Population genetics study of differential fertility in humans (based on an example of habitual abortion). III. Distribution of individual heterozygosity and genotype combinations for 9 polymorphic loci

Distribution of individual heterozygosity (the number of heterozygous loci per individual), wife/husband genetical differences and frequencies of genotypes formed by paired combination of eight polymorphic loci were studied in a group of couples and single women with repeated spontaneous abortions, and in a group of couples with normal fertility. No statistically significant differences were found for the first two parameters. Marked increase of genetical variability was shown for the women with repeated spontaneous abortions, as consequence of elevation of frequency of rare genotypic paired combinations. Therefore, differential fertility, as a component of stabilizing selection, alters the distribution of complex genotypes in human populations.     

Population genetic study of differential fertility in man (illustrated by habitual abortion). IV. Distribution of blood groups and frequency of incompatible marriages

Hereditary variation of 5 immunological systems coded by 8 loci was compared in 148 couples and 100 women with repeated spontaneous abortions in anamnesis (experimental group) and 141 couples and 100 women with normal fertility (control group). Marked differences in distributions of genotypes and frequencies of 3 systems (MNSs, Rhesus, Duffy) and frequency of AB0-incompatible couples were found between control and experimental groups. An average value of observed heterozygosity in experimental group was lower, as compared to the expected value. Possible influence of immunological factors on recurrent fetal wastage is discussed.     

Population genetics study of differential fertility in humans (based on an example of habitual abortion). II. Distribution of genotypes and heterozygosity levels for a variety of biochemical markers

Hereditary variation of 21 blood proteins coded by 22 monomorphic and 9 polymorphic loci was compared in 171 couples and 120 women with repeated spontaneous abortions in anamnesis (experimental group) and 183 couples with normal fertility (control group). Significant elevation of frequency of rare protein electrophoretic variants, marked deviation in distribution of genotypes for polymorphic loci, alteration in observed heterozygosity level were not found in experimental group. Statistically significant decrease in average value of D index (D = (hobs-hexp)/hexp; hobs, hexp--observed and expected heterozygosity per locus) was found in women of experimental group.     

Use of restriction fragment length polymorphisms for genetic counseling: Population genetic considerations

Two-locus population genetic models are analyzed to evaluate the utility of restriction fragment length polymorphisms for purposes of genetic counseling. It is shown that the linkage disequilibrium between a neutral marker and a tightly linked overdominant mutant will increase rapidly as the mutant moves to its polymorphic equilibrium. The linkage disequilibrium decays for deleterious recessive mutants. Two measures involving the linkage disequilibrium are investigated to determine how much information the transmission of the neutral marker provides about the transmission of the selected gene. In certain kinds of matings, where the parental two-locus genotypes and linkage phases are known, it is possible to determine whether or not a progeny is homozygous for the selected gene on the basis of the fetal genotype at the marker locus. A quantity of primary interest is the fraction of matings between individuals heterozygous for the selected gene in which exact diagnosis can be made in this way. The expected proportion of such matings, taken over all two-locus matings involving heterozygotes at the selected locus, is calculated as a function of the gene frequencies at the two loci and the linkage disequilibrium between them. This expected value is maximized when the linkage disequilibrium is at its maximum in absolute value. Fewer than half of all matings are informative if the linkage disequilibrium is small in magnitude or if the gene frequencies at the two loci are quite different. Consideration is also given to various conditional measures of association that may be useful when the parental two-locus genotypes are unknown. The results suggest that the utility of tightly linked neutral marker genes in predicting the transmission of a selected gene is generally less when selection acts against a recessive gene than for overdominant selection.     

Association of the heart fatty acid-binding protein (FABP3) gene with milk traits in Manchega breed sheep

The ovine fatty acid-binding protein type 3 gene has been chosen as a functional candidate gene for milk traits. Two different single nucleotide polymorphisms (SNPs) of ovine FABP3 gene have been tested in a daughter design comprising 13 families. No association was found between estimated breeding values for milk yield, protein and fat contents (FC) and genotypes across families using anova and transmission disequilibrium test (TDT). In within-family analysis, one family showed a significant effect for FC. These results could indicate linkage disequilibrium between the FABP3 gene and a quantitative trait loci (QTL) for FC, with the heterozygous genotype associated with a positive effect in this trait.     

