THE INHIBITORS OF NF-κB (IκBs) play an important role in the regulation of the NF-κB pathway. IκBR (for IκB-Related) is proposed to be a novel member of this family. We report the cloning and characterization of the region of the human gene encoding the previously reported mRNA. This region contains 13 exons, spread over 6550 bp of genomic sequence. The coding sequence is only weakly similar to other IκBs and the exons display a more complicated structure than has been found in other members of the IκB gene family. Moreover, the positions of intron-exon junctions are different from those found in other IκB genes, even within the otherwise conserved ankyrin-like repeat region, suggesting that the IκBR gene is not a member of this extended gene family. We report a revised mRNA and protein sequence for IκBR, which predicts that the protein is larger than originally described. We also report the chromosomal localisation of the human IκBR gene (approved gene symbol NFKBIL2) to 8q24.3 using PCR-based somatic cell hybrid panel analysis and fluorescence in situ hybridization (FISH) mapping.

Twin studies are widely used to study genetic and environmental influences on human measurements. Correlations are often used in such studies to compare the levels of similarity between monozygotic and dizygotic twins with respect to a specified trait. In this paper, we compare three procedures for testing the equality of twin correlations when the outcome variable of interest is multinominal. One method is a likelihood ratio test based on an underlying Dirichlet-multinomial distribution. The second method is based on the estimated large sample variance of the estimated correlation, and the third method is based on a χ2 goodness-of-fit test. The results of a Monte Carlo simulation show that the three methods have similar properties if the number of twin pairs is large (> 100), and the prevalence of the underlying trait is not extreme. Otherwise, the goodness-of-fit approach is to be preferred. We illustrate the methods by analyzing data from a previously published smoking study.

Scenarios, such as populations experiencing a bottleneck or an exponential growth, have been suggested as candidates for explaining the observed differences among mitochondrial DNA sequences in a sample of a given population closed to migrations. Here, population size is considered as capable of varying, and the set of the at least 95% most probable population paths capable of producing the observed mean number of pairwise nucleotide differences is delineated. To do this, the mean and the variance of coalescence times of two genes taken in an n-genes sample with varying population size are expressed. The observed mean coalescence time already echoed a set of population paths due to the variance associated to the coalescent process, but only specific scenarios have been studied, such as the bottleneck or the exponential function. However, mitochondrial DNA data does not reflect a single scenario, after the effect of the variance. These scenarios implied by pairwise nucleotide differences are described through a set-valued function, the ‘regulation map’, a convenient way to represent temporal population paths.

The novel gene, Diphor-1, was recently cloned from rat kidney and shown to increase phosphate uptake in cells when co-expressed with a Na+-Pi cotransporter, indicating that it may play a substantial role in cellular phosphate balance. Previously, the phosphate wasting disorder, autosomal dominant hypophosphatemic rickets (ADHR) was mapped to chromosome 12p13 by linkage analysis. In the present work, PDZK1, a PDZ domain-containing protein highly homologous to rat Diphor-1, was shown to be expressed in human kidney. Based upon its sequence similarity to rat Diphor-1, we considered PDZK1 a feasible candidate gene for ADHR. PDZK1 was found to localize to human chromosome 1q21, thereby ruling it out as a candidate for ADHR.

We have studied the impact of natural selection on the Italian population, analysing the relationship between stillbirth and three related variables: birth weight, birth order and maternal age. A progressive relaxation of selection with time has been demonstrated by the reduction of the Haldane index calculated with respect to the three variables.

Previously we showed (Wang, Guerra & Cohen 1998) that a statistically robust version of the Haseman & Elston (1972) sib-pair method greatly increased power to detect linkage in the presence of outliers. In this paper we report on M-estimation to accommodate outliers in the variance-components approach to linkage analysis developed by Amos (1994). Simulations show that in the presence of outliers the robust variance-components approach provides substantially greater power, more precise estimation of heritabilities, and better false–positive rates than the original Gaussian based approach. In the absence of outliers the performance of the robust variance-components approach is similar to that of the Gaussian based approach. For illustration we apply the method to two well characterized lipoprotein systems.

Risch and Zhang recently proposed to use extreme discordant sib pairs for mapping quantitative trait loci. Here, it is shown that the set of genetically possible distributions of the number of marker alleles in such sib-pairs is described by two inequalities. Thus, a likelihood ratio test analogous to Holmans's possible triangle test for affected sib pairs can be defined. The performance of this test is compared to the mean test considered by Risch and Zhang. For most of the genetic models considered, the mean test is slightly more powerful than the restricted likelihood ratio test. However, for models with a rare recessive gene (or equivalently a common dominant gene), the restricted likelihood ratio test is much more powerful.

