Interlocus Interactions Research Articles

Sex-specific features of interlocus interactions determining susceptibility to hypertension

Background: Hypertension (HT) belongs to a group of widespread diseases in both men and women, but at the same time the disease is more often registered (≈20%) in men than in women. Genetic factors determining the sex characteristics of the prevalence of HT are largely unknown. The aim of the study: To establish sex-specific features of intergenic interactions of GWAS-significant loci determining susceptibility to HT. Materials and methods: The sample of men included 564 patients with HT and 257 controls (total sample size n=821), women – 375 patients with HT and 209 controls (total sample size n=584). Genotyping of 10 polymorphisms that showed associations with HT (blood pressure (BP)) in previously conducted genome-wide studies (GWAS) was performed. The intergenic interactions determining the susceptibility to HT in men and women were evaluated by the MB-MDR method. Results: In men, susceptibility to HT is determined by the interlocus interaction rs932764- PLCE1 × rs7302981-CERS5 × rs1799945-HFE × rs8068318-TBX2 (Wald St. = 32.12 pperm =0.001) with the most pronounced effect of two-locus interaction rs1799945-HFE × rs8068318-TBX2 (determines 0.76% of entropy). Among women, the most significant in relation to HT is the four-locus model, which includes polymorphic loci rs932764-PLCE1 × rs8068318-TBX2 × rs1173771- AC026703.1 × rs167479-RGL3 (Wald St. = 33.53 pperm <0.001) with the maximum contribution to the entropy of the disease (2.26%) of the pair interaction rs8068318-TBX2 × rs167479-RGL3. Polymorphisms rs932764-PLCE1 and rs8068318-TBX2 are very significant in both men and women. Conclusion: The intergenic interactions of HT-significant GWAS loci are sex-specific.

An interplay between genes <i>SLCO1B1</i>, <i>NR2F2</i>, <i>JMJD1C</i> and obesity in developing breast cancer

Aim: to evaluate a role of polymorphic variants rs4149056 SLCO1B1, rs8023580 NR2R2 and rs7910927 JMJD1C in developing obesity-related female breast cancer (BC).Materials and Methods. A retrospective comparative study was performed on a sample of 1,498 women (358 BC patients and 1,140 control subjects) stratified into 2 groups based on verified obesity: obese (119 BC patients and 253 control subjects) and non-obese (239 BC patients and 887 control subjects). Genotyping of three single nucleotide polymorphisms (SNP) – rs7910927 JMJD1C, rs8023580 NR2F2, rs4149056 SLCO1B1 was performed to be further analyzed separately in each group of obese and non-obese women for associations of such loci and interplay with breast cancer.Results. Polymorphisms rs8023580 NR2F2, rs4149056 SLCO1B1 and rs7910927 JMJD1C are not independently associated with BC in obese and non-obese women, whereas their interlocus interactions are BC-significant in each of the examined groups (pperm = 0.047 and pperm = 0.0012, respectively). Among obese women, the combination of TC-TT-GG genotypes (for rs8023580–rs4149056–rs7910927) is associated with a low risk of developing BC (β = –2.45), whereas the combination of TC-TC-GG genotypes is associated with increased BC risk (β=1.42). In non-obese women, a combination of the TC-TT-GT genotypes (β = –0.47) has a protective effect on the BC occurrence, and the risk effect is coupled to TC-TC-GT (β = 0.91) and TC-CC-GT (β = 1.45). The appearance of allele C rs4149056 in female genotype and its increased "concentration" results in higher BC risk.Conclusion. The allele variant C rs4149056 in the interlocus interactions between the SLCO1B1, NR2F2 and JMJD1C genes is a "universal" factor that elevates BC risk in both obese and non-obese women. The genotype GG rs7910927 is BC-significant in interlocus interactions in obese women, whereas in non-obese women it is coupled to the genotype GT rs7910927.

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia.

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n = 821 in total: n = 564 HTN, n = 257 control) and women (n = 584 in total: n = 375 HTN, n = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C, and (ATP2B1) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men's and women's cohorts. The men-women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with HFE rs1799945 C > G (genotype GG was risky; ORGG = 11.15 ppermGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism BAG6 rs805303 G > A (genotype AA was protective; ORAA = 0.30 ppermAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.