Population-genetical study of differential fertility in humans (based on an example of habitual abortion). I. Approach to the problem and analysis of morpho-physiological and demographic traits

It was shown that women from the studied group of married couples, suffering from repeated spontaneous abortions (the main group), have earlier menarche and their husbands are taller, as compared with the control group of couples with normal reproductive performance. The degree of similarity between mates in age and stature appeared to be lower in the main group than in the control group. The variation of the characters under study is supposed to provide an auxiliary criterion in selecting couples at high risk of repeated spontaneous abortions.     

Population genetic structure and adaptation of malaria parasites on the edge of endemic distribution

To determine whether the major human malaria parasite Plasmodium falciparum exhibits fragmented population structure or local adaptation at the northern limit of its African distribution where the dry Sahel zone meets the Sahara, samples were collected from diverse locations within Mauritania over a range of ~1000 km. Microsatellite genotypes were obtained for 203 clinical infection samples from eight locations, and Illumina paired‐end sequences were obtained to yield high coverage genomewide single nucleotide polymorphism (SNP) data for 65 clinical infection samples from four locations. Most infections contained single parasite genotypes, reflecting low rates of transmission and superinfection locally, in contrast to the situation seen in population samples from countries further south. A minority of infections shared related or identical genotypes locally, indicating some repeated transmission of parasite clones without recombination. This caused some multilocus linkage disequilibrium and local divergence, but aside from the effect of repeated genotypes there was minimal differentiation between locations. Several chromosomal regions had elevated integrated haplotype scores (|iHS|) indicating recent selection, including those containing drug resistance genes. A genomewide F_ST scan comparison with previous sequence data from an area in West Africa with higher infection endemicity indicates that regional gene flow prevents genetic isolation, but revealed allele frequency differentiation at three drug resistance loci and an erythrocyte invasion ligand gene. Contrast of extended haplotype signatures revealed none to be unique to Mauritania. Discrete foci of infection on the edge of the Sahara are genetically highly connected to the wider continental parasite population, and local elimination would be difficult to achieve without very substantial reduction in malaria throughout the region.     

A theoretical treatment of interval mapping of a disease gene using transmission disequilibrium tests

The genetic basis of the transmission disequilibrium test (TDT) for two-marker loci is explored from first principles. In this case, parents doubly heterozygous for a given haplotype at the pair of marker loci that are each in linkage disequilibrium with the disease gene with the further possibility of a second-order linkage disequilibrium are considered. The number of times such parents transmit the given haplotype to their affected offspring is counted and compared with the frequencies of haplotypes that are not transmitted. This is done separately for the coupling and repulsion phases of doubly heterozygous genotypes. Expectations of the counts for each of the sixteen cells possible with four-marker gametic types (transmitted vs not transmitted) are derived. Based on a test of symmetry in a square 4 × 4 contingency table, chi-square tests are proposed for the null hypothesis of no linkage between the markers and the disease gene. The power of the tests is discussed in terms of the corresponding non-centrality parameters for the alternative hypothesis that both the markers are linked with the disease locus. The results indicate that the power increases with the decrease in recombination probability and that it is higher for a lower frequency of the disease gene. Taking a pair of markers in an interval for exploring the linkage with the disease gene seems to be more informative than the single-marker case since the values of the non-centrality parameters tend to be consistently higher than their counterparts in the single-marker case. Limitations of the proposed test are also discussed.     

