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The Danish breast cancer data collected by Jacobsen (1946) have been reanalysed using morbid risks which incorporate mortality due to breast cancer. A dominant gene is favoured for familial breast cancer, supporting the conclusions of Williams & Anderson (1984) and later authors. Neglect of specific mortality does not greatly alter estimates of gene frequency and displacement, but the evidence for a major gene is inflated. No evidence for heterogeneity was found. Earlier claims of non-Mendelian transmission are in error since we have discovered that transmission probabilities are not correctly implemented in the computer program POINTER. Cases with bilateral breast cancer and males with breast cancer all belonged to families favouring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer is significant in this material.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

Background Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro. Objective In this study we tested the hypothesis that two such polymorphisms, lymphotoxin α NcoI B*1 and − 308 TNF2 may be components of the genetic predisposition to asthma. Methods Five hundred and fifty-six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTα NcoI locus. Results There was an association between allele two of the − 308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04–4.32, P = 0.036). However, there was no association with LTα NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR. Conclusions We conclude that the − 308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.

Every science begins in folklore and matures as it reacts against dogma and myth. Astronomy developed in the Neolithic, but it did not outgrow astrology until the sixteenth century. Chemistry discarded alchemy at about the same time. On the contrary, the short history of genetics has been concurrent with the pseudo-science of eugenics, which, at times, has been widely accepted and incorporated in population policy and directive genetic counselling, with rare opposition by geneticists. Societal pressures are likely to increase with the power of genetic technology, the fear it generates and the perception that population growth threatens human welfare. Without a pertinent ethical code, geneticists are vulnerable to both temptation and opprobrium. The intrusion of eugenics into genetic counselling has been a recent source of concern to societies and congresses of genetics. This review traces the causes of this concern and the manner of its expression in the absence of an international voice for genetics that could address ethical and other common interests.

Genetic epidemiological studies are useful for the knowledge of the association of markers and genes involved in diseases. In the present work, we studied the frequency of four adenomatous polyposis coli intragenic RFLP markers often used in risk evaluation in a population of 10 familial adenomatous polyposis patients from 10 unrelated Portuguese familial adenomatous polyposis families not sharing the same mutation, and in a population of 55 unrelated healthy Portuguese volunteers. We compared the frequency obtained to normal and affected populations and to results already reported in other populations. We observed allelic frequencies for the Portuguese population that agree with the published ones. The intragenic polymorphisms show strong gametic disequilibrium suggesting little recombination between them. We observed haplotype frequencies significantly different in patients and controls. The gametic disequilibrium may be due to a common founder for a proportion of apparently unrelated probands.

Traits related to atopy and asthma were defined in a random cohort of 131 families with three or more children. Correlation analysis provides no evidence of imprinting, maternal effect, or a major role of environment shared by sibs. Commingling analysis favours more than one distribution, the upper one being common for asthma and very common for atopy. Segregation analysis of rank-transformed variables provides only equivocal evidence of major genes against a polygenic background but suggests that such genes (if present) are individually common and not of large effect. Segregation analysis under a two-locus model gives consistent results with minimal distributional assumptions. To enter combined segregation analysis we favour a restricted model in which the major locus is additive on the liability scale and the pseudopolygenic modifier locus accounts for at least half the genetic variance. Total IgE and bronchial reactivity are proposed for meta-analysis of atopy and asthma respectively. Genetic analysis of complex inheritance is discussed and it is shown that allelic association with random loci is not a feasible approach.

Summary The AD1 locus on chromosome 21 (MIM 104300) maps to the β-amyloid precursor locus (APP) at approximately 27·7 Mb from pter (10·9 cM in males and 33·9 cM in females), flanked proximally by D21S8 and distally by D21S111, with D21S124 and D21S210 close but of uncertain order. AD1 accounts for 63±11 % of multiplex Alzheimer pedigrees for which lod scores have been reported. Since a much smaller proportion of pedigrees have mutations in the cDNA for β-amyloid (APP exons 16 and 17), it is likely that the AD1 locus spans controlling elements near those exons. There is no evidence for a second locus on chromosome 21. The remaining pedigrees may include sporadic cases as well as mutations at an AD2 locus on another chromosome.

