Linkage Disequilibrium between Allozymes in Natural Populations of Lodgepole Pine

Pairwise linkage disequilibrium values (D) were estimated for 14 allozyme loci in two natural populations of lodgepole pine (Pinus contorta ssp. latifolia). Maternal multilocus genotypes were inferred from samples of (haploid) megagametophytic seed-endosperms. Coupling/repulsion double heterozygotes were distinguished for closely linked pairs of loci. Assays of seven of the loci in seed embryos allowed estimates of D for these loci in the outcross pollen pool (estimates of outcrossing rates indicate no significant departures from random mating in either population). No disequilibrium was observed between unlinked loci in either maternal genotypes or outcross pollen. However, significant disequilibrium was observed within and between gametes for some allelic combinations of four tightly linked loci; the assumption of random association of gamete types within individuals is thus invalid for some loci in lodgepole pine. Possible causes of the observed D were examined using the noncentrality parameter of the general noncentral chi square distribution. We concluded, from estimates of population size, linkage and measurements of population substructure, that neither drift nor population subdivision was responsible for the significant values of D which were observed and that epistatic selection was the most likely cause of the disequilibrium observed.     

Genomic Scans of Zygotic Disequilibrium and Epistatic SNPs in HapMap Phase III Populations

Previous theory indicates that zygotic linkage disequilibrium (LD) is more informative than gametic or composite digenic LD in revealing natural population history. Further, the difference between the composite digenic and maximum zygotic LDs can be used to detect epistatic selection for fitness. Here we corroborate the theory by investigating genome-wide zygotic LDs in HapMap phase III human populations. Results show that non-Africa populations have much more significant zygotic LDs than do Africa populations. Africa populations (ASW, LWK, MKK, and YRI) possess more significant zygotic LDs for the double-homozygotes (D_AABB) than any other significant zygotic LDs (D_AABb, D_AaBB, and D_AaBb), while non-Africa populations generally have more significant D_AaBb’s than any other significant zygotic LDs (D_AABB, D_AABb, and D_AaBB). Average r-squares for any significant zygotic LDs increase generally in an order of populations YRI, MKK, CEU, CHB, LWK, JPT, CHD, TSI, GIH, ASW, and MEX. Average r-squares are greater for D_AABB and D_AaBb than for D_AaBB and D_AABb in each population. YRI and MKK can be separated from LWK and ASW in terms of the pattern of average r-squares. All population divergences in zygotic LDs can be interpreted with the model of Out of Africa for modern human origins. We have also detected 19735-95921 SNP pairs exhibiting strong signals of epistatic selection in different populations. Gene-gene interactions for some epistatic SNP pairs are evident from empirical findings, but many more epistatic SNP pairs await evidence. Common epistatic SNP pairs rarely exist among all populations, but exist in distinct regions (Africa, Europe, and East Asia), which helps to understand geographical genomic medicine.     

Linkage Disequilibrium in Natural Populations of Trypanosoma cruzi (Flagellate), the Agent of Chagas’ Disease1

ABSTRACT. We have studied linkage disequilibrium in natural populations of Trypanosoma cruzi, the agent of Chagas’ disease, by analyzing (i) a set of 524 stocks from the whole geographical range of the parasite, characterized at four gene loci coding for enzymes; (ii) a subsample of 121 stocks characterized at 12 enzyme loci; and (iii) a subset of 386 stocks from six locations in Bolivia, characterized by four enzyme loci. Our results show that the linkage disequilibrium reaches the maximum possible value, given the observed allelic frequencies, for almost all the locus pairs. This result is most consistent with the hypothesis that genetic recombination is absent or very rare in T. cruzi natural populations. Partition of the linkage disequilibrium variance for the six Bolivian populations shows that both inter- and intrapopulation components are substantial and that the relationships among the components are D_IS² < D_ST², and D'_IS² < D'_ST². These inequalities are interpreted as the result of an interplay between genetic drift, rare or absent mating, and clonal selection in generating linkage disequilibrium in T. cruzi populations.     