A theoretical treatment of interval mapping of a disease gene using transmission disequilibrium tests

The genetic basis of the transmission disequilibrium test (TDT) for two-marker loci is explored from first principles. In this case, parents doubly heterozygous for a given haplotype at the pair of marker loci that are each in linkage disequilibrium with the disease gene with the further possibility of a second-order linkage disequilibrium are considered. The number of times such parents transmit the given haplotype to their affected offspring is counted and compared with the frequencies of haplotypes that are not transmitted. This is done separately for the coupling and repulsion phases of doubly heterozygous genotypes. Expectations of the counts for each of the sixteen cells possible with four-marker gametic types (transmitted vs not transmitted) are derived. Based on a test of symmetry in a square 4 x 4 contingency table, chi-square tests are proposed for the null hypothesis of no linkage between the markers and the disease gene. The power of the tests is discussed in terms of the corresponding non-centrality parameters for the alternative hypothesis that both the markers are linked with the disease locus. The results indicate that the power increases with the decrease in recombination probability and that it is higher for a lower frequency of the disease gene. Taking a pair of markers in an interval for exploring the linkage with the disease gene seems to be more informative than the single-marker case since the values of the non-centrality parameters tend to be consistently higher than their counterparts in the single-marker case. Limitations of the proposed test are also discussed.     

The multiple-locus symmetric fertility model

Selection due to variation in the fecundity among matings of genotypes with respect to many loci each with two alleles is studied. The fitness of a mating depends only on the genotypic distinction between homozygote and heterozygote at each locus in the two individuals, and differences among loci are allowed. This symmetric fertility model is therefore a generalization of the multiple-locus symmetric viability model. The phenomena seen in the two-locus symmetric fertility model generalize—e.g., the possibility of joint stability of equilibria with linkage equilibrium and with linkage disequilibrium, and the existence of different types of totally polymorphic equilibria with the gametic proportions in linkage equilibrium. The central equilibrium with genotypic frequencies in Hardy-Weinberg proportions and gametic frequencies in Robbins proportions exists for all symmetric fertility models. For some symmetric fertility regimes additional equilibria exist with gametic frequencies in linkage equilibrium and with genotypic frequencies in Hardy-Weinberg proportions at all except one locus. These equilibria may exist in the dioecious symmetric viability model, and then they will be locally stable. For free recombination the stable equilibria show linkage equilibrium, but several of these with different numbers of polymorphic loci may be stable simultaneously.     

Contrasting genetic structure in Plasmodium vivax populations from Asia and South America

Populations of Plasmodium falciparum show striking differences in linkage disequilibrium, population differentiation and diversity, but only fragmentary data exists on the genetic structure of Plasmodium vivax. We genotyped nine tandem repeat loci bearing 2-8 bp motifs from 345 P. vivax infections collected from three Asian countries and from five locations in Colombia. We observed 9-37 alleles per locus and high diversity (He=0.72-0.79, mean=0.75) in all countries. Numbers of multiple clone infections varied considerably: these were rare in Colombia and India, but > 60% of isolates carried multiple alleles in at least one locus in Thailand and Laos. However, only one or two of the nine loci show >1 allele in many samples, suggesting that mutation within infections may result in overestimation of true multiple carriage rates. Identical nine-locus genotypes were frequently found in Colombian populations, contributing to strong linkage disequilibrium. These identical genotypes were strongly clustered in time, consistent with epidemic transmission of clones and subsequent breakdown of allelic associations, suggesting high rates of inbreeding and low effective recombination rates in this country. In contrast, identical genotypes were rare and loci were randomly associated in all three Asian populations, consistent with higher rates of outcrossing and recombination. We observed low but significant differentiation between different Asian countries (standardized FST = 0.13-0.45). In comparison, we see greater differentiation between collection locations within Colombia (standardized FST = 0.4-0.7), and strong differentiation between continents (standardized FST = 0.48-0.79). The observed heterogeneity in multiple clone carriage rates, linkage disequilibrium and population differentiation are similar in some, but not all, respects to those observed in P. falciparum, and have important implications for the design of association mapping studies, and interpretation of P. vivax epidemiology.     