Summary The genetic basis for colorectal cancer was investigated by complex segregation analysis of a published series of consecutive pedigrees ascertained through patients undergoing treatment for colorectal cancer. Analysis favoured a dominant gene or genes with a frequency of 0·006 with a lifetime penetrance of 0·63. These genes account for 81% of colorectal cancer in patients under 35, however, by 65 about 85% are phenocopies.

Summary A theory is given for complex phenotypes represented by an ordered polychotomy separately for affected (as severity) and for normals (as diathesis), with consideration of history, ascertainment, sampling frames, and phenotype systems. Nonrandom selection of probands by severity is permitted. Both probit and logistic models are developed in a form compatible with segregation and/or linkage analysis. Probabilities are set out in detail in the Appendix. This approach avoids problems that have been encountered with quantitative traits and correlated phenotypes, although using this information.

SUMMARY To achieve consensus more exact definitions of genetical maps are required, of which standard, comprehensive and skeletal might be some. A standard genetic map gives distance from pter in centimorgans (cM), uses the international nomenclature for assigned loci, is sex-specific, and allows as well as possible for interference and typing errors. A standard physical map gives distance from pter in megabases (Mb). A standard map is called comprehensive if it aims to include all syntenic loci, and skeletal if it is limited to loci whose order is well supported. Loci with established order are called skeletal, and are used to define regional assignments of other loci. These principles are illustrated using the CEPH data for chromosome 10. Map lengths by multiple 2-point analysis under supported interference are in good agreement with other evidence, but multipoint mapping gives a substantial overestimate. There are currently 21 loci in the skeletal genetic map and 40 loci in the comprehensive genetic map. From these data, cytogenetic assignments, and partial genetic maps the physical location has been estimated for 85 loci. MEN2A is in a region close to the centromere in which male recombination per megabase is much reduced. Order of DNA markers in this densely mapped region has not been determined, and therefore the exact location of MEN2A is uncertain, although it is likely to lie between D10S34 and D10S30 and close to D10S11.

A haplotype block is a DNA sequence containing polymorphisms in strong linkage disequilibrium (LD) and with low haplotype diversity, separated from other blocks by steps of low LD with high haplotype diversity. Haplotype blocks may be as short as 2 kb or more than 150 kb, depending both on block definition and the spacing of LD cold spots, which tend to be shorter than blocks. Haplotype diversity measured by the effective number of haplotypes is said to be low if smaller than the number of polymorphisms defining the haplotype. To be useful in genetic analysis, the haplotype should be shorter than a typical block. Keywords: haplotype block; linkage disequilibrium; haplotype diversity; linkage disequilibrium map; selective sweep

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 ?2 = ?2 ln L we use the Akaike criterion AIC = df[?2/min ?2?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(?) = Me d, where ? 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 ?2.

We report a combined segregation and linkage analysis of a Danish sample of 216 insulin-dependent diabetes mellitus (IDDM) nuclear families: of these 216, twenty multiplex families were haplotyped regarding HLA-DR and -B markers. The analysis was conducted using the computer program COMBIN, which includes a modifier to absorb family resemblance that is additional to the effect of the major locus that is assumed linked to a marker locus, eg, within the HLA region. The initial analysis could clearly reject a dominant major locus but could not discriminate between other models with or without modifier. However, after adding supplementary information on population associations between HLA and IDDM together with the identity-by-descent (IBD) distribution to the analysis, a final model was identified. This invokes an additive major locus, linked to HLA with recombination not significantly different from 0, a disease gene frequency of 0.217, plus a dominant modifier. From this model it can be predicted that about 0.15% of the general population is at 100% risk of IDDM, about 5% is at intermediate risk (approximately 10%), while the remaining population has a risk of 0. The model predicts recurrence risks compatible with empirically estimated values. Particularly strong, positive haplotype associations were found for the DR3,B8, DR3,B18, and DR4,B15 haplotypes, but detailed analyses showed that neither these particular haplotypes nor the DR3 and DR4 haplotypes in general could entirely explain the HLA-associated susceptibility. The DR2 haplotypes showed a strong negative association. The results are discusssed in the light of available data on the epidemiology of IDDM in order to provide a framework for further epidemiological studies.

