Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate

Mitchell LE, Risch N. Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate. Clin Genet 1993: 43: 255–260. © Munksgaard, 1993 Multivariate analysis was used to determine which characteristics: sex of the proband, sibling sex, severity of the proband's defect or family history, are the best predictors of recurrence risk among siblings of individuals with non-syndromic cleft lip with or without cleft palate (CL \pm P). Sibling recurrence risks are not significantly related to the sex of the proband. Severity of the proband's defect, classified by the extent of the lip defect (unilateral versus bilateral), was found to be a significant predictor of sibling recurrence, whereas involvement of the palate in the proband's defect was not. A positive family history of clefting (i.e. at least one affected first-degree relative in addition to the proband) and the sex of the sibling were also found to be significant predictors of sibling recurrence. The associations between sibling risk and family history, and sibling risk and bilaterality of the proband's defect appear to be mildly confounded. After adjusting for the effects of family history, the risk to siblings of probands with bilateral lip defects is twice the risk to siblings of probands with unilateral defects (O.R. = 2.00; 95% C.I. 1.25-3.19). A positive family history of clefting increases the risk to siblings by greater than 4-fold (O.R. =4.49; 95% C.I. 2.74-7.35), after adjusting for the extent of the proband's lip defect. These results provide a rational strategy for identifying subsets of the ‘at risk’ population which have markedly different recurrence risks. This information is important for genetic counseling, since it allows for more precise estimation of sibling recurrence risks in individual cases. Furthermore, our findings indicate that the power to detect linkage between a genetic marker or a candidate gene and CL \pm P will increase if the study population is ascertained through individuals with bilcteral clefts of the lip, rather than through individuals with either unilateral or bilateral CL \pm P.     

Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren’s syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr × C3H/lpr) F1 intercross, and MRL/lpr × (MRL/lpr × C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.     

Sequential movement representations based on correlated neuronal activity

We tested the hypothesis that sequential movements are represented in the correlated activity of motor cortical neurons. We simultaneously recorded multiple single neurons in the motor cortex while monkeys performed a two-segment movement sequence. Before any movement began the correlated spike firing between pairs of neurons differed when these sequences were planned as whole (planned) as compared to when they were planned one segment at a time (unplanned) even when the firing rates of these neurons did not distinguish between the two conditions. Moreover, the correlation strength was significantly larger when the directional preferences of the neurons matched the direction of the final segment of the sequence. Our results suggest that spatially distributed groups of MI neurons form dynamic correlation structures that distinguish different forms of sequential action. Electronic Publication     

Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction

PROBLEM: To provide insight into the mechanisms of action of the major-histocompatibility-complex (MHC)-linked genes affecting reproduction. METHOD OF STUDY: The data were obtained using a variety of cellular and molecular techniques in experimental animals and from population genetic studies in humans. RESULTS: In the mouse, the preimplantation embryonic development (Ped) locus, whose functional gene is Q9, regulates fast and slow cleavage of the early embryo. There is also evidence for a growth and reproduction complex (Grc)-like region from serologic, molecular, and cytogenetic studies. In the human, the human leukocyte antigen (HLA)-G gene has been associated with an increased rate of embryonic cleavage in those embryos that express the HLA-G antigen. Sharing of HLA antigens in couples has been associated with recurrent spontaneous abortions, gestational trophoblastic tumors, and unexplained infertility. Detailed mapping studies showed that the genes responsible are not the HLA genes themselves, but genes closely linked to the HLA-DR-DQ-B genes. The HLA region genes can interact epistatically with the C3 allele of transferrin to increase the incidence of fetal loss. In the rat, the Grc region, which is closely linked to the MHC, has been associated with embryonic loss, growth defects, and susceptibility to chemical carcinogens. The Grc can interact epistatically with the tail anomaly lethal (Tal) gene or the hood restriction (Hre) gene to enhance these effects. CONCLUSIONS: There are two basic mechanisms for the effects of MHC-linked genes on reproduction and development: individual gene effects (Ped [Q9], HLA-G) and extended genetic effects (MHC-linked genes in the rat [Grc] and in the human). The nature of these genetic effects, particularly the MHC-linked effects, can also provide some insight into the different theories of human origins: These effects are most consistent with the monogenic theory.     

Willignes to drive when drunk and personality: A twin study

In a laboratory study of psychomotor sensitivity to alcohol, twins were asked “Would you drive a car now?” at 1, 2, and 3 h after drinking a standard dose of ethanol (0.75 g/kg). Correlations among these binary items, the Eysenck personality scales, and age were investigated using PRELIS and LISREL. Willingness to drive and Extraversion correlate at all three times in both males and females. In males, willingness to drive also correlates with Psychoticism, and in females it correlates negatively with the Lie (or Social Desirability) scale. Most correlations between cotwins in willingness to drive were significant in both monozygotic (MZ) and dizygotic (DZ) male twins but correlations were lower in female twins. Factor and Markovian models were fitted. In males there seem to be both genetic and cultural influences on willingness to drive when drunk. About half the genetic variance seems to be the pleiotropic effects of genes influencing Extraversion. The correlationswith Psychoticism, on the other hand, seem to be largely environmental in origin. The small sample size and lack of proper significance tests mean that these results must be interpreted with caution.     

