Research Clinic (LRC), indicated some heterogeneity. Whereas the sibling environmental effect (b) was the only source of heterogeneity between the two studies for TG, the correlation between marital environments (u) may also be considered as a source of heterogeneity for CH. Under parsimonious hypothesis, intergenerational differences in heritabilities were not found to be significant for either trait (y1 = y2 = z1 = z2 = 1). Maternal effects were significant for CH but not for TG. Correlations between marital environments (u1 and u2) were not significant for TG, and may be considered nonsignificant for CH also under parsimonious hypotheses. In any case, the genetic (h2) and cultural (c2) heritabilities cannot be considered to be heterogeneous between the two studies. Based on pooled data, parsimonious hypothesis yields: h2 = .594 +/- .041 and c2 = .035 +/- .008 for CH, and h2 = .259 +/- .034 and c2 = .108 +/- .014 for TG.     

Models of comorbidity for multifactorial disorders.

We develop several formal models for comorbidity between multifactorial disorders. Based on the work of D. N. Klein and L. P. Riso, the models include (i) alternate forms, where the two disorders have the same underlying continuum of liability; (ii) random multiformity, in which affection status on one disorder abruptly increases risk for the second; (iii) extreme multiformity, where only extreme cases have an abruptly increased risk for the second disorder; (iv) three independent disorders, in which excess comorbid cases are due to a separate, third disorder; (v) correlated liabilities, where the risk factors for the two disorders correlate; and (vi) direct causal models, where the liability for one disorder is a cause of the other disorder. These models are used to make quantitative predictions about the relative proportions of pairs of relatives who are classified according to whether each relative has neither disorder, disorder A but not B, disorder B but not A, or both A and B. For illustration, we analyze data on major depression (MD) and generalized anxiety disorder (GAD) assessed in adult female MZ and DZ twins, which enable estimation of the relative impact of genetic and environmental factors. Several models are rejected--that comorbid cases are due to chance; multiformity of GAD; a third independent disorder; and GAD being a cause of MD. Of the models that fit the data, correlated liabilities, MD causes GAD, and reciprocal causation seem best. MD appears to be a source of liability for GAD. Possible extensions to the models are discussed.     

The Hartnup phenotype: Mendelian transport disorder, multifactorial disease.

The Hartnup mutation affects an amino acid transport system of intestine and kidney used by a large group of neutral charge alpha-amino acids (six essential and several nonessential). We compared developmental outcomes and medical histories of 21 Hartnup subjects, identified through newborn screening, with those of 19 control sibs. We found no significant differences in means of growth percentiles and IQ scores between Hartnup and control groups (but all low academic performance scores were found in the Hartnup group, and various skin lesions occurred in five Hartnup subjects), no significant difference between means of the summed plasma values for amino acids affected by the Hartnup gene in Hartnup and control groups, two Hartnup subjects with clinical manifestations--impaired somatic growth and IQ in one, impaired growth and a "pellagrin" episode in the other--who had the lowest summed plasma amino acid values in the Hartnup group; the corresponding values for their sibs were the low outliers in the control group, and two tissue-specific forms of the Hartnup (transport) phenotype: renal and intestinal involvement (15 families) and renal involvement alone (one family), both forms having been inherited as autosomal recessives (the symptomatic probands had the usual form). Whereas deficient activity of the "Hartnup" transport system is monogenic, the associated plasma amino acid value (measured genotype) is polygenic. The latter describes the parameter of homeostasis and liability to disease. Cause of Hartnup disease is multifactorial.     

Models of a dual inheritance system

In higher plants, animals and fungi, there are two inheritance systems: the familiar system, depending on DNA sequence, used in transmitting information between sexual generations, and an epigenetic inheritance system, depending on gene activation, responsible for the transmission of states of differentiation during development. Occasionally, epigenetic changes are transmitted in sexual reproduction. A formal model of such a dual inheritance system is presented, and it is shown how the separation between the two systems can sometimes break down. The evolutionary significance of such breakdowns is discussed.     

The transmission of schizophrenia under a multifactorial threshold model.

