A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans.

N-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants.

Analysis of the molecular variance at the phenylalanine hydroxylase (PAH) locus.

The frequencies of the different haplotypes identified at the phenylalanine hydroxylase (PAH) locus were analyzed for both phenylketonuria (PKU) and normal haplotypes of various European, Asiatic, Polynesian and Black American populations. These molecular variants were studied by applying a specific model of multivariate analysis of variance, allowing an estimation of components of variance at different levels of hierarchical subdivisions (intrapopulation, among different geographical groups of populations, and between PKU and normal haplotypes within populations). The results indicate that the PAH polymorphism could be appropriate to study divergence between African, European and Asiatic population groups, but is not sufficient to explain the diversity among European populations. However, the differences in PAH haplotype frequencies between PKU and normal haplotypes are statistically significant over all European populations.

A cladistic analysis of the Trichostrongyloidea (Nematoda).

A morphologically based cladistic analysis of 40 genera included within the Trichostrongyloidea (Amidostomatidae, Dromaeostrongylidae and Trichostrongylidae) is proposed. Two genera were used as outgroups, one from the Strongylina and the other from the Ancylostomatina. Seven genera do not appear in the matrix because some significant morphological characters remain unknown for these genera. Nonetheless, except for Moguranema which is excluded as incertae sedis, a likely systematic position could be assigned to them based on the morphological characters that are known. The classification which best fits the consensus tree is composed of three families. In adding the genera not included in the tree, we obtain: (i) Trichostrongylidae with three sub-families, Amidostomatinae (four genera), Filarinematinae (three genera) and Trichostrongylinae (five genera); (ii) Haemonchidae with two sub-families: Ostertagiinae (eight genera) and Haemonchinae (five genera); (iii) Cooperiidae with three sub-families: Libyostrongylinae (five genera), Obeliscoidinae n. subfam. (five genera) and Cooperiinae (ten genera). Dromaeostrongylus and Ortleppstrongylus, whose females have a caudal spine, are excluded from the Trichostrongyloidea and are placed in the Molineoidea. The hypotheses relating to the evolutionary history of the Trichostrongyloidea are: the origin of the superfamily could have occurred during the upper Cretaceous period. The two most ancient sub-families (Amidostomatinae and Filarinematinae) would be of Gwondwanan origin and evolved during the Paleocene period within Neotropical aquatic birds and within the Australian marsupials. The Trichostrongylinae would have arisen during the Eocene period within birds and then adapted to diverse archaic mammals in the Neotropical region on one hand and in the Nearctic region, on the other hand and lastly adapted to the Lagomorpha and subsequently to the Ruminantia. In both families originating from the Trichostrongylidae, the adaptation to the Lagomorpha may have taken place during the Oligocene but in a different way. In the Haemonchidae, the Ostertagiinae may have passed directly from the Neartic region to Europe. In the Cooperiidae, the adaptation to Lagomorpha may have occurred either within the Libyostrongylinae which may have remained in the Ethiopian region since the Paleocene, or, more likely, by the passage of the Obeliscoidinae from the Nearctic region to the Asian, through the Bering strait. In all cases, the adaptation of the Trichostrongyloidea of Lagomorpha to Ruminants apparently took place during the Miocene, mainly in the Palearctic and the Ethiopian regions.

Exploring a phylogenetic approach for the detection of correlated substitutions in proteins.