By comparison with a more general theory, data on trisomy in live births, amniocenteses, and spontaneous abortions by year of maternal age are shown to fit a logistic augmented by a proportion independent of maternal age. The frequency of trisomy increases monotonically, with no discrepancy at extremely low or high maternal age. Trisomy 16 is exceptional in that all cases appear to be age-dependent. For groups A, B, and C most trisomies arise by a process independent of maternal age. A small proportion of these trisomies and about half of trisomies for smaller chromosomes (excluding trisomies 16 and perhaps 22) originate by some process dependent on maternal (but not paternal) age and therefore presumably independent of crossingover, which in the female takes place before birth.

Malécot's theory of isolation by distance under 'continuous' migration is shown to fit acceptably to various human populations. Although it provides a less complete and reliable prediction of population structure than migration matrices, it is applicable to a greater range of structures and data.

Summary Historical demography, surname concordance (isonymy), migration, and genealogy give a consistent description of population structure. The census size has averaged about 1400 over the last five centuries. Conjoined with an effective migration rate of 0.05 per generation as estimated by three different methods, this gives an evolutionary size of 638, random kinship of 0–008 and inbreeding of 0.007 relative to the rest of Britain. The population structure of Barra is similar to other British isolates in the recent past, but an order of magnitude less inbred than slash-and-burn agriculturalists and Pacific Islanders. Some consequences for rare genes and polymorphisms are discussed.

Copper incorporation studies were performed on individuals from 58 pedigrees, comprising 140 sibships. As previously reported, there is considerable overlap between heterozygotes and normal homozygotes. Segregation analysis supports recessive inheritance of disease, with residual heritability for 64Cu uptake in cultured cells. The population frequency of sporadic cases is compatible with the 1/3 expected for an X-linked lethal with equal mutation rates in egg and sperm, which implies a mutation rate of 6.7 X 10(-6)/gamete/generation. The parameters estimated here are likely to provide the best basis for genetic counseling until more reliable carrier tests are performed on a systematic sample from a large, defined population.

Two hundred forty-four Toronto pedigrees of Duchenne muscular dystrophy patients have been partitioned into nuclear families with pointers for complex segregation analysis under a mixed model. The model takes into account the major X-linked locus and a multifactorial transmissible component for creatine kinase activity in females. The incidence in the province of Ontario is estimated to be 292 per million male births. The proportion of sporadic cases is 1/3, demonstrating equal mutation rates in males and females. A multifactorial component (H = 0.379) contributes to family resemblance for creatine kinase measurements. Examples are presented of the application of a computer program, COUNSEL, to derive genetic risks for genetic counseling with consideration of the multifactorial component.

The present paper demonstrates algorithms for applying gene counting estimation of haplotype frequencies in very large genetic systems. A factor union representation of phenotypes is used which conveniently yields the sets of potential haplotypes and diplotypes for each phenotype. Methods for storing and rapidly retrieving the relevant haplotypes are given. An example with several hundred frequencies is given which required a few seconds computing time for each estimation iteration on a small computer. A computer program employing the methods described has been written in Fortran-77 and is available to any investigator on request.

Erythrocyte catechol-O-methyltransferase (COMT) activity was measured in 142 members of 32 nuclear families in which one child had Down syndrome (DS). The mean activity in subjects with trisomy 21 appears higher than in parents and sibs, though not significantly so. However, this fact does not seem to modify the properties expected for a trait genetically controlled in a diploid population. The commingling analysis of the COMT activity in the whole group, and in each subgroup of relatives, suggests a mixture of two or, more likely, three components, the latter being in agreement with a transmission model of genes without dominance. The most parsimonious hypothesis supported by the mixed model segregation analysis is that of an additive major locus (d = 0.5) with an estimated frequency of 0.40 +/- 0.03 for the COMTH gene, to which a small polygenic effect (H = 0.067) can be added. This hypothesis is supported further by the analysis of family resemblance, r = 0.45 +/- 0.12 being the maximum likelihood estimator of the intraclass correlation among sibs. The higher COMT activity in DS subjects may reflect a situation of general enzyme disorder only indirectly connected with trisomy of chromosome 21.

