MUC1 is a highly polymorphic mucin type glycoprotein expressed on the surface of many epithelia, including gastric mucosa, and is present in several body fluids and mucous secretions. A genetic polymorphism due to variation in length of a 60 bp tandemly repeated sequence domain constitutes more than half of the coding region of the glycoprotein. We demonstrated previously in a Portuguese population sample that the frequency of small MUC1 alleles is increased in patients with gastric carcinoma, suggesting that the possession of small MUC1 alleles confers increased risk for gastric carcinoma development. This finding raised the possibility that the very high prevalence of gastric carcinoma in Portugal could be partly due to a high frequency of small MUC1 alleles in the Portuguese population. In the present study we compared the MUC1 allele distribution in a population of Danish blood donors with the distribution in a population of Portuguese blood donors. The frequency of small MUC1 alleles was significantly higher in the Danish than in the Portuguese sample, thus failing to lend support to the hypothesis that a relatively higher frequency of the small MUC1 alleles might account for the high prevalence of gastric carcinoma in Portugal when compared to Denmark.

Editorial Note

This book review arrived here at the beginning of this year with a very apologetic note from the author, Bill Hamilton, about the long delay in producing the review and its ‘rambling essay format’. Sadly, Hamilton died just a few weeks later from complications following malarial infection. Several tributes have been published, such as Science (2000), 287, 2438, and we continue the tributes with a final unedited manuscript from the hand of this unique, colourful and idiosyncratic evolutionary theorist.

Dysgenics: Genetic Deterioration in Modern Populations. Human Evolution, Behaviour, and Intelligence Series. By R. LYNN (Series Editor: S. ITZKOFF). Westport, Connecticut and London: Praeger. 1996. Pp. 237. £47.50 (hardback).

In a sense a dominance hierarchy has only one satisfied individual – she or he at the top. If the hierarchy is bottom-numerous rather than linear, as is the case with most human hierarchies, it is all the more true that the vast majority of people are dissatisfied, wishing they were higher up, a thought which provides a basic reason why democracies (and especially, within democracies, such institutions as their state school systems) have to be unstable. We see a wobbly pyramid, and particularly within that pyramid we see certain side stairs all human examples have by which demagogues skip up a level or two so as to shout down to the restless base that the whole structure is somehow ‘wrong’. Under a different system, the demagogue shouts, ‘You could be higher too’.

The mitochondrial haplogroup T, characterized by the nucleotide motif 16126C–16294T in the hypervariable segment I (HVS I), is one of the most frequent among Europeans. It has been shown that this haplogroup includes the only well-resolved subgroup, T1, but that other HVS I sequences cannot be differentiated into subgroups due to possible homoplasies at nucleotide positions 16292, 16296 and 16304, leading to the reticulations in the topology of phylogenetic networks. To study the problem of molecular instability at these positions, we have performed an analysis of 159 previously published West Eurasian HVS I sequences belonging to haplogroup T, together with 12 new HVS I sequences of Eastern Slavs. These 12 sequences represent 16.9% of a total of 71 samples analysed and identified as haplogroup T mtDNAs by RFLP analysis in this study. A search for rare point mutations associated with different combinations of nucleotides 16292T, 16296T and 16304C within the haplogroup T sequences, and specific to certain populations or a group of closely related-by-descent populations, was performed. This analysis revealed 11 marker mutations, each of which was characteristic for a certain group of linguistically or geographically close individuals – the Adygei, Germans, Kazakhs and linguistic isolates of the Eastern Italian Alps. The occurrence of these rare population-specific polymorphisms in association with various combinations of mutations at positions 16292 and 16296 on the haplogroup T background provides evidence of molecular instability at these nucleotide positions. Molecular instability in the haplogroup T HVS I sequences is also suggested by multiple independent losses of the haplogroup T diagnostic nucleotide variants in different populations. The results of the present study suggest that identical haplogroup T HVS I sequence types might have arisen independently in different human populations.

The growth factor independent 1 (GFI1) gene encodes a zinc finger protein which acts as a transcriptional repressor and confers growth factor independence on tumor cells, as suggested by the study of its mouse ortholog, Gfi1. We previously isolated the human GFI1 gene but no information about the structure and location of the promotor of this gene has been reported. In this study we have cloned and characterized the human GFI1 promoter. The nucleotide sequence of the promoter region is GC-rich and does not contain a typical TATA or CAAT box. Several Sp1 sites are present and computer predictions indicate that either of the two Sp1 sites might serve as the sites for transcription initiation. Analysis of various lengths of the promoter region using the luciferase reporter assay identifies a functional promoter that is active in NIH3T3 cells. The strongest activity lies within a region 312–602 basepairs upstream from the translation start site.