The remarkable conservation of protein structure, compared with that of sequences, suggests that in the course of evolution, residue substitutions which tend to destabilize a particular structure must be compensated by other substitutions that confer greater stability on that structure. Several approaches have been designed to detect correlated changes in a set of homologous sequences. However, most of them do not take into account the phylogeny of the sequences, and it has been shown that their detection power is weak. It remains unclear whether coevolution could be a general process at the level of amino acids of proteins. In the present study, we analyze the phylogenetic reconstruction of 15 sets of homologous proteins to assess, under different conditions, whether a significant amount of coevolving sites can be detected. Two criteria are used to detect significantly cosubstituting sites. One criterion corresponds to that of Shindyalov, Kolchanov, and Sander. The second one is based on intensive simulations of evolution of protein sequences along a phylogeny to estimate the significance of the number of observed cosubstitutions for pairs of sites. Our results show an important sensitivity of the detection of cosubstituting sites to the model used for the phylogenetic reconstruction. Not considering the uncertainty associated with the reconstructed data might lead to detecting numerous false-positive pairs of sites. Finally, significant amounts of coevolving pairs could be found only when substitutions affecting the physicochemical properties of the amino acids were considered. Such results suggest evidence of a cosubstitution mechanism in protein evolution. However, the identification of nonambiguous coevolving sites is still unresolved.

Relationships between consanguinity and migration rate from surname distributions and isonymy in France.

The distribution of surnames in France during the period 1916-40 is analysed from the civil birth registers for each of the 36,500 administrative units. The migration rate estimated from surnames is compared with the migration rate obtained from demographic census data. The correlations calculated among the 90 Departments ranges between 0.52 and 0.76 according to the size of the communes. Moreover, the migration rate is shown to be highly correlated with the average coefficient of consanguinity based on dispensations for marriages between relatives. These findings point to the validity and the usefulness of quantifying migrations on the basis of surname data and they show that migration flux and consanguinity are inversely and closely linked.

Genetic Analysis Workshop II: study of Problem 2 linkage relationships by different methods.

Segregation and linkage analyse were performed on Problem 2 simulated data. Segregation analysis showed evidence for nearly recessive major susceptibility locus with parameter estimates close to the simulation input values. Linkage between this susceptibility locus (X) and the ten marker loci (A to J) led us to propose the following map: X-G-F-B.

A Bayesian approach to infer geographical origins of migrants through surnames.

BACKGROUND: Surnames are an easy tool to analyse human genetic structure, mobility and evolution. Few studies use surnames to estimate human migration at different geographical level. PRIMARY OBJECTIVE: Here we propose the application of a Bayesian method to estimate the probability of geographical origin (pgo) of migrants in a given area using surnames. METHOD: This method can be applied with data recordings when they are available for at least two successive periods and in the areas which are the potential sources of emigration. The principle is that the new surnames which are arriving during the second period in the area under investigation can provide information on their geographical origins. The probability of the origin of migrants can easily be estimated iteratively from the frequency of surnames by using the Bayes' theorem. RESULTS: This method is exemplified using civil birth registers at different geographical scales. The pgo of migrants, estimated between two periods (1891-1915 and 1916-1940), (i) from French departments to Paris (ii), from these departments to Tarbes, and (iii) from counties surrounding Tarbes to Tarbes, are mapped and discussed.

[A study in twins of the urinary excretion of vanilmandelic acid, 17-keto-steroids, 17-hydroxycorticosteroids, and creatinine]. / Etude gémellaire de l'excrétion urinaire de l'acide vanilmandélique, des 17-cétostéroides, des 17-hydroxycorticostéroides et de la créatinine.

The 24-hour urinary excretion rates of creatinine, vanilmandelic acid (VMA), 17-hydroxycorticosteroids, 17-ketosteroids were analysed in 30 female twin pairs. For each of these variables, a comparative study based on the breakdown of total variance into interpair and intrapair variance was undertaken, first on identical (MZ) and fraternal (DZ) twins and then on twins who live together or separately. The comparison of test results shows a strong likeness in the MZ group and in the living together group with respect to the urinary excretion of 17-OH. The variability of VMA excretion can be explained by genetic factors while the variability of 17-ketosteroids and creatinine can be explained with reference to environmental factors.

Cladistic analysis of haplotypes as an attempt to detect disease susceptibility.