Family studies of schizophrenia have reported elevated rates of both definite and definite-plus-probable schizophrenia among the relatives of definite schizophrenics. These elevated rates imply a strong association between the two forms of diagnosis and suggest some form of familial transmission. Here we have used recently developed maximum likelihood methods to investigate this association and characterize the nature of the familial transmission. Results indicated that although the two forms of diagnosis were strongly related, they could not be considered alternative manifestations of a single liability distribution. Heritability estimates for either form of diagnosis were comparable (h2 = .668 +/- .052 and c2 = .191 +/- .038 for definite while h2 = .628 +/- .073 and c2 = .236 +/- .106 for definite-plus-probable), although cultural transmission (i.e., c2) was statistically significant only for definite-plus-probable. For either form of diagnosis, residual twin resemblance was statistically significant and could not be explained in terms of the effects of genetic dominance. These results are comparable to those of an earlier analysis based upon a similar data set. Finally, the statistical correction used to adjust for between-study heterogeneity in morbidity risk figures did not noticeably alter the parameter estimates.     

Neurons from radial glia: the consequences of asymmetric inheritance

Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of a neuron. Among the proteins that direct cell fate in Drosophila melanogaster that have known mammalian homologs, Numb is the best candidate to have a similar function in radial glia. During asymmetric divisions of radial glial cells, the basal cell may inherit the radial glial fibre, while the apical cell sequesters the majority of the Numb protein. We suggest two models that make opposite predictions as to whether the radial glia or nascent neuron inherit the radial glial fiber or the majority of the Numb protein.     

Preeclampsia: multiple approaches for a multifactorial disease

Preeclampsia is a pregnancy-specific disorder characterized by hypertension and excess protein excretion in the urine. It is an important cause of maternal and fetal morbidity and mortality worldwide. The disease is almost exclusive to humans and delivery of the pregnancy continues to be the only effective treatment. The disorder is probably multifactorial, although most cases of preeclampsia are characterized by abnormal maternal uterine vascular remodeling by fetally derived placental trophoblast cells. Numerous in vitro and animal models have been used to study aspects of preeclampsia, the most common being models of placental oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal vascular damage and anomalous maternal-fetal immune interactions. Investigations into the pathophysiology and treatment of preeclampsia continue to move the field forward, albeit at a frustratingly slow pace. There remains a pressing need for novel approaches, new disease models and innovative investigators to effectively tackle this complex and devastating disorder.     

The inheritance of chemical phenotype in Cannabis sativa L

Four crosses were made between inbred Cannabis sativa plants with pure cannabidiol (CBD) and pure Delta-9-tetrahydrocannabinol (THC) chemotypes. All the plants belonging to the F(1)'s were analyzed by gas chromatography for cannabinoid composition and constantly found to have a mixed CBD-THC chemotype. Ten individual F(1) plants were self-fertilized, and 10 inbred F(2) offspring were collected and analyzed. In all cases, a segregation of the three chemotypes (pure CBD, mixed CBD-THC, and pure THC) fitting a 1:2:1 proportion was observed. The CBD/THC ratio was found to be significantly progeny specific and transmitted from each F(1) to the F(2)'s derived from it. A model involving one locus, B, with two alleles, B(D) and B(T), is proposed, with the two alleles being codominant. The mixed chemotypes are interpreted as due to the genotype B(D)/B(T) at the B locus, while the pure-chemotype plants are due to homozygosity at the B locus (either B(D)/B(D) or B(T)/B(T)). It is suggested that such codominance is due to the codification by the two alleles for different isoforms of the same synthase, having different specificity for the conversion of the common precursor cannabigerol into CBD or THC, respectively. The F(2) segregating groups were used in a bulk segregant analysis of the pooled DNAs for screening RAPD primers; three chemotype-associated markers are described, one of which has been transformed in a sequence-characterized amplified region (SCAR) marker and shows tight linkage to the chemotype and codominance.     