Given the enormous progress in the knowledge of the human genome, genetic markers are now available throughout the genome. Haplotype analysis, allowing the simultaneous use of information from several markers, has thus become increasingly popular. However, we often face the problem of missing data and of haplotype identification. We have proposed a haplotype based method for the genetic study of multifactorial diseases in founder populations, the MILC method (Bourgain et al. 2000). MILC is based on the contrast of identity length between haplotypes transmitted to affected offspring and haplotypes non-transmitted. In this study, the impact of different strategies, regarding missing data, on the MILC method are evaluated. A real situation is considered where data are derived from a genome screen for asthma susceptibility alleles in the Hutterites. Results are illustrated on this asthma data set.

Spielman et al. (1993) popularized the transmission/disequilibrium test (TDT) to test for linkage between disease and marker loci that show a population association. Several authors have proposed extensions to the TDT for multi-allelic markers. Many of these approaches exhibit a ‘swamping’ effect in which a marker with a strong effect is not detected by a global test that includes many markers with no effect. To avoid this effect, Schaid (1996) proposed using the maximum of the bi-allelic TDT statistics computed for each allele versus all others combined. The maximal TDT statistic, however, no longer follows a chi-square distribution. Here, a refinement to Bonferroni's correction for multiple testing provided by Worsley (1982) based on maximal spanning trees is applied to calculate accurate upper bounds for the type I error and p-values for the maximal TDT. In addition, an accurate lower Bonferroni bound is applied to calculate power. This approach does not require any simulation-based analysis and is less conservative than the standard Bonferroni correction. The bounds are given for both the exact probability calculations and for those based on the normal approximation. The results are assessed through simulations.

The chromosomal localization of the human CD83 gene was determined using somatic cell hybrids, a radiation hybrid mapping panel and FISH analysis on human metaphase chromosomes. PCR-based analysis of a single chromosome hybrid panel identified the presence of the CD83 gene on human chromosome 6 and subsequent analysis of the Genebridge4 radiation panel located the gene between AFMa192wg9 and AFMb322wd1 with a lod score of 9.2. Finally, using FISH analysis the CD83 gene was localized to chromosome 6 band p23.

Eight common DNA polymorphisms have been described for the linked C6 and C7 genes. We now describe a ninth polymorphism in C7 exon 13 which is located in a tight cluster with two previously reported markers. We have used all these markers to investigate the heterogeneity of C7 deficiency. Five of the nine C7 deficient probands (resident in Ireland, South Africa, Russia and Israel) are heterozygous for C6/C7 haplotypes. Seven different C7 deficient haplotypes were found for C7 markers alone, but all the four Israelis share one and three out of four Irish haplotypes share another. The markers appear to be a good guide to the heterogeneity of C7 deficiency and have been useful in choosing homozygous subjects for the investigation of molecular defects.

The euchromatic regions of chromosomes 21 and 22 are almost completely sequenced and have similar lengths (33.7–34.6 Mb). This similarity effectively controls for the influence of length, making comparisons of recombination and interference interesting. For both chromosomes, there is less male than female recombination, and male recombination is associated with GT/CA repeats. The striking sex difference may result from greater condensation of chromosomes in paternal meiosis, possibly restricting recombination to regions with longer repeat tracts and/or higher repeat densities. Chiasma interference in both sexes for chromosome 22 and in females for chromosome 21 is close to the genome average. Chromosome 21 is significantly different in male meiosis, with near complete interference, suggesting that even when double recombinants occur they are widely spaced. We propose that this difference is related to the different distribution of GT/CA dinucleotides. These repeats are widely distributed on chromosome 22, perhaps offering greater opportunities for double recombinants to occur within smaller regions, whereas they are largely subtelomeric in distribution on chromosome 21.

We previously sequenced the 4333-nucleotide cDNA of the COPA (HEP-COP) gene which encodes the human homologue of the α-subunit of the coatomer protein complex, involved in intracellular protein transport. Within the 3′ untranslated region at nucleotides 4049–4333 was observed an Alu repeat containing conserved A and B block elements, and showing high homology to the human Alu-Sx subfamily consensus sequence. Upstream of the Alu repeat were noted a TATA box, a CAAT motif and two activating transcription factor (ATF)-like binding sites, which represent putative regulatory elements directing Alu transcription. In addition, the 25 and 35 N-terminal amino acid residues of COPA and its bovine homologue were identical to xenin-25 and proxenin, respectively. Xenin-25 is a gastrointestinal hormone that stimulates exocrine pancreatic secretion. This peptide is related to xenopsin, neurotensin and neuromedin N which are bioactive peptides derived from larger precursors via proteolytic cleavage by cathepsin E at processing sites determined by conserved C-terminal sequences, i.e. proline/valine-X-X-hydrophobic amino acid. Given the conformity of the C-terminal residues of xenin-25 (PWIL) and of its progenitor molecule, proxenin (VIQL), it is proposed that these peptides are generated by a similar mechanism of post-translational modification involving a parent precursor represented by the α-subunit of coatomer.

Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. It has a very strong HLA class II association to the DQ locus. The nature of the involvement of the DQ locus in the susceptibility to CD has been examined by tissue culture experiments, association and peptide binding studies. We examined the role of the DQ molecules in the pathogenesis from the perspective of a genetic family study. Using flanking microsatellite markers to the class II region of the MHC to establish the parental origin of the susceptibility DQ alleles, we have evidence suggesting that the HLA association is probably due to the necessity to have these DQ alleles in order to express CD and there is no support for the presence of a rare mutation within the DQ alleles nor any rare HLA-linked gene nearby in linkage disequilibrium with the DQ locus. This approach is applicable to other diseases demonstrating strong association with common alleles, and can be used to predict whether screening the region for rare mutations is likely to be worthwhile.

Inaugural Lecture delivered at University College on 21 Jan. 1946 and reprinted with permission from The Lancet, 29 June 1946, pp. 949–953

For academic purposes, eugenics is defined as the study of agencies under social control that may improve or impair the racial qualities of future generations either physically or mentally. This formula allows many different interpretations. The subject matter might involve almost any material studied in medicine, psychology or social science. In the light of knowledge of its frequent misuse, inclusion of the term “racial” in the definition seems unfortunate. A racial quality is presumably any character which differs in frequency or which (when it is metrical) differs in average value in two or more large groups of people. No qualities have been found to occur in every member of one race and in no member of another. Furthermore, as Morant (1939) has shown in his analysis of European populations, differences between average measurements in the so-called races are often much smaller than commonly supposed. The qualities by which people differ can be treated as legitimate material for scientific investigation without employing any invidious concept of race. The human race constitutes the field of eugenic inquiry.

A popular view of eugenics, which has in the past been encouraged by propaganda groups such as eugenic societies and human betterment foundations, implies active interference in human reproduction. The general grounds for interference are often held to be that civilisation has tended to reverse the process of natural selection because the weaklings are now being fostered at the expense of the naturally strong. Not only are the physically and mentally inferior prevented from perishing in infancy by the activities of medical and social services but also, when the weaklings grow up, they are supposed to be more fertile than the normal. As Karl Pearson (1909) once put it, “we have suspended the racial purgation maintained in the less developed communities by natural selection.” Degeneration of the physical and mental level of civilised peoples is believed to be inevitable unless eugenic measures are taken to counteract it.

Defects in the AGXT gene mapped to chromosome 2q37.3 cause primary hyperoxaluria type 1 (PH1), one of the inherited disorders of endogenous oxalate overproduction. In order to identify diagnostically useful linkage markers in this region of chromosome 2 we have typed three microsatellite loci mapping to the q37 region of chromosome 2 in 192 individuals from 30 families. They were additionally studied for mutations and polymorphisms in the AGXT gene. Maximum lod scores of 29·1, 22·8 and 15·8 were obtained for D2S140, D2S125 and D2S395 respectively at recombination fractions (theta) of 0·001, 0·015 and 0·02. Confidence intervals for recombination as determined by the ‘lod-1 rule’ were 0·015, 0·05 and 0·06. Three recombinants were identified between AGXT and D2S125/D2S395, whereas no recombination between AGXT and D2S140 was observed. These data allow the calculation of the risk of incorrect prenatal diagnosis of PH1 based solely on linkage analysis with these extragenic markers.

Coeliac disease (CD) is a multigenic and multifactorial enteropathy triggered by gluten-composing proteins. A possible involvement of the intestinal Aminopeptidase N (APN) was investigated by an association analysis. SSCP analysis detected four variants at position 281, 378, 956 and 2957 (referred to no. g178535, GenBank) that were studied in 193 Italian CD families. The haplotypic combinations were determined from family segregation and pairwise linkage disequilibria (D′ = D/Dmax) between the polymorphic sites were calculated. Significant D′ values ranged between 0.78 and 0.31. Association with CD was tested by TDT (Transmission Disequilibrium Test) utilizing as markers the nucleotide substitutions and their haplotypic combinations. No statistically significant transmission distortion to the probands or to their clinically silent sibs was observed. Our data exclude an involvement in CD of the tested markers and of further undetected variation in strong linkage disequilibrium (D′ ≅ 1) with them. The power of the test was not adequate to detect an association with an unknown polymorphism which is not in complete linkage disequilibrium with those analysed.

