Comparison of parametric and nonparametric methods to map oligogenes by linkage

A sample of 95 sib pairs affected with insulin-dependent diabetes and typed with their normal parents for 28 markers on chromosome 6 has been analyzed by several methods. When appropriate parameters are efficiently estimated, a parametric model is equivalent to the β model, which is superior to nonparametric alternatives both in single point tests (as found previously) and in multipoint tests. Theory is given for meta-analysis combined with allelic association, and problems that may be associated with errors of map location and/or marker typing are identified. Reducing by multipoint analysis the number of association tests in a dense map can give a 3-fold reduction in the critical lod, and therefore in the cost of positional cloning.

Using rare mutations to estimate population divergence times: A maximum likelihood approach

In this paper we propose a method to estimate by maximum likelihood the divergence time between two populations, specifically designed for the analysis of nonrecurrent rare mutations. Given the rapidly growing amount of data, rare disease mutations affecting humans seem the most suitable candidates for this method. The estimator RD, and its conditional version RDc, were derived, assuming that the population dynamics of rare alleles can be described by using a birth–death process approximation and that each mutation arose before the split of a common ancestral population into the two diverging populations. The RD estimator seems more suitable for large sample sizes and few alleles, whose age can be approximated, whereas the RDc estimator appears preferable when this is not the case. When applied to three cystic fibrosis mutations, the estimator RD could not exclude a very recent time of divergence among three Mediterranean populations. On the other hand, the divergence time between these populations and the Danish population was estimated to be, on the average, 4,500 or 15,000 years, assuming or not a selective advantage for cystic fibrosis carriers, respectively. Confidence intervals are large, however, and can probably be reduced only by analyzing more alleles or loci.

Global air-sea flux of CO2: An estimate based on measurements of sea–air pCO2 difference

Approximately 250,000 measurements made for the pCO2 difference between surface water and the marine atmosphere, ΔpCO2, have been assembled for the global oceans. Observations made in the equatorial Pacific during El Nino events have been excluded from the data set. These observations are mapped on the global 4° × 5° grid for a single virtual calendar year (chosen arbitrarily to be 1990) representing a non-El Nino year. Monthly global distributions of ΔpCO2 have been constructed using an interpolation method based on a lateral advection–diffusion transport equation. The net flux of CO2 across the sea surface has been computed using ΔpCO2 distributions and CO2 gas transfer coefficients across sea surface. The annual net uptake flux of CO2 by the global oceans thus estimated ranges from 0.60 to 1.34 Gt-C⋅yr−1 depending on different formulations used for wind speed dependence on the gas transfer coefficient. These estimates are subject to an error of up to 75% resulting from the numerical interpolation method used to estimate the distribution of ΔpCO2 over the global oceans. Temperate and polar oceans of the both hemispheres are the major sinks for atmospheric CO2, whereas the equatorial oceans are the major sources for CO2. The Atlantic Ocean is the most important CO2 sink, providing about 60% of the global ocean uptake, while the Pacific Ocean is neutral because of its equatorial source flux being balanced by the sink flux of the temperate oceans. The Indian and Southern Oceans take up about 20% each.

A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis. The virus does not replicate efficiently in cell cultures, and it is therefore difficult to assess infection-neutralizing antibodies and to evaluate protective immunity in vitro. To study the binding of the HCV envelope to cell-surface receptors, we developed an assay to assess specific binding of recombinant envelope proteins to human cells and neutralization thereof. HCV recombinant envelope proteins expressed in various systems were incubated with human cells, and binding was assessed by flow cytometry using anti-envelope antibodies. Envelope glycoprotein 2 (E2) expressed in mammalian cells, but not in yeast or insect cells, binds human cells with high affinity (Kd approximately 10(-8) M). We then assessed antibodies able to neutralize E2 binding in the sera of both vaccinated and carrier chimpanzees, as well as in the sera of humans infected with various HCV genotypes. Vaccination with recombinant envelope proteins expressed in mammalian cells elicited high titers of neutralizing antibodies that correlated with protection from HCV challenge. HCV infection does not elicit neutralizing antibodies in most chimpanzees and humans, although low titers of neutralizing antibodies were detectable in a minority of infections. The ability to neutralize binding of E2 derived from the HCV-1 genotype was equally distributed among sera from patients infected with HCV genotypes 1, 2, and 3, demonstrating that binding of E2 is partly independent of E2 hypervariable regions. However, a mouse monoclonal antibody raised against the E2 hypervariable region 1 can partially neutralize binding of E2, indicating that at least two neutralizing epitopes, one of which is hypervariable, should exist on the E2 protein. The neutralization-of-binding assay described will be useful to study protective immunity to HCV infection and for vaccine development.