Linkage disequilibrium with the island model

Linkage disequilibrium between two linked loci was studied for a finite population with a subdivided population structure. Wright's island model was used; extinction and replacement of colonies were also incorporated. Two alleles (A₁ and A₂ at the first locus, and B₁ and B₂ at the second locus) with symmetric mutation rates were assumed, and equilibrium properties of linkage disequilibrium coefficients were analyzed. In terms of analogy with the subdivision of inbreeding coefficient, the variance of linkage disequilibrium is divided into several components: D²_IS (variance of within-colony disequilibrium), D²_ST (variance of correlation of A₁ and B₁ of different gametes of one colony relative to that of the total population), and D²_IT (total variance of disequilibrium). Other subdivisions are D'²_IS (variance of correlation of A₁ and B₁ of one gamete of a colony relative to that of the average gamete of the population) and D'²_ST (variance of the ordinary disequilibrium of the whole population). When migration is limited, the variance becomes large if the correlation of A₁ and B₁ of one colony is taken relative to that of the whole population (D²_ST and D'²_IS). Also, when the rate of extinction-replacement of colonies is high, the whole-population disequilibrium coefficient (D'²_ST) can become fairly large. Observed linkage disequilibria, such as those among markers in the major histocompatibility complex of man and mouse, may well be explained by limited migration, without assuming epistatic natural selection.     

Purging deleterious mutations under self fertilization: paradoxical recovery in fitness with increasing mutation rate in Caenorhabditis elegans

Background

The accumulation of deleterious mutations can drastically reduce population mean fitness. Self-fertilization is thought to be an effective means of purging deleterious mutations. However, widespread linkage disequilibrium generated and maintained by self-fertilization is predicted to reduce the efficacy of purging when mutations are present at multiple loci.

Methodology/Principal Findings

We tested the ability of self-fertilizing populations to purge deleterious mutations at multiple loci by exposing obligately self-fertilizing populations of Caenorhabditis elegans to a range of elevated mutation rates and found that mutations accumulated, as evidenced by a reduction in mean fitness, in each population. Therefore, purging in obligate selfing populations is overwhelmed by an increase in mutation rate. Surprisingly, we also found that obligate and predominantly self-fertilizing populations exposed to very high mutation rates exhibited consistently greater fitness than those subject to lesser increases in mutation rate, which contradicts the assumption that increases in mutation rate are negatively correlated with fitness. The high levels of genetic linkage inherent in self-fertilization could drive this fitness increase.

Conclusions

Compensatory mutations can be more frequent under high mutation rates and may alleviate a portion of the fitness lost due to the accumulation of deleterious mutations through epistatic interactions with deleterious mutations. The prolonged maintenance of tightly linked compensatory and deleterious mutations facilitated by self-fertilization may be responsible for the fitness increase as linkage disequilibrium between the compensatory and deleterious mutations preserves their epistatic interaction.     

HLA-D typing in 111 multiple sclerosis patients: Distribution of four HLA-D alleles

Multiple sclerosis patients-111 of them-were typed for theHLA-D allelesw1, w2, andw3 and a new determinant, EI. Statistically significant increase was obtained for thew2 andw3 frequencies as compared to healthy controls. The distribution of HLA-D phenotypes among MS patients revealed a good fit according to the Hardy-Weinberg law. By calculating linkage disequilibrium parameters, theHLA-B7,Dw2 allele combination was found to be more closely associated than in normal controls, whereas forHLA-Bw35, Dw1, no linkage disequilibrium could be detected in the patients' group. From these data we conclude that in multiple sclerosis, the disturbance affects the frequency ofDw3 and the gametic association between alleles of theHLA-B andD loci, as well as the already known increase ofHLA-B7 andDw2.     