The role of polymorphism of candidate genes in the development of knee osteoarthritis in men of the Central Chernozem region of Russia

Knee osteoarthritis (OA) is a disease resulting from the interaction of many local and systemic risk factors, among which an important role is played by genetic (hereditary) factors. This disease affects both men and women, but there are certain differences in the development and progression of the disease in different sexes.Aim: To study associations of polymorphic loci of candidate genes with the risk of developing knee ОА in the male population of the Central Chernozem region of Russia.Material and Methods. The study sample included 410 men (208 patients with knee OA and 202 controls). Ten polymorphic loci of candidate genes were genotyped: rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1, rs1060105 and rs56116847 SBNO1, rs6499244 NFAT5, rs34195470 WWP2, rs143384 GDF5. The study of associations of polymorphic genetic loci with the development of the disease was carried out by the method of logistic regression, taking into account covariates (age, BMI). The MB-MDR method was used to study intergenic interactions of polymorphisms associated with the disease.Results and Discussion. It was found that nine out of ten polymorphic loci of candidate genes (with the exception of rs6976 GLT8D1) are associated with the formation of knee OA in men in four models of interlocus interactions (pperm ≤ 0.024). The rs3771501 TGFA polymorphic locus (included in three of the four most significant models of gene-gene interactions) demonstrates the greatest contribution to the development of the disease in men. Independent effects of the studied polymorphic loci of candidate genes in the development of knee OA in men have not been identified (р > 0,05).Conclusion. Polymorphic loci rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1, rs1060105 and rs56116847 SBNO1, rs6499244 NFAT5, rs34195470 WWP2, rs143384 GDF5 involved in the development of knee osteoarthritis in men in four models of intergenic interactions. Among the studied loci, rs3771501 of the TGFA gene has the greatest contribution to disease susceptibility.

Contribution of intergenic interactions of polymorphic variants of candidate genes to the development of a gastric ulcer

Introduction: Peptic ulcer disease occurs in 5-10% of the adult population, and is characterized by a high percentage of complications, which is a serious medical and social problem. The contribution of hereditary factors to the etiopathogenesis of the disease leaves 5.5-50%. The aim of the study was to study the contribution of intergenic interactions of polymorphic variants of candidate genes (rs2294008, rs505922, rs6136, rs8176720, rs2519093, rs507666, rs651007, rs579459, rs649129) to the development of gastric ulcer (GU). Materials and methods: The sample consisted of 217 patients with GU and 347 individuals from the control group, the regulatory potential of polymorphic loci were evaluated using the online databases, and genotyping was performed by PCR. The study of SNP×SNP interactions of polymorphic variants of candidate genes associated with the development of GU was carried out using a modification of the MDR (Multifactor Dimensionality Reduction) - Model-Based-MDR (MB-MDR) method, data visualization was carried out in the form of a dendrogram and graph using MDR software (v. 3.0.2). Results: All 9 studied SNPs as part of 10 significant models of interlocus interactions are involved in the formation of GU. The largest number of models includes rs8176720 of the ABO gene and rs2294008 of the PSCA gene. These polymorphic variants have a pronounced regulatory potential in many organs (tissues), incl. in the target organ of GU (stomach).

Polymorphisms of the filaggrin gene are associated with atopic dermatitis in the Caucasian population of Central Russia.

Association of the filaggrin (FLG) gene with atopic dermatitis (AD) in Caucasians from Central Russia was studied in the sample of 700 patients and 612 controls. In total ten SNPs of the gene (rs61816761, rs12130219, rs77199844, rs558269137, rs4363385, rs12144049, rs471144, rs6661961, rs10888499, rs3126085), their haplotypes and interlocus interactions were analyzed using logistic regression. The functional effects of the AD risk candidate loci and their proxies (136 SNPs) were evaluated by in silico analysis. All analyzed SNPs were associated with AD: two SNPs (rs3126085 and rs12144049) manifested the independent association, nine SNPs were associated within 30 haplotypes, and seven SNPs showed interlocus interaction effects within ten most significant epistatic models. Alleles A rs3126085 and C rs12144049 were associated with a higher risk of AD according to the allelic (ORs being 1.75, pperm=0.002 and 1.45, pperm=0.011 respectively), additive (ORs being 1.69, pperm=0.004 and 1.47, pperm=0.011 respectively) and dominant (ORs being 1.79, pperm=0.004 and 1.63, pperm=0.005 respectively) genetic models. Three haplotypes, GT[rs3126085-rs12144049] (OR=0.60), GGT[rs61816761-rs3126085-rs12144049] (OR=0.59), and AWGGT[rs12130219-rs558269137-rs61816761-rs3126085-rs12144049] (OR=0.63) demonstrated the protective effect (pperm=0.001). The in silico analysis suggested that the AD risk variants and their proxies apparently produce various effects on 38 genes in various tissue/organs (including 20 genes in the skin). The biological process enrichment analyses suggest that the target AD candidate genes influence the formation of the cornified envelope, keratinization and cornification, and more than twenty other pathways related to skin development, programmed cell death, and regulation of water loss via skin.