The impact of the three most common apolipoprotein E (APOE) genotypes (ε32, ε33, and ε43) on means, variances, and correlations of nine plasma lipid and apolipoprotein traits (total cholesterol, lnTriglycerides, HDL cholesterol, and apolipoproteins AI, AII, B, CII, CIII, and lnE) was studied in 212 unrelated female and 219 unrelated male children aged 5–21.5 years from 278 pedigrees ascertained without regard to health status from Rochester, Minnesota. There was significant heterogeneity (p[les ]0.05) among genotypes for the mean plasma levels of lnApo E, Apo CII, Apo CIII, and lnTriglycerides (lnTrig) in females, and for the means of lnApo E, Apo B, and total cholesterol (Total-C) in males. Significant heterogeneity of intragenotypic variance was observed in males for Apo CII, lnTrig, and HDL-C; no significant heterogeneity was observed in females. Pairwise correlations between traits differed significantly among APOE genotypes in both females (6 of 36 pairs) and males (5 of 36 pairs). These results differ from those obtained from studies of the parental generation from the same sample of pedigrees. Our study further demonstrates that, with the exception of mean lnApo E levels, the univariate and bivariate distributions of traits that are measures of lipoprotein metabolism are influenced by variation in the APOE gene in a gender- and generation-dependent manner.

We have studied the impact of natural selection through stillbirth on the Italian population, taking into account the socio-economic heterogeneity of the country. The results suggest that older age at delivery and lower cultural level of the mothers, indicators of critical biological and socio-economic conditions, even at present increase stillbirth risk. Moreover, in the less favourable environment of the southern regions, selection is still sex-specific.

There is good evidence from linkage analysis and mouse model knockouts that the endothelin-1 gene (EDN1) is a good candidate for non-syndromic orofacial cleft (OFC) disease. EDN1 maps to the chromosomal region of the OFC1 locus in 6p23. Therefore we have examined three other candidate genes in the endothelin pathway (ECE1, EDNRA and EDNRB, which map to chromosomes 1, 4 and 13 respectively) in a linkage study of 9 families with OFC, where the disorder is not linked to chromosome 6p23. The total lod score for these 9 multiplex families never exceeded −2.00 and thus our data suggest that EDN1 and related genes are not involved in non-syndromic familial OFC.

The mammalian low molecular weight phosphotyrosine protein phosphatase is expressed as two distinct isoforms. The human ‘fast’ and ‘slow’ isoforms differ only in the sequence of an internal segment of 34 residues, and the ACP1 gene contains two adjacent exons (E3F and E3S) which encode these segments. We have previously suggested that the fast and slow isoforms are generated by mutually exclusive pre-mRNA splicing of E3F and E3S. The common alleles ACP1*A, *B and *C express the fast and slow isoforms in different ratios. The *A and *C alleles differ from *B by C → T transitions in E3S and E3F respectively. To test the idea that the fast[ratio ]slow ratio is determined by nucleotide substitutions in the E3F-I3F-E3S region, four groups of rare ACP1 variants with unusual fast[ratio ]slow ratios and the rare *E and *R alleles, expressing fast[ratio ]slow ratios similar to *C and *B, respectively, were analysed. Gene segments of the I2-I3S region were amplified by PCR and analysed by SSCP and variant bands were excised and sequenced. For each of the rare isozymic variants one of six different nucleotide substitutions in E3F (nts+42, +85, +109, +110), I3F (nt+1) and I3S (nt+8) was observed. The *E and *R alleles showed C and B sequence, respectively, in accordance with the fast[ratio ]slow ratio. The results support the hypothesis that the fast[ratio ]slow ratio is constitutive.

A patient (64-year-old, male) with familial cholinesterasemia caused by BChE deficiency was studied. DNA sequence analysis of all exons identified a point mutation, an A→G transition at codon 128, resulting in a Tyr→Cys substitution. The propositus showed extremely low BChE activity, but his other family members (three individuals) showed from intermediate to normal BChE activity. An immunological method revealed the absence of BChE protein in serum of the propositus. Both PCR primer introduced restriction analysis (PCR-PIRA) and sequence analysis revealed all three family members to be heterozygotes for this mutation.

The chromosomal location of the human fast skeletal muscle troponin C (TNNC2) gene was determined using somatic cell hybrids. PCR-based analysis of a ‘monochromosomal’ hybrid panel identified the presence of the TNNC2 gene on human chromosome 20 and subsequent analysis of the Genebridge4 radiation hybrid panel located the gene between D20S721 and GCT10F11 with a lod score of >3.