Genetic and light intensity effects on the activity and emigratory behavior of the house fly,Musca domestica (L.)

The emigratory behavior and locomotor activity of yellow-eyed (y/y), wildtype (+/+), and heterozygous (+/y) house flies was examined at 8 fc (86 lx) and 1600 fc (17,223 lx) light intenstities. At 8 fc, emigration rate and activity of the y/y flies was similar to that of the +/+ and +/y flies. However, at 1600 fc, the y/y flies emigrated at twice the rate and showed an activity of about one-third that of the other genotypes. The behavior of the +/+ and +/y flies remained similar regardless of the experimental design or light intensity. The excessive neural stimulation by high-intensity light resulting from reduced shielding pigments led to behavioral modifications in the visual and tactile responses of the y/y flies.This research was supported in part by grants from the CUNY Faculty Research Award Program (No. 1103) and NIH Biomedical Research Support Grant 5-S05-R-07064.     

Genetic analysis of cercarial emergence rhythms ofSchistosoma mansoni

Using two chronobiological variants ofSchistosoma mansoni (a blood fluke infecting man) from Guadeloupe (French West Indies), we carried out experimental crossbreeding between schistosomes with an early and those with a late cercarial shedding pattern. The results obtained on the F₁ (intermediate shedding patterns) and F₂ generations (early, intermediate, and late patterns) demonstrate that the cercarial emergence rhythms of schistosomes are genetically determined. This genetic variability is interpreted as a consequence of the selective pressure exerted by the two different hosts (man and rat) implicated in the life cycle ofS. mansoni from the Guadeloupean focus of schistosomiasis.This work received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases and the CNRS.     

Apolipoprotein B gene DNA polymorphisms are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus

Ukkola O, Savolainen MJ, Salmela PI, von Dickhoff K, Kesäniemi YA. Apolipoprotein B gene DNA polymorphisms are associated with macro-and microangiopathy in non-insulin-dependent diabetes mellitus. Clin Genet 1993: 44: 177–184. © Munksgaard, 1993 The relationship between diabetic macroangiopathy or microangiopathy and apolipoprotein B (apoB) polymorphism was studied in 139 male and 129 female patients with non-insulin-dependent diabetes (NIDDM) mellitus, comprising consecutive patients with poor diabetic control (HBA1 13.2%\pm2.7 (SD)) referred to our hospital. Plasma cholesterol and triglyceride concentrations were higher in the patients who were homozygous for the X2 allele (presence of Xba I cleavage site). Patients with the X1 allele (absence of Xba I cleavage site) tended to have a higher frequency of macroangiopathy, although the differences were not statistically significant. There was no difference in the prevalence of microangiopathy between the groups. In subjects with only an R1 allele (= R +; homozygous for the presence of EcoR I cleavage site) the prevalence of coronary heart disease (CHD) was observed to be high (61.9%) as compared to the subjects possessing an R2 allele (= R —; homozygous or heterozygous for the absence of the EcoR I cleavage site) (46.7%; p<0.02). When the polymorphisms Xba I (subjects homozygous for the absence of the cutting site = X +; subjects homozygous or heterozygous for the presence of the cutting site = X —) and EcoR I were combined, the prevalence of macroangiopathy was observed to be high in X + R + (80.0%) as compared with X + R- (44.2%), X-R+ (56.8%) and X-R- (50.0%) (p<0.03). The prevalence of macroangiopathy tended to be particularly high in patients with the apoprotein E4 allele (phenotype E4\4 or E4/3), combined with either X+ or R +. Our findings suggest that variation at the apoB locus is one of the factors involved in predisposing diabetic patients to the development of arterial disease. As in previous studies the effect of the variation at the apoB gene on circulating lipid levels was observed. The data also support a role for the e4 allele of the apolipoprotein E gene as an important determinant of macroangiopathy in NIDDM.     

Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.     

Frequency and ethnic distribution of the common DHCR7 mutation in Smith‐Lemli‐Opitz syndrome

Smith‐Lemli‐Opitz syndrome (SLOS) is an inherited multiple malformation syndrome caused by enzymatic deficiency of 3β‐hydroxysterol‐Δ⁷‐reductase (DHCR7). SLOS is thought to be most common among European Caucasians, with an incidence of 1 in 20,000 to 1 in 30,000 births. To define the carrier rate and ethnic distribution of SLOS, we screened DNA samples from 2,978 unrelated individuals for the most common SLOS mutation (IVS8‐1G→C). Twenty‐four heterozygotes of the IVS8‐1G→C mutation were detected in 2,978 individuals of European Caucasian and Black backgrounds. For European Caucasians, the carrier rate for SLOS may be as high as 1 in 30, suggesting an incidence of 1 in 1,700 to 1 in 13,400. This high number is supported by the recent observation of newborn and prenatal incidence of 1 in 22,000 in the Caucasian population. Ours is the first report of the IVS8‐1G→C mutation in persons of African ancestry. Published 2001 Wiley‐Liss, Inc.