We report the results of our analyses of the Genetic Analysis Workshop 12 simulated data set, using phylogenetic methods to reconstruct the history of haplotypes. We selected candidate gene 1 and 6, drawn from the isolate population. In a first step, haplotypes were inferred using family data. In a second step, cladistic approaches were performed to select the most parsimonious trees under various conditions of character state transformation and ancestral hypotheses, in order to check whether the affected status is more frequent in some clades than in others. Sites which are synapormophies of such clades can be viewed as candidate sites for the disease susceptibility. The method seems to be efficient for the candidate gene 1, but not for the candidate gene 6. Effects of the genetic model underlying the affection status are discussed, particularly dominance, penetrance, and, in the context of this simulated data, procedure followed to generate haplotypes. These preliminary results deserve further investigations.

Segregation analysis of a-b ridge count in human palms.

Frequency distribution and segregation analyses have been performed on a-b ridge counts from 422 families. The results support the hypothesis of two commingled distributions of the trait, high-value distributions being 5.4% in females and 2.4% in males of the whole population. Segregation analyses point out evidence for simultaneously a multi-factorial inheritance (h = 0.72) and a major effect (P = 0.01). However, by testing different hypotheses on transmission laws for the major effect, we cannot decide between Mendelian transmission and no transmission. Hypothesis of an accident occurring in the developmental process of the a-b count has to be investigated further.

The probability of exclusion of ancestries based on genetic observations.

One can extend exclusion of ancestry beyond paternity: for example, to grandparents or other types of ancestors. Naturally, the probability of successful exclusion is smaller for more remote ancestors. The case that we have especially considered is that of exclusion on the basis of grandparents, of which there have been recent applications. A method of calculating the average probability of exclusion, P, in such situations is developed and applied to different genetic systems including DNA polymorphisms available today. As usual, multiallelic genes like HLA are by far the most informative, but a substantial number of other genes should also be tested to reach a reasonable probability of exclusion. The effect of inbreeding on P is demonstrated to be negligible.

[Evidences for genetic transmission of pulse arterial pressure]. / Evidences pour une transmission génétique de la pulsatilité artérielle.

Systolic (PS), diastolic (PD), and pulse (PULS) arterial blood pressure were examined in 151 French-West-Indies families. After adjustment for sex, age, Na/K urinary ratio, alcohol consumption, use of anti-hypertensive drug, the distributions of PS and PD were correctly fitted by two commingled normal distributions, one of them including 5% of the highest values of blood pressure which have to be compared to the high prevalence of hypertension in this population (10 to 20%). By performing segregation analyses under Lalouel et al.'s unified model we do not support any genetic transmission for PS and PD. On the contrary, large evidence for genetic transmission of PULS was found, involving one locus, two equally frequent alleles. However dominance cannot be correctly inferred. Accordingly, PULS appears to be of larger interest than PS and PD to study the genetic regulation of the arterial blood pressure.

Surname distribution in France: a distance analysis by a distorted geographical map.

The distribution of surnames in 90 distinct regions in France during two successive periods, 1889-1915 and 1916-1940, is analysed from the civil birth registers of the 36,500 administrative units in France. A new approach, called 'Mobile Site Method' (MSM), is developed to allow representation of a surname distance matrix by a distorted geographical map. A surname distance matrix between the various regions in France is first calculated, then a distorted geographical map called the 'surname similarity map' is built up from the surname distances between regions. To interpret this map we draw (a) successive map contours obtained during the step-by-step distortion process, revealing zones of high surname dissimilarity, and (b) maps in grey levels representing the displacement magnitude, and allowing the segmentation of the geographical and surname maps into 'homogeneous surname zones'. By integrating geography and surname information in the same analysis, and by comparing results obtained for the two successive periods, the MSM approach produces convenient maps showing: (a) 'regionalism' of some peripheral populations such as Pays Basque, Alsace, Corsica and Brittany; (b) the presence of preferential axes of communications (Rhodanian corridor, Garonne valley); (c) barriers such as the Central Massif, Vosges; (d) the weak modifications of the distorted maps associated with the two periods studied suggest an extension (but limited) of the tendency of surname uniformity in France. These results are interpreted, in the nineteenth- and twentieth century context, as the consequences of a slow process of local migrations occurring over a long period of time.