Effect of Mating Structure on Variation in Linkage Disequilibrium

Measurement of linkage disequilibrium involves two sampling processes. First, there is the sampling of gametes in the population to form successive generations, and this generates disequilibrium dependent on the effective population size (N_e) and the mating structure. Second, there is sampling of a finite number (n) of individuals to estimate the population disequilibrium.——Two-locus descent measures are used to describe the mating system and are transformed to disequilibrium moments at the final sampling. Approximate eigenvectors for the transition matrix of descent measures are used to obtain formulae for the variance of the observed disequilibria as a function of N_e, mating structure, n, and linkage or recombination parameter.——The variance of disequilibrium is the same for monoecious populations with or without random selfing and for dioecious populations with random pairing for each progeny. With monogamy, the variance is slightly higher, the proportional difference being greater for unlinked loci.     

New properties of the two-locus partial selfing model with selection

Analytic solutions are obtained for the equilibria of a simple two-locus, heterotic selection model with mixed selfing and random outcrossing. Two general phenomena are possible, depending upon the viabilities and the degree of selfing: (1) Negative disequilibrium potential, under which only gametic disequilibrium is possible; and (2) positive disequilibrium potential, which can result in permanent gametic disequilibrium provided that linkage is sufficiently tight. Under random mating (s = 0), these two situations correspond to negative and positive additive epistasis, respectively. With partial self-fertilization, however, this is no longer true, and a more appropriate measure of gametc disequilibrium potential, Δ(s), is introduced. A numerically aided examination of the model results in the discovery of two new properties of partial selfing with selection: (1) With negative disequilibrium potential (Δ(s) < 0), the equilibrium mean fitness increases with increasing recombination. With positive disequilibrium potential (Δ(s) > 0), the opposite is true. (2) Gametic disequilibrium can increase or decrease as the degree of selfing is increased. Therefore, it is apparent that partial selfing and linkage are not analogous as regards the maintenance of disequilibrium.     

Population genetics of modifiers of meiotic drive III. Equilibrium analysis of a general model for the genetic control of segregation distortion

Prout, Bungaard and Bryant (1973, Theor. Popul. Biol. 4, 446–465) presented the first formal treatment of a model of meiotic drive involving a modifier locus which controls the intensity of drive. They studied the equilibrium behavior in the simplest model where it is assumed that drive is maximal when not suppressed. In that case there is one polymorphic equilibrium at which there is linkage disequilibrium. The equilibrium solutions in the general model of meiotic drive proposed by Prout, et al. are given in this paper together with a stability analysis. It is shown that up to three polymorphic equilibria may exist, two of which are in linkage disequilibrium and one in linkage equilibrium. These equilibria exhibit behavior qualitatively opposite to what is widely accepted as the usual for two locus systems and which is not seem in the simple case originally treated. The polymorphic equilibria with linkage disequilibrium may be stable for loose linkage and not for tight while that with linkage equilibrium is stable in an interval of relatively tight linkage values.     

A microsatellite-based analysis for the detection of selection on BTA1 and BTA20 in northern Eurasian cattle (Bos taurus) populations

Background

Microsatellites surrounding functionally important candidate genes or quantitative trait loci have received attention as proxy measures of polymorphism level at the candidate loci themselves. In cattle, selection for economically important traits is a long-term strategy and it has been reported that microsatellites are linked to these important loci.

Methods

We have investigated the variation of seven microsatellites on BTA1 (Bos taurus autosome 1) and 16 on BTA20, using bovine populations of typical production types and horn status in northern Eurasia. Genetic variability of these loci and linkage disequilibrium among these loci were compared with those of 28 microsatellites on other bovine chromosomes. Four different tests were applied to detect molecular signatures of selection.

Results

No marked difference in locus variability was found between microsatellites on BTA1, BTA20 and the other chromosomes in terms of different diversity indices. Average D'' values of pairwise syntenic markers (0.32 and 0.28 across BTA 1 and BTA20 respectively) were significantly (P < 0.05) higher than for non-syntenic markers (0.15). The Ewens-Watterson test, the Beaumont and Nichol''s modified frequentist test and the Bayesian F_ST-test indicated elevated or decreased genetic differentiation, at SOD1 and AGLA17 markers respectively, deviating significantly (P < 0.05) from neutral expectations. Furthermore, lnRV, lnRH and lnRθ'' statistics were used for the pairwise population comparison tests and were significantly less variable in one population relative to the other, providing additional evidence of selection signatures for two of the 51 loci. Moreover, the three Finnish native populations showed evidence of subpopulation divergence at SOD1 and AGLA17. Our data also indicate significant intergenic linkage disequilibrium around the candidate loci and suggest that hitchhiking selection has played a role in shaping the pattern of observed linkage disequilibrium.

Conclusion

Hitchhiking due to tight linkage with alleles at candidate genes, e.g. the POLL gene, is a possible explanation for this pattern. The potential impact of selective breeding by man on cattle populations is discussed in the context of selection effects. Our results also suggest that a practical approach to detect loci under selection is to simultaneously apply multiple neutrality tests based on different assumptions and estimations.     

The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies

Background

We studied linkage disequilibrium (LD) patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient.

Results

BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG).

Conclusion

Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.     

Evolution of recombination due to random drift

In finite populations subject to selection, genetic drift generates negative linkage disequilibrium, on average, even if selection acts independently (i.e., multiplicatively) upon all loci. Negative disequilibrium reduces the variance in fitness and hence, by Fisher's (1930) fundamental theorem, slows the rate of increase in mean fitness. Modifiers that increase recombination eliminate the negative disequilibria that impede selection and consequently increase in frequency by "hitchhiking." Thus, stochastic fluctuations in linkage disequilibrium in finite populations favor the evolution of increased rates of recombination, even in the absence of epistatic interactions among loci and even when disequilibrium is initially absent. The method developed within this article allows us to quantify the strength of selection acting on a modifier allele that increases recombination in a finite population. The analysis indicates that stochastically generated linkage disequilibria do select for increased recombination, a result that is confirmed by Monte Carlo simulations. Selection for a modifier that increases recombination is highest when linkage among loci is tight, when beneficial alleles rise from low to high frequency, and when the population size is small.     

Genetic Variation and Differentiation among Populations of Chum Salmon Oncorhynchus ketaWalbaum from Southern Russian Far East

Allozyme variation of populations of chum salmon Oncorhynchus ketafrom southern Russian Far East was examined. Of 55 loci screened, 31 were polymorphic. Within-population variation accounted for most of the allele diversity; F _STaveraged over loci was 0.052. Linkage disequilibrium was found in less than 5% of locus pairs in the chum population examined. Analysis of within- and among-population variance components of linkage disequilibrium using D-statistics (Ohta, 1982) showed that most genetic variation was distributed among populations.     

Exome-based linkage disequilibrium maps of individual genes: functional clustering and relationship to disease

Exome sequencing identifies thousands of DNA variants and a proportion of these are involved in disease. Genotypes derived from exome sequences provide particularly high-resolution coverage enabling study of the linkage disequilibrium structure of individual genes. The extent and strength of linkage disequilibrium reflects the combined influences of mutation, recombination, selection and population history. By constructing linkage disequilibrium maps of individual genes, we show that genes containing OMIM-listed disease variants are significantly under-represented amongst genes with complete or very strong linkage disequilibrium (P = 0.0004). In contrast, genes with disease variants are significantly over-represented amongst genes with levels of linkage disequilibrium close to the average for genes not known to contain disease variants (P = 0.0038). Functional clustering reveals, amongst genes with particularly strong linkage disequilibrium, significant enrichment of essential biological functions (e.g. phosphorylation, cell division, cellular transport and metabolic processes). Strong linkage disequilibrium, corresponding to reduced haplotype diversity, may reflect selection in utero against deleterious mutations which have profound impact on the function of essential genes. Genes with very weak linkage disequilibrium show enrichment of functions requiring greater allelic diversity (e.g. sensory perception and immune response). This category is not enriched for genes containing disease variation. In contrast, there is significant enrichment of genes containing disease variants amongst genes with more average levels of linkage disequilibrium. Mutations in these genes may less likely lead to in utero lethality and be subject to less intense selection.     