Polymorphisms of the TNF, LTA, and TNFRSF1B genes are associated with onsets of menarche and menopause in US women of European ancestry

Background The TNF, LTA and TNFRSF1B genes have been implicated in various traits related to menarche and menopause. Aim To analyse the TNF, LTA and TNFRSF1B genes for their association with ages at menarche (AM) and natural menopause (ANM). Subjects and methods The study sample consisted of 314 unrelated females of European ancestry. Twenty SNPs located in and near the genes were analysed using various statistical methods. In addition, the functional significance of the loci associated with AM and ANM was analysed in silico. Results Locus rs2229094 of the LTA gene was associated with AM according to the additive (β = −0.295, p perm = 0.016) and recessive (β = −0.940, p perm = 0.016) genetic models. Haplotype GG rs1148459-rs590368 of the TNFRSF1B gene was associated with AM (β = 0.307, p perm = 0.023). Haplotype GCA rs2844484-rs2229094-rs1799964 was associated with ANM after adjustment for covariates (β = −1.020, p perm = 0.035). All studied loci were associated with ANM after adjustment for breastfeeding (raw p < 0.05). In addition, eight of the most significant models of interlocus interactions were associated with AM and five with ANM. Conclusion The results of the present study suggest that the TNF, LTA and TNFRSF1B genes are associated with AM and ANM.

Production of hybrid potatoes: Are heterozygosity and ploidy levels important?

It has been proposed that maximizing heterosis for yield in potato may be achieved by maximizing heterozygosity and associated intra and interlocus interactions. Tetraploids offer more opportunities to create such interactions than diploids hence the general observations that tetraploids are higher yielding than diploids. Consequently, efforts have been made to increase heterozygosity in tetraploids by introgressing allelic diversity from other Solanum species into cultivated potato. However, conventional potato breeding is difficult because the cultivated potato is an autotetraploid with tetrasomic inheritance and it comprises highly heterozygous individuals which suffer inbreeding depression upon selfing; breeding at the tetraploid level is slow and less efficient than at diploid level. At the diploid level, it is possible to breed for and fix traits under recessive genetic control; it is nearly impossible to do so at the tetraploid level. There is also rapid response to selection due to greater variation in diploids than tetraploids. Consequently, there have been efforts to convert potato from an asexually propagated tetraploid crop into an inbred seed-propagated diploid; this is by production of inbred lines through selfing of the tetraploids to assemble desirable combinations of genes in the inbreds. These efforts are at the experimental stages and a lot of research needs to be done before they are confirmed. Because currently there is little experimental evidence to support superiority of the inbred seed-propagated diploid strategy, it appears the theory that heterosis for yield in potato may be achieved by maximizing heterozygosity and associated intra and interlocus interactions remain unchallenged; these interactions are more in tetraplods than in diploids. This paper therefore looks at genetic basis of yield heterosis in cultivated potato and the role of heterozygosity and ploidy level in production of hybrid potatoes.

Pathway-induced allelic spectra of diseases in the presence of strong genetic effects.

Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data.

Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia.