Escherichia coli molecular phylogeny using the incongruence length difference test.

Molecular phylogeny of the species Escherichia coli using the E. coli reference (ECOR) collection strains has been hampered by (1) the absence of rooting in the commonly used phenogram obtained from multilocus enzyme electrophoresis (MLEE) data and (2) the existence of recombination events between strains that scramble phylogenetic trees reconstructed from the nucleotide sequences of genes. We attempted to determine the phylogeny for E. coli based on the ECOR strain data by extracting from GenBank the nucleotide sequences of 11 chromosomal structural and 2 plasmid genes for which the Salmonella enterica homologous gene sequences were available. For each of the 13 DNA data sets studied, incongruence with a nonnucleotide whole-genome data set including MLEE, random amplified polymorphic DNA, and rrn restriction fragment length polymorphism data was measured using the incongruence length difference (ILD) test of Farris et al. As previously reported, the incongruence observed between the gnd and plasmid gene data and the whole-genome data was multiple, indicating numerous horizontal transfer and/or recombination events. In five cases, the incongruence detected by the ILD test was punctual, and the donor group was identified. Congruence was not rejected for the remaining data sets. The strains responsible for incongruences with the whole-genome data set were removed, leading to a "prior-agreement" approach, i.e., the determination of a phylogeny for E. coli based on several genes, excluding (1) the genes with multiple incongruences with the whole genome data, (2) the strains responsible for punctual incongruences, and (3) the genes incongruent with each other. The obtained phylogeny shows that the most basal group of E. coli strains is the B2 group rather than the A group, as generally thought. The D group then emerges as the sister group of the rest. Finally, the A and B1 groups are sister groups. Interestingly, the most primitive taxon within E. coli in terms of branching pattern, i.e., the B2 group, includes highly virulent extraintestinal strains with derived characters (extraintestinal virulence determinants) occurring on its own branch.

Genealogical and genetical African admixture estimations, blood pressure and hypertension in a Caribbean community.

This study examines the relationships between blood pressure, prevalence of hypertension, and the degree of black African admixture in the population of the Caribbean Island of La Désirade which is homogeneous with respect to the environmental factors and for which the socioeconomical stratification does not match racial origin. The degree of admixture was estimated by using both genealogical information and genetic markers. Blood pressure was repeatedly measured using an automatic sphygmomanometer. After adjustment for age, sex, ponderal index, Na/K urinary ratio, and clinical alcoholism, blood pressure and prevalence of hypertension were found to be significantly higher for the individuals having the largest proportion of genes of black origin. Identical results were obtained when either genetic markers or genealogical information were used as an individual--estimator of admixture.

Genetic regulation of plasma and red blood cell magnesium concentration in man. II. Segregation analysis.

A previous paper in this series reported that genetic factors play a major role in the familial transmission of plasma (P) and red blood cell (RBC) magnesium (Mg) concentrations. We report here the results of commingling analysis based on a random sample of unrelated individuals, and complex segregation analysis of a random sample of nuclear families. For RBC Mg, there is evidence for a mixture of two distributions, but not for three. For P Mg, there is no evidence for commingling. Complex segregation analysis under a mixed model yielded significant support for a major gene effect on RBC Mg, but not on P Mg. Parameter estimates indicated that the data are compatible with a rather common major gene (q = .23) for elevated RBC Mg, roughly 5% of the population being homozygotes for this gene, that the nonfamilial factors account for a small fraction of the total variance, and that the overlap of distributions of homozygotes is not large.

A genetic study of red blood cell zinc concentration in man.