The inclusion of HLA data in genetic studies of insulin-dependent diabetes mellitus (IDDM) has not led to conclusive segregation models for IDDM so far. As a new approach, we first applied complex segregation analysis, independently of HLA data, to two combined Danish family materials. Then the best fitting segregation model was entered into linkage analysis of a third material, including family as well as HLA data. The best solution obtained in the segregation analysis was a mixed model, including an intermediate gene, which on the penetrance scale acts as a recessive, together with a polygenic component. The linkage analysis showed an overall recombination fraction of 0.0417 with high coupling frequencies for the HLA-DR3 and HLA-DR4 alleles and the putative disease susceptibility gene. However, when the pedigrees were divided according to whether or not the proband had the heterozygous HLA-phenotype DR3/DR4, a maximum likelihood ratio test for heterogeneity was significant, with estimated recombination fractions of 0.0 and 0.0963 in HLA-DR3/DR4 pedigrees and the remaining pedigrees, respectively. In total, we found convincing evidence that two familial factors contribute to IDDM: a locus within HLA, which very well may be DR; and an unlinked mechanism which is unimportant for HLA-DR3/DR4 but simulates recombination. If confirmed, this conclusion has important implications for further genetic studies of IDDM and complex segregation analyses of family materials sampled according to criteria which include HLA data of the probands are highly needed.

Classical segregation analysis was performed on 651 male probands in 597 families with Duchenne muscular dystrophy (DMD) collected from 20 of 25 National Institutions for Muscle Diseases in Japan. The proportion of sporadic cases is compatible with 1/3 expected for an X-linked lethal trait with an equal mutation rate in egg and sperm, the estimated mutation rates being 9.2 × 10−5 and 10.9 × 10−5 /gamete/generation, respectively. The incidence and prevalence among males were estimated to be 29.2 × 10−5 and 6.7 × 10−5, respectively. These results indicated no difference from the patterns of DMD in Western countries.

Segregation analysis of four Lp assays on 557 children in 227 families reveals a dominant major gene and a residual heritable component that may reflect one or more alleles of weaker effect. Close or moderate linkage to esterase-D (ESD) is excluded.

The phenotype bioassay has been applied to samples of Indians from 12 countries of Central and South America. Using five blood group systems, more than 7,000 tested individuals were studied. The mean coefficient of kinship for pairs from the same place (a) is about 0.025, which is considerably higher than has been found for industrialized populations. The decline of kinship with distance (b) is moderate (0.003), indicating substantial migration. These results are similar to two other primitive populations.

Resume Dans quatre grandes familles bresiliennes parmi lesquelles 31 enfants ont pu etre testes, aucun d'entr'eux n'etait du type Kell et Sutter des parents, K + Js(a+) et K -Js(a -). Ceci confirme l'hypothese que le groupe Sutter fait partie du complexe Kell pour lequel une notation est proposee. Zusammenfassung In vier grosen brasilianischen Familien wies von 31 untersuchten Kindern keines den elterlichen Kell und Sutter Typ K + Js(a+) und K -Js(a-) auf. Dieser Befund zeigt, das die Sutter-Gruppen einen Teil des komplexen Kell-Systems darstellen, fur welchen eine Bezeichnungsweise vorgeschlagen wird.

Summary In a northeastern Brazilian population with 30% Negro admixture, the frequencies of S-s- alleles at the MNS locus are N* = 0.0189, M* = 0.0138, where the asterisk signifies that the reaction with anti-U is not specified. Of 8 independent homozygotes, 4 reacted with anti-U. This is greater than, but not significantly different from the proportions of U + and U- reported in American Negroes by Allenet al. (1963), and the pooled estimate is that 16% of N* genes are NU and 5% of M* genes are MU. After deleting parentage exclusions by other systems, the frequency of parentage errors among inferred N* and M* heterozygotes is shown to be 0.048±0.038, and the overall frequency of undetected parentage errors is 0.010±0.006. Neither estimate is significantly different from zero, nor is the racial phenotype of inferred heterozygotes significantly different from its expectation on the hypothesis that (almost) all inferred heterozygotes in this population are genuine, and not the result of extramarital parentage. No recombination was observed between MN and inferred S-s- alleles in 180 gametes tested. As an explanation of N* and M* “alleles”, the data clearly exclude an unlinked modifier (P

A method to construct genetic maps using two-point lod tables was applied to the simulated pedigree data. The analysis provided the correct map order and distance between markers with remarkable accuracy. The methodology discussed.