Dynamics of Correlated Genetic Systems. V. Rates of Decay of Linkage Disequilibria in Experimental Populations of DROSOPHILA MELANOGASTER

The dynamic behavior of four-locus gametic frequency distributions was studied in five replicate cage populations of Drosophila melanogaster for up to 50 generations. The joint frequency distributions were resolved into gene frequencies and various disequilibrium measures. In addition, F statistics for marginal single-locus genotypic frequency distributions were followed through time. The gene frequency, disequilibrium and F statistics were obtained for four chromosome 3 enzyme marker loci [isocitrate dehydrogenase (3–27.1), esterase-6 (3–36.8), phosphoglucomutase (3–43.4) and esterase-C (3–49.0)]. The initial structure of the experimental populations featured random mating proportions, and two complementary gametic types with respect to the marker loci, thus assuring complete pairwise linkage disequilibrium among the markers.——The experimental results indicate: (1) the between-replicate variance in gene frequency varied substantially among loci, with isocitrate dehydrogenase showing the greatest between-replicate variance, and esterase-C the least. (2) The F statistics initially were strongly negative but decayed to the neighborhood of zero for all marker loci except esterase-C. The rate at which the F statistics approached zero varied among the marker loci, indicating substantial differences in the distribution of selective effects along the chromosome. The centromeric region, marked by esterase-C, shows the strongest selective effects. (3) The rate of decay of linkage disequilibrium was much faster than expected for pairs of neutral loci, averaging 1.82 times the neutral rate over all replicates and pairs of loci. This acceleration, which was observed for all six pairwise combinations of loci, was interpreted as resulting from the interaction between selection and recombination. Our experimental results are consistent with many investigations of linkage disequilibrium in natural populations of Drosophila melanogaster that show little or no disequilibrium among enzyme loci. (4) A fortuitous contamination of two cages revealed an apparent regulatory interaction between the migrant and nonmigrant chromosomes at the esterase-C locus. The migrant chromosomes were very rapidly absorbed into the recipient populations, despite this interaction. This result suggests that the dynamics of migration in populations may be phenomenologically richer than anticipated by simple theory.     

Positive Selection in the Chromosome 16 VKORC1 Genomic Region Has Contributed to the Variability of Anticoagulant Response in Humans

VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.     

Properties of 2-locus genealogies and linkage disequilibrium in temporally structured samples

Archeogenetics has been revolutionary, revealing insights into demographic history and recent positive selection. However, most studies to date have ignored the nonrandom association of genetic variants at different loci (i.e. linkage disequilibrium). This may be in part because basic properties of linkage disequilibrium in samples from different times are still not well understood. Here, we derive several results for summary statistics of haplotypic variation under a model with time-stratified sampling: (1) The correlation between the number of pairwise differences observed between time-staggered samples (πΔt) in models with and without strict population continuity; (2) The product of the linkage disequilibrium coefficient, D, between ancient and modern samples, which is a measure of haplotypic similarity between modern and ancient samples; and (3) The expected switch rate in the Li and Stephens haplotype copying model. The latter has implications for genotype imputation and phasing in ancient samples with modern reference panels. Overall, these results provide a characterization of how haplotype patterns are affected by sample age, recombination rates, and population sizes. We expect these results will help guide the interpretation and analysis of haplotype data from ancient and modern samples.     

The Direction of Linkage Disequilibrium

The previous paper (Langley, Tobari and Kojima 1974) reports that the directional linkage disequilibria, D_ω = P_ABP_ab-P_AbP_aB, tend to be negative for data between allozymes and linked to inversions. A and B stand for the two alleles with the greatest frequency in the population. In this paper we show that linkage disequilibrium in this direction is produced at equilibrium when double homozygotes have fitnesses that are a constant fraction of the product of the two component single homozygote fitnesses, a pattern that is frequently observed in experimental data.     

SNP frequency, haplotype structure and linkage disequilibrium in elite maize inbred lines

Background  

Recent studies of ancestral maize populations indicate that linkage disequilibrium tends to dissipate rapidly, sometimes within 100 bp. We set out to examine the linkage disequilibrium and diversity in maize elite inbred lines, which have been subject to population bottlenecks and intense selection by breeders. Such population events are expected to increase the amount of linkage disequilibrium, but reduce diversity. The results of this study will inform the design of genetic association studies.