An RFLP-based genetic map of pearl millet (Pennisetum glaucum)

Analysis of a sample of diverse pearl millet genotypes with 200 genomic DNA probes revealed this crop species to be extremely polymorphic. Among these genotypes, 85% of probes detected polymorphism using only two restriction enzymes, with an average pair-wise polymorphism between all of the probe-enzyme combinations of 56%. Two crosses were employed to construct an RFLP-based genetic map. In an intervarietal F₂ population, derived from a single F₁ plant, 181 loci were placed on a linkage map. The total length of this map, which comprised seven linkage groups, was 303 cM and the average map distance between loci was about 2 cM, although a few intervals in excess of 10 cM were present at the ends of a few linkage groups. Very few clones, including those which hybridized to more than one copy, detected more than one locus in the pearl millet genome. The analysis was complicated initially because 83 of the 181 loci mapped to a single linkage group. Analysis of a second cross identified a probable translocation breakpoint in the middle of this large linkage group.     

Utility and efficiency of linked marker genes for genetic counseling. III. Proportion of informative families under linkage disequilibrium.

A marker locus closely linked to a disease locus is often useful for genetic counseling provided that a counselee is heterozygous at both disease and marker loci. Furthermore, the linkage phase of these genes in the counselee must be known. When the linkage between the disease and marker loci is very close, one often finds linkage disequilibrium between the loci. To evaluate the effect of such nonrandom associations on the utility of linked marker genes for genetic counseling, the proportion of informative families is studied for X-linked recessive and autosomal dominant diseases. This proportion is higher for X-linked genes than for autosomal genes, if other factors are the same. In general, codominant markers are more useful than dominant markers. Also, under appropriate conditions, the proportion of informative families is higher when linkage disequilibrium is present. The results obtained in this paper are useful for evaluating the utility of polymorphic restriction endonuclease cleavage sites as markers in genetic counseling.     

Impact of non-ignorable missingness on genetic tests of linkage and/or association using case-parent trios

The transmission/disequilibrium test was introduced to test for linkage disequilibrium between a marker and a putative disease locus using case-parent trios. However, parental genotypes may be incomplete in such a study. When parental information is non-randomly missing, due, for example, to death from the disease under study, the impact on type I error and power under dominant and recessive disease models has been reported. In this paper, we examine non-ignorable missingness by assigning missing values to the genotypes of affected parents. We used unrelated case-parent trios in the Genetic Analysis Workshop 14 simulated data for the Danacaa population. Our computer simulations revealed that the type I error of these tests using incomplete trios was not inflated over the nominal level under either recessive or dominant disease models. However, the power of these tests appears to be inflated over the complete information case due to an excess of heterozygous parents in dyads.     

Linkage disequilibria between pairs of loci within a highly polymorphic region of chromosome 2Q.

A recently described region on chromosome 2q contains seven restriction fragment length polymorphisms (RFLPs) revealed by single-copy probes isolated from a 20-kilobase (kb) segment of a single cosmid insert. Analysis of six of these loci demonstrates modest amounts of linkage disequilibrium. This reflects the presence of a substantial number of different haplotypes in this chromosome region and indicates that the region could be used as one highly polymorphic locus. No consistent relationship is found between the amount of linkage disequilibrium and the physical distance between pairs of loci. For seven of the 10 pairs of diallelic loci studied, the observed disequilibrium can be attributed primarily to the absence of the minor haplotype from the population. These results suggest that, for small regions of the genome, factors such as mutation, genetic drift, and population admixture may have effects that outweight those of recombination. In addition, results are reviewed which show that estimates of linkage disequilibrium coefficients for tightly linked loci are very imprecise. Thus, the inference of gene order from linkage disequilibrium values must be regarded with caution.     

Negative correlation between heterozygosity and potential fertility in the Eveny population of Iakutiia

The relationship between heterozygosity of 9 polymorphic loci and fertility of women surviving beyond the menopause was studied in the North-Siberian tribe Eveny. The number of pregnancies negatively correlated with the individual heterozygosity (r = -0.2913 + 0.1302, P less than 0.05). Drastic fertility reduction in heterozygous women was observed for G1M, ACP and HP loci.     

Simultaneous detection of linkage disequilibrium and genetic differentiation of subdivided populations

We propose a new method for simultaneously detecting linkage disequilibrium and genetic structure in subdivided populations. Taking subpopulation structure into account with a hierarchical model, we estimate the magnitude of genetic differentiation and linkage disequilibrium in a metapopulation on the basis of geographical samples, rather than decompose a population into a finite number of random-mating subpopulations. We assume that Hardy-Weinberg equilibrium is satisfied in each locality, but do not assume independence between marker loci. Linkage states remain unknown. Genetic differentiation and linkage disequilibrium are expressed as hyperparameters describing the prior distribution of genotypes or haplotypes. We estimate related parameters by maximizing marginal-likelihood functions and detect linkage equilibrium or disequilibrium by the Akaike information criterion. Our empirical Bayesian model analyzes genotype and haplotype frequencies regardless of haploid or diploid data, so it can be applied to most commonly used genetic markers. The performance of our procedure is examined via numerical simulations in comparison with classical procedures. Finally, we analyze isozyme data of ayu, a severely exploited fish species, and single-nucleotide polymorphisms in human ALDH2.     

A genetic linkage map of Theobroma cacao L.

A linkage map of the cocoa genome comprising 193 loci has been constructed. These loci consist of 5 isozymes, 101 cDNA/RFLPs, 4 loci from genes of known function, 55 genomic DNA/RFLPs and 28 RAPDs. A population of 100 individuals derived from a cross between two heterozygous genotypes was used. Segregation analyses were performed with the JoinMap program. Ten linkage groups, which putatively correspond to the ten gametic chromosomes of cocoa, were identified. The map covers a total length of 759 cM with a 3.9 cM average distance between 2 markers. A small fraction (9%) of the markers deviated significantly from the expected Mendelian ratios.     

Independence of Vntr Alleles Defined as Fixed Bins

An analysis is presented of data collected by the Federal Bureau of Investigation at six unlinked variable number of tandem repeats (VNTR) loci for the United States population. Databases have been constructed of VNTR profiles of Caucasians, Blacks and Hispanics from Florida, Texas and California. There was very little evidence for correlations between lengths for pairs of VNTR fragments, within or between loci. When the fragment lengths were amalgamated into discrete bins, there was also little evidence for disequilibrium over all genotypes, within or between loci, for the Caucasian database, although some disequilibrium was found for the Black and Hispanic databases. No disequilibrium was found for the Caucasian or Black databases when tests were confined to heterozygous individuals. In cases of global disequilibrium, local tests can be applied to specific genotypes. The results suggest that, at the bin level, frequencies of VNTR profiles can generally be estimated as the products of the frequencies of the constituent elements. This overcomes the problem of estimating population frequencies when any particular profile does not exist in the database. There is some evidence for different frequencies, at the individual bin level, between geographic samples within each of the Caucasian, Black and Hispanic databases, and considerable evidence for differences between the three databases. These differences are less evident for the frequencies of four-locus profiles.     

Recombination and linkage disequilibrium among mitochondrial genes in structured populations of the gynodioecious plant Silene vulgaris

The impact of intergenic recombination on the population genetics of plant mitochondrial genomes is unknown. In an effort to study this in the gynodioecious plant Silene vulgaris three-locus PCR/RFLP genotypes (based on the mitochondrial genes atpA, cox1, and cob) were determined for 239 individuals collected from 20 North American populations. Seventeen three-locus PCR/RFLP genotypes were found. Recombination was indicated by observation of each of the four two-locus genotypes possible when the two most common alleles are considered for each of two loci. Based on these common alleles the absolute values of standardized linkage disequilibrium |D'| between pairs of loci range from 0.17 to 0.78. This indicates modest disequilibrium, rather than the maximum value expected in the absence of recombination |D'=1|, or the linkage equilibrium expected if recombination is pervasive (D'=0). Values of D' did not depend on which pair of loci contributed alleles to the analysis. The direction of D' obtained for the common atpA and cox1 alleles was comparable in sign and magnitude to that obtained by examining similar information obtained in a prior study of European samples. All three loci indicated a high degree of population structure (average FST=0.63), which would limit the within-population genetic diversity required for intergenic recombination to create novel genotypes, if most mating is local. Thus, population structure acts as a constraint on the approach to linkage equilibrium.