Female inheritance of malarial lap genes is essential for mosquito transmission

Members of the LCCL/lectin adhesive-like protein (LAP) family, a family of six putative secreted proteins with predicted adhesive extracellular domains, have all been detected in the sexual and sporogonic stages of Plasmodium and have previously been predicted to play a role in parasite-mosquito interactions and/or immunomodulation. In this study we have investigated the function of PbLAP1, 2, 4, and 6. Through phenotypic analysis of Plasmodium berghei loss-of-function mutants, we have demonstrated that PbLAP2, 4, and 6, as previously shown for PbLAP1, are critical for oocyst maturation and sporozoite formation, and essential for transmission from mosquitoes to mice. Sporozoite formation was rescued by a genetic cross with wild-type parasites, which results in the production of heterokaryotic polyploid ookinetes and oocysts, and ultimately infective Deltapblap sporozoites, but not if the individual Deltapblap parasite lines were crossed amongst each other. Genetic crosses with female-deficient (Deltapbs47) and male-deficient (Deltapbs48/45) parasites show that the lethal phenotype is only rescued when the wild-type pblap gene is inherited from a female gametocyte, thus explaining the failure to rescue in the crosses between different Deltapblap parasite lines. We conclude that the functions of PbLAPs1, 2, 4, and 6 are critical prior to the expression of the male-derived gene after microgametogenesis, fertilization, and meiosis, possibly in the gametocyte-to-ookinete period of differentiation. The phenotypes detectable by cytological methods in the oocyst some 10 d after the critical period of activity suggests key roles of the LAPs or LAP-dependent processes in the regulation of the cell cycle, possibly in the regulation of cytoplasm-to-nuclear ratio, and, importantly, in the events of cytokinesis at sporozoite formation. This phenotype is not seen in the other dividing forms of the mutant parasite lines in the liver and blood stages.     

Expression and inheritance of a desynaptic phenotype with impaired homologous synapsis in rye

The cytological phenotype was studied in a desynaptic form isolated from a population of rye cultivar Vyatka. The primary defect of desynaptic plants was identified as nonhomologous (heterologous) chromosome synapsis, which was observed by electron microscopy of synaptonemal complexes (SCs) in meiotic prophase I. Synapsis defects involved switches of synapsing axial elements to nonhomologous partners, asynapsis in the switching region, and foldbacks formed by the SC lateral elements. Defective bivalent formation was observed at later stages: the univalent number varied and multivalent chromosome associations were observed in single cells in metaphase I. The desynaptic phenotype was controlled by two recessive genes, sy8a and sy8b, which acted and were inherited independently. In a hybrid combination with line Ku-2/63, the desynaptic phenotype was suppressed by the dominant allele of a third gene for inhibitor I; the segregation in hybrid families corresponded to 57:7.     

Cooperative Effects in Models of Steady-State Transport across Membranes: IV. One-Site, Two-Site, and Multisite Models

Several different one-site, two-site, and multisite models of steady-state ion transport across a membrane are investigated. The basic features, including cooperative interactions between channels, are the same as in earlier papers in this series. In particular, the present paper represents a considerable elaboration of part III. The models might apply to artificial or possibly to biological membranes, but particular applications must await further elucidation of the molecular structure and operation of these membranes.     

PON-mt-tRNA: a multifactorial probability-based method for classification of mitochondrial tRNA variations

Transfer RNAs (tRNAs) are essential for encoding the transcribed genetic information from DNA into proteins. Variations in the human tRNAs are involved in diverse clinical phenotypes. Interestingly, all pathogenic variations in tRNAs are located in mitochondrial tRNAs (mt-tRNAs). Therefore, it is crucial to identify pathogenic variations in mt-tRNAs for disease diagnosis and proper treatment. We collected mt-tRNA variations using a classification based on evidence from several sources and used the data to develop a multifactorial probability-based prediction method, PON-mt-tRNA, for classification of mt-tRNA single nucleotide substitutions. We integrated a machine learning-based predictor and an evidence-based likelihood ratio for pathogenicity using evidence of segregation, biochemistry and histochemistry to predict the posterior probability of pathogenicity of variants. The accuracy and Matthews correlation coefficient (MCC) of PON-mt-tRNA are 1.00 and 0.99, respectively. In the absence of evidence from segregation, biochemistry and histochemistry, PON-mt-tRNA classifies variations based on the machine learning method with an accuracy and MCC of 0.69 and 0.39, respectively. We classified all possible single nucleotide substitutions in all human mt-tRNAs using PON-mt-tRNA. The variations in the loops are more often tolerated compared to the variations in stems. The anticodon loop contains comparatively more predicted pathogenic variations than the other loops. PON-mt-tRNA is available at http://structure.bmc.lu.se/PON-mt-tRNA/.