Little is known about the association between the single nucleotide polymorphisms (SNPs) and haplotypes of the dedicator of cytokinesis 7 (DOCK7), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2) and serum lipid traits in the Chinese populations. This study was to determine the association between nine SNPs in the three genes and their haplotypes and hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG), and to identify the possible gene-gene interactions among these SNPs. Genotyping was performed in 733 HCH and 540 HTG participants. The haplotype of C-C-G-C-T-G-C-C-G [in the order of DOCK7 rs1168013 (G>C), rs10889332 (C>T); PCSK9 rs615563 (G>A), rs7552841 (C>T), rs11206517 (T>G); and GALNT2 rs1997947 (G>A), rs2760537 (C>T), rs4846913 (C>A) and rs11122316 (G>A) SNPs] was associated with increased risk of HCH and HTG. The haplotypes of C-C-G-C-T-G-C-C-A and G-C-G-T-T-G-T-C-G were associated with a reduced risk of HCH and HTG. The haplotypes of G-C-G-C-T-G-C-C-A and G-C-G-C-T-G-T-C-G were associated with increased risk of HCH. The haplotypes of C-T-G-C-T-G-C-C-G, G-C-A-C-T-G-C-C-G and G-C-G-C-T-G-C-C-A were associated with an increased risk of HTG. The haplotypes of G-C-G-C-T-G-T-C-A and G-C-G-T-T-G-T-C-G were associated with a reduced risk of HTG. In addition, possible inter-locus interactions among the DOCK7, PCSK9 and GALNT2 SNPs were also noted. However, further functional studies of these genes are still required to clarify which SNPs are functional and how these genes actually affect the serum lipid levels.

Heritability assessment of cartilage metabolism. A twin study on circulating procollagen IIA N-terminal propeptide (PIIANP)

The aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders. 598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18-59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene-environment interaction. The intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60-0.76) and 0.46 (0.34-0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21-70%), shared environment 24% (7-53%) and non-shared environment 31% (24-39%) of the total variance. The heritability estimate did not differ across ages and between genders. The study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age.

FRI0043 Heritability assessment of cartilage collagen metabolism. a twin study on circulating pro-collagen iia n-terminal pro-peptide (piianp)

BackgroundCollagen is produced and secreted as a precursor molecule with C-and N-terminal extensions termed procollagen peptides. In the extracellular space these are cleaved off by specific C- and N-peptidases after...

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

Several recent studies have examined different aspects of mammalian higher order chromatin structure – replication timing, lamina association and Hi-C inter-locus interactions — and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.

Heritability assessment of cartilage metabolism. A twin study on procollagen II N-terminal propeptide (PIIANP)

Heritability assessment of cartilage metabolism. A twin study on procollagen II N-terminal propeptide (PIIANP)

Heritability of optic disc diameters: a twin study

To assess the relative influence of genetic and environmental factors on optic disc size and cup/disc ratio in healthy eyes. A sample of 55 monozygotic and 50 dizygotic healthy twin pairs aged 20-46, all having the same sex within pairs (47 pairs were male) had optic discs measured from colour fundus photographs according to the Wisconsin Protocol. Structural equation modelling was used to estimate the relative contribution of genetic and environmental factors to the phenotype. Disc dimensions did not vary significantly by age or sex. After adjusting for age and sex, additive genetic factors (i.e. heritability) explained 77% (95% CI: 65-85%) of variation of vertical disc diameters, whereas estimated unshared environmental effect was 23% (95% CI: 15-35%). For vertical cup diameters, heritability accounted for 70% (95% CI: 55-80%) and environmental factors 30% (95% CI: 20-45%). For cup/disc ratio, additive genetic and unshared environmental factors explained 66% (95% CI: 48-77%) and 34% (95% CI: 23-52%) of the variations, respectively. In this healthy twin sample, we found that three quarters of the variations in vertical optic disc and optic cup diameters were attributable to genetic influence.

Including non-additive genetic effects in Bayesian methods for the prediction of genetic values based on genome-wide markers

BackgroundMolecular marker information is a common source to draw inferences about the relationship between genetic and phenotypic variation. Genetic effects are often modelled as additively acting marker allele effects. The true mode of biological action can, of course, be different from this plain assumption. One possibility to better understand the genetic architecture of complex traits is to include intra-locus (dominance) and inter-locus (epistasis) interaction of alleles as well as the additive genetic effects when fitting a model to a trait. Several Bayesian MCMC approaches exist for the genome-wide estimation of genetic effects with high accuracy of genetic value prediction. Including pairwise interaction for thousands of loci would probably go beyond the scope of such a sampling algorithm because then millions of effects are to be estimated simultaneously leading to months of computation time. Alternative solving strategies are required when epistasis is studied.MethodsWe extended a fast Bayesian method (fBayesB), which was previously proposed for a purely additive model, to include non-additive effects. The fBayesB approach was used to estimate genetic effects on the basis of simulated datasets. Different scenarios were simulated to study the loss of accuracy of prediction, if epistatic effects were not simulated but modelled and vice versa.ResultsIf 23 QTL were simulated to cause additive and dominance effects, both fBayesB and a conventional MCMC sampler BayesB yielded similar results in terms of accuracy of genetic value prediction and bias of variance component estimation based on a model including additive and dominance effects. Applying fBayesB to data with epistasis, accuracy could be improved by 5% when all pairwise interactions were modelled as well. The accuracy decreased more than 20% if genetic variation was spread over 230 QTL. In this scenario, accuracy based on modelling only additive and dominance effects was generally superior to that of the complex model including epistatic effects.ConclusionsThis simulation study showed that the fBayesB approach is convenient for genetic value prediction. Jointly estimating additive and non-additive effects (especially dominance) has reasonable impact on the accuracy of prediction and the proportion of genetic variation assigned to the additive genetic source.

