A symposium in honour of the centenary of the birth of Lionel Penrose, Galton Professor at UCL and editor of this journal from 1945 to 1965, was held on 13 March 1998 and attended by about 150 people. This included a number of distinguished scientists from several countries (particularly the USA) who returned to honour their mentor. The scientific theme of the day was the current understanding of genetic causes of mental handicap, a field in which Penrose made many major contributions. The programme is reproduced here. A detailed account of the meeting, including a summary of the papers presented is available from the Centre for Human Genetics, University College London, Wolfson House, 4 Stephenson Way, London, NW1 2HE.

[Email: hgadmin@galton.ucl.ac.uk or http://www.gene.ucl.ac.uk/chg]

From a vast selection of seminal papers by Lionel Penrose, we have chosen to reprint his inaugural lecture on Phenylketonuria delivered at University College on 21 January 1946. This was published in the Lancet (29 June 1946, pp. 949–953) and is reproduced by kind permission.

We feel that in 1998 it is well worth re-reading!

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.

The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.

A genetic polymorphism is responsible for determining that some humans express lactase at high levels throughout their lives and are thus lactose tolerant, while others lose lactase expression during childhood and are lactose intolerant. We have previously shown that this polymorphism is controlled by an element or elements which act in cis to the lactase gene. We have also reported that 7 polymorphisms in the lactase gene are highly associated and lead to only 3 common haplotypes (A, B and C) in individuals of European extraction. Here we report the frequencies of these polymorphisms in Caucasians from north and south Europe and also from the Indian sub-continent, and show that the alleles differ in frequency, the B and C haplotypes being much more common in southern Europe and India. Allelic association studies with lactase persistence and non-persistence phenotypes show suggestive evidence of association of lactase persistence with certain alleles. This association was rather more clear in the analysis of small families, where haplotypes could be determined. Furthermore haplotype and RNA transcript analysis of 11 unrelated lactase persistent individuals shows that the persistence (highly expressed) allele is almost always on the A haplotype background. Non-persistence is found on a variety of haplotypes including A. Thus it appears that lactase persistence arose more recently than the DNA marker polymorphisms used here to define the main Caucasian haplotypes, possibly as a single mutation on the A haplotype background. The high frequency of the A haplotype in northern Europeans is consistent with the high frequency of lactase persistence.

Congenital erythropoietic porphyria (CEP) results from profoundly deficient activity of the fourth enzyme of the haeme biosynthetic pathway, uroporphyrinogen III synthase (UROIIIS). CEP is a rare, recessively inherited disorder, and mutations in the UROIIIS gene detected in CEP patients are heterogeneous. The notable exception to this rule is a single missense mutation, designated C73R, which represents over 40% of all mutant UROIIIS alleles. In this study, we investigated three separate families with CEP from different ethnic backgrounds. We performed haplotype analysis using two microsatellite markers that closely flank the UROIIIS gene on chromosome 10q24, spanning a region of 4 cM on the GB4 linkage panel. Haplotype analysis revealed the occurrence of C73R on different haplotypes in four out of four disease chromosomes studied. The results are consistent with the hypothesis that C73R is a hotspot mutation for CEP, and does not represent wide dispersion of a single ancestral mutant C73R allele.

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.

The Klippel–Trenaunay–Weber syndrome (KTWS) is generally thought to occur sporadically, following a somatic mutation model. However, in some cases, clinical manifestations of the syndrome have been found in family members, suggesting an autosomal dominant inheritance. Here we present an epidemiological analysis of a consecutive series of cases with KTWS identified in the Spanish Collaborative Study of Congenital Malformations (ECEMC). We found an increase in parental age and in the number of pregnancies, as well as familial occurrence of haemangiomas. These observations suggest a genetic contribution to the occurrence of KTWS.

For most of the past century, prehistorians have had to rely on the fossil and archaeological records in order to reconstruct the past. In the last few decades, this evidence has been substantially supplemented from classical human genetics. More recently, phylogenetic analyses of DNA sequences that incorporate geographical information have provided a high-resolution tool for the investigation of prehistoric demographic events, such as founder effects and population expansions. These events can be dated using a molecular clock when the mutation rate and founder haplotypes are known. We have previously applied such methods to sequence data from the mitochondrial DNA control region, to suggest that most extant mitochondrial sequences in western Europe have a local ancestry in the Early Upper Palaeolithic, with a smaller proportion arriving from the Near East in the Neolithic. Here, we describe a cladistic notation for mitochondrial variation and expand upon our earlier analysis to present a more detailed portrait of the European mitochondrial record.

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 prepared a transferrin (TF) cDNA from total RNA of peripheral blood cells of an individual with a TF B variant (TF Bv) phenotype to analyze the molecular basis for the TF Bv. The TF B variant allele (TF Bv) was found to contain an A to G transition at nucleotide 1879 in the coding region that may result in substitution of glutamic acid for lysine at codon 627 located in exon 16. In addition, a transient expression study by transfection of each plasmid containing TF C1, TF C2 or TF Bv cDNA into monkey kidney (COS7) cells indicated that the products from specific TF alleles were able to be identified respective phenotypes by isoelectrofocusing electrophoresis and immunoblotting analyses. Based on this nucleotide substitution, we also established a PCR–RFLP method to detect the TF Bv allele from genomic DNA. Thus, peripheral blood cells were useful as an alternative source for preparation of cDNA from human liver for the molecular analysis of TF polymorphism.