In the presence of gametic phase disequilibrium and inbreeding, multiple locus genotype frequencies cannot be written solely in terms of identity by descent (IBD) probabilities. Following Cockerham & Weir (1973) we introduce the concept of ‘equivalence by descent’ (EBD), an extension of the concept of IBD to include non-allelic genes. Two genes are said to be EBD if they derive ultimately from the same founding gamete of a pedigree. Allelic genes that are EBD are also IBD. For two loci 11 EBD probabilities, the ‘J-coefficients,’ are required and for three loci 117 J-coefficients are required to write genotype probabilities. It is shown how the 117 J-coefficients for three loci can be reduced to a basic set of 37. Computer programs, written in the algebraic programming language, MAPLE™, are described which are capable of calculating the two- and three-locus J-coefficients for any pedigree, subject only to size limitations. The MAPLE™ packages are available from the author upon request.

This study is part of our effort to map recombination hotspots in two regions (site A, 18 kb; site B, 40 kb) of the human phosphoglucomutase PGM1 gene. Twenty-two PCR amplified fragments comprising six groups, covering about 5.2 kb, were screened for single nucleotide polymorphisms (SNPs) using non-isotopic single stranded conformation polymorphism (SSCP) analysis. Fourteen fragments were variable and seven of these showed common polymorphism. Our strategy for screening for polymorphic sites in the PGM1 gene was based on the results of allelic association analysis between each new marker and the sites of the classical isozyme polymorphism (2/1 in exon 4 and +/− in exon 8). Samples from four populations (Caucasian, Chinese, Vietnamese and New Guinean) were typed for each of the seven polymorphic markers. Between two and four common alleles were found in each case, together with a few rare alleles. Co-dominant inheritance patterns were demonstrated by family studies. The molecular basis of each new marker was determined by direct sequencing of the PCR products: most were SNPs except two that were small insertions/deletions. Direct sequence analysis of a 2.1 kb segment in sixteen individuals revealed no additional nucleotide variation indicating a very high level of efficiency of the SSCP screening method used in this study. The overall nucleotide diversity (θ) for PGM1 was estimated as 0.9×10−3 based on 33 segregating sites in a sequence of 5187 nt and a sample size of 614 individuals.

The GM immunoglobulin (Ig) allotype distributions of 49 native Amerindian populations from North to South America were analysed by a new technique called ‘Mobile Sites Method’ (MSM). This allows the global interpretation of genetic diversity in space by means of a distorted geographic map called a ‘genetic similarity map’. This approach has been improved by superimposing in the distorted geographic map both the haplotype set (represented by hypothetical populations having a 100% frequency of the haplotype considered) and the ‘geography-genetics discontinuities’ (i.e. the zones between homogeneous population clusters). This bidimensional representation completes the interpretation of the genetic distances between populations in terms of local genetic diversity and possible migrations. Our results concerning the spatial distribution of the Amerindian populations show: (i) a great interdependence of the geographic locations and the GM haplotype distributions (the importance of the geographic factor was checked with the usual technique of ‘random sampling’ and the percentage of explained distance variability decreases from 78% with the observed data to a level less than 67% with the random data); (ii) a parallelism between genetics and linguistics groups as indicated by the population clusters in the similarity map, and (iii) a complex distorted map revealing the presence of multiple population migrations and admixtures in the course of time. A particular distortion of South America suggests possible migrations by sea along the western and eastern coasts of Central America, or multiple migration waves without population admixture across Central America.

It is well known that the TDT proposed by Spielman et al. (1993) is potentially anti-conservative if families with one missing parental genotype are included (Curtis & Sham, 1995). We now bring attention to another situation that could give rise to an inflated rate of false positive results. This occurs when families in which the affected offspring and both parents have the same heterozygous genotype are excluded. If the heterozygous genotype is denoted as AB, then it is clear that one parent must have transmitted allele A and the other allele B. The standard TDT procedure is to increment the counts for transmissions of both A and B by one. It may seem reasonable to disregard such trios because it is ambiguous which parent has transmitted which allele. Although the resulting test statistic would retain all the information concerning preferential transmission of alleles, it can be shown that referring it to a χ2 distribution would lead to an increased type I error rate (see Appendix A).

The chromosomal localization of the human ARNO3 gene (PSCD3) was determined using monochromosomal somatic cell hybrid and radiation hybrid mapping panel. PCR analysis of a hybrid DNA panel localized the ARNO3 gene to human chromosome 7. The analysis of the Genebridge4 radiation hybrid panel using PCR amplification located the ARNO3 gene between NIB1822 (9.5 cR) and D7S481 (5.5 cR) with a lod score of >3.0. This region is located in the human chromosome band 7p21.

Data on the GM and KM haplotypes and RFLPs in the immunoglobulin IGHG loci are reported intending to evaluate the genetic contribution of the different populations (Europeans and Africans) who settled Tenerife Island. The GM and KM allotypic systems reveal an estimated European genetic admixture of 88%. The only possible African contribution is the presence of the GM*1,17;..;5* haplotype (2.5%), but no other traces of Black African characteristic haplotypes are found. Although new RFLP haplotypes are described, DNA variation is similar to that reported in Caucasoids with a marked absence of restriction fragments characteristic of Black Africans.

HNA is an autosomal dominant recurrent focal neuropathy involving the brachial plexus. The etiology of HNA is unknown but the genetic defect most likely affects a non-neuronal tissue. We previously described linkage to chromosome 17q24–q25 in two HNA-families. Here we report the mutation analysis of two candidate genes: a cDNA encoding a putative sialyltransferase and the SFRS2 splicing factor including the c-myb ET-locus which is encoded on the opposite strand of the SFRS2 gene. The complete protein coding regions of both genes were studied by direct DNA sequencing. We did not find a disease associated mutation indicating that these genes are most likely not involved in the pathogenesis of HNA. However, we identified and characterized a rare AvaII polymorphism in the SFRS2 gene and detected a sequencing error, leading to an amino acid change (Val11Leu) in the published sequence of the putative sialyltransferase.

In the paper by Goldstein et al. (Genomics, 1995), the authors carried out a simulation study to investigate the relative efficiencies of a no interference linkage analysis to an analysis with certain models that allow for interference. They showed that, for completely informative and independent recombination data, the analysis with the no interference model was inefficient, in the present of interference. In practice, the assumption of completely informative markers is unrealistic with data from human pedigrees. We report the results of a study investigating whether this conclusion still holds for gametes arising within pedigrees. We consider the same two mapping problems as Goldstein et al.: exclusion mapping and gene ordering. The results obtained were consistent with their findings, although the efficiency gains for analyses using the chi-square model were not as great in some cases. This is not unexpected with less than fully informative data. These results point to the need for research of developing new statistical and computational methods to incorporate interference into multipoint linkage mapping using pedigree data. This would make efficient use of available, but sometimes scarce data, especially in disease gene mapping.

A year ago there was hope that a finished sequence of the human genome would soon be publicly available and would give a more reliable locus order than an unconstrained radiation hybrid or genetic map. Alas, there are now different draft orders for each region, none of which may be correct because of gaps, uncertain polarity of contigs, and errors in assembly. Shortly before these drafts became available, we analysed allelic association (also called linkage disequilibrium, LD) in the FRAX region in a large sample of haplotypes (Ennis et al. 2000). We demonstrate here that this material discriminates among alternative draft orders. To express support for discrimination between two values of χ2 = −2 ln L we use the Akaike criterion AIC = df[χ2/min χ2 −1]. Excluding premutations and full mutations at FMR1, all maps have 715 degrees of freedom (df) among 717 pairs of alleles after accepting L = 0 and estimating M, ∈ in the Malecot equation E(ρ) = Me −∈d, where ρ is the association between a pair of alleles at distance d. An AIC in excess of 2 provides evidence against a map with the larger χ2 .

Population samples from Liguria, Piacenza and Pavia provinces, and North Lombardy are compared for surnames and HLA gene frequencies. The genetic structure inferred from the principal coordinate analysis of surname frequencies is different from that inferred from HLA gene frequencies. The latter may represent ancient migrations, since surnames are relatively recent genetic markers dating from a.d. 1500. Ligurian and Celts were the ancient inhabitants of this northern Italy geographic area. Genetic distances, derived from HLA gene frequencies, and represented with an unrooted tree show the presence of a Ligurian and a Celtic pole. The aggregation of the subpopulations to each pole accords with the history and the archaeological findings in the area.

We have identified a highly polymorphic intragenic marker composed of two dinucleotide repeats in an intron of the human interferon regulatory factor (IRF3) gene. This polymorphic marker has allowed us to map IRF3 to the boundary of 19q13.3–13.4 between the polymorphic markers D19S604 and D19S206 close to KLK1. An intron is present in a homologous position in the mouse Irf3 gene, but lacks the dinucleotide repeats present in the human intron. Syntenic conservation between this region of 19q13.3–13.4 maps Irf3 to either mouse chromosome 7 or 17.

Three apolipoprotein B (apoB) genetic polymorphisms, the XbaI, MspI and EcoRI restriction fragment length polymorphisms (RFLPs), were analysed for 221 individuals in Senegal by polymerase chain reaction. Allelic frequency determination revealed that this population has 0.79 XbaI− (X−), 0.96 MspI+ (M+), and 0.89 EcoRI+ (E+). Major genotypes were X−/X− (0.62), M+/M+ (0.92) and E+/E+ (0.80). The XbaI allele frequency is different (p<10−9) from that in Caucasians (0.47) and from that in Mongoloids (0.98). Significant differences between Senegalese and Caucasians, and between Senegalese and Mongoloids were also observed for the EcoRI and MspI alleles of the apoB genes.