Red blood cell zinc levels vary linearly with age within each sex. Age- and sex-adjusted zinc levels generated 6 familial correlations in nuclear families and twins. A simple additive polygenic model, with genetic heritability of zinc (h2) as the only unknown parameter, gave an excellent fit (X2(5) = 0.97, p greater than 0.96), with the corresponding estimate of h2 = 0.790 +/- 0.032. Commingling analysis supported the hypothesis that the logarithmic zinc values are approximately distributed according to a mixture of three normal distributions. Some support was found for a major gene hypothesis by complex segregation analysis under the mixed model. However, all the evidence came just from one family in which one of the 3 children's zinc value was over 3 standard deviations above the mean. When that family was excluded, there was no more evidence for a major gene. Under the most parsimonious mutlifactorial model that assumes equal heritabilities in children and adults, the heritability was estimated as 0.748 +/- 0.079, in good agreement with the outcome of path analysis. Biological interpretations are put forward and discussed.

Genetic regulation of plasma and red blood cell magnesium concentrations in man. I. Univariate and bivariate path analyses.

This paper concerns an analysis of family resemblance for magnesium concentrations, based on data from nuclear families and twins. Neither red blood cell magnesium nor plasma magnesium varies with age in children (under 20 years of age). Whereas adult plasma magnesium varies linearly with age, the red cell magnesium clearly showed a nonlinear trend: quadratic for males and a fifth-degree polynomial for females. Transformed magnesium concentrations generated six correlations in nuclear families and twins for each of the two traits. Separate univariate analyses, using a simple linear model with four parameters, strongly suggested that genetic factors are primarily responsible for the observed family resemblance. Both traits were then analyzed simultaneously using a simple bivariate model. We found that one common genetic factor alone could not explain all the 24 correlations generated for the bivariate analysis. The most parsimonious model involved only three parameters: genetic heritability for red blood cell magnesium (.922 +/- .014), genetic heritability for plasma magnesium (.721 +/- .040), and the genetic correlation between the two traits (.233 +/- .040).

Human genetics and human rights. Identifying the families of kidnapped children.

Between 1975 and 1983 in Argentina, at least 145 children were kidnapped with their parents or born in captivity to imprisoned women and then separated from their mothers. The parents of these children generally remain among the missing persons. However, the grandparents of the kidnapping victims and the Argentinian government are concerned with identifying these children. Genetic analysis can aid in determining whether a child who may be among the kidnap victims is related biologically to a particular family. Laboratory analysis of genetic markers in human blood enables the calculation of an "index of grandpaternity." This index reflects the probability that a child shares genes with a specified set of grandparents because he is their grandchild compared to the probability he and they share similar genes only by chance. The most useful system for this analysis is HLA, although other genetic markers including blood groups, red cell enzymes, plasma proteins, and DNA polymorphisms can be tested to provide adequate information in families with only one or two living grandparents. This approach has been applied successfully in Argentina, with an index of grandpaternity for one family of 99.9%, based on HLA typing only.

The inheritance of plasma and red blood cell magnesium and zinc levels studied from twin and family data.

The variability of magnesium and zinc concentrations in plasma and erythrocytes was investigated by twin and family studies. Twins were sampled in two distinct ways and in two different West-European regions. In one of the samples, a distinction was made between twins liver together and twins living apart. Two series of families were studied, one in a homogeneous environment, the other in a more diverse environment. Samples were compared by variance analysis. The results show 1) that genetic variability is significant for red blood cell (RBC) magnesium and zinc, minor for plasma magnesium and absent for plasma zinc; 2) that the family environment affects the extent of resemblance between twins and between siblings more for plasma levels than for RBC levels of magnesium and zinc. Furthermore, the intercorrelation analysis suggests that the genetic regulation systems of RBC magnesium and zinc are different, whereas some of the environmental regulation systems of plasma magnesium and zinc are the same. Biological interpretations are brought forward and discussed.