Modeling QTL for complex traits: detection and context for plant breeding

The genetic architecture of a trait is defined by the set of genes contributing to genetic variation within a reference population of genotypes together with information on their location in the genome and the effects of their alleles on traits, including intra-locus and inter-locus interactions, environmental dependencies, and pleiotropy. Accumulated evidence from trait mapping studies emphasizes that plant breeders work within a trait genetic complexity continuum. Some traits show a relatively simple genetic architecture while others, such as grain yield, have a complex architecture. An important advance is that we now have empirical genetic models of trait genetic architecture obtained from mapping studies (multi-QTL models including various genetic effects that may vary in relation to environmental factors) to ground theoretical investigations on the merits of alternative breeding strategies. Such theoretical studies indicate that as the genetic complexity of traits increases the opportunities for realizing benefits from molecular enhanced breeding strategies increase. To realize these potential benefits and enable the plant breeder to increase rate of genetic gain for complex traits it is anticipated that the empirical genetic models of trait genetic architecture used for predicting trait variation will need to incorporate the effects of genetic interactions and be interpreted within a genotype-environment-management framework for the target agricultural production system.

Direct evidence that genetic variation in glycerol-3-phosphate and malate dehydrogenase genes (Gpdh and Mdh1) affects adult ethanol tolerance in Drosophila melanogaster.

Many studies of alcohol adaptation in Drosophila melanogaster have focused on the Adh polymorphism, yet the metabolic elimination of alcohol should involve many enzymes and pathways. Here we evaluate the effects of glycerol-3-phosphate dehydrogenase (Gpdh) and cytosolic malate dehydrogenase (Mdh1) genotype activity on adult tolerance to ethanol. We have created a set of P-element-excision-derived Gpdh, Mdh1, and Adh alleles that generate a range of activity phenotypes from full to zero activity. Comparisons of paired Gpdh genotypes possessing 10 and 60% normal activity and 66 and 100% normal activity show significant effects where higher activity increases tolerance. Mdh1 null allele homozygotes show reductions in tolerance. We use piggyBac FLP-FRT site-specific recombination to create deletions and duplications of Gpdh. Duplications show an increase of 50% in activity and an increase of adult tolerance to ethanol exposure. These studies show that the molecular polymorphism associated with GPDH activity could be maintained in natural populations by selection related to adaptation to alcohols. Finally, we examine the interactions between activity genotypes for Gpdh, Mdh1, and Adh. We find no significant interlocus interactions. Observations on Mdh1 in both Gpdh and Adh backgrounds demonstrate significant increases in ethanol tolerance with partial reductions (50%) in cytosolic MDH activity. This observation strongly suggests the operation of pyruvate-malate and, in particular, pyruvate-citrate cycling in adaptation to alcohol exposure. We propose that an understanding of the evolution of tolerance to alcohols will require a system-level approach, rather than a focus on single enzymes.

Simultaneous fine mapping of closely linked epistatic quantitative trait loci using combined linkage disequilibrium and linkage with a general pedigree

Causal mutations and their intra- and inter-locus interactions play a critical role in complex trait variation. It is often not easy to detect epistatic quantitative trait loci (QTL) due to complicated population structure requirements for detecting epistatic effects in linkage analysis studies and due to main effects often being hidden by interaction effects. Mapping their positions is even harder when they are closely linked. The data structure requirement may be overcome when information on linkage disequilibrium is used. We present an approach using a mixed linear model nested in an empirical Bayesian approach, which simultaneously takes into account additive, dominance and epistatic effects due to multiple QTL. The covariance structure used in the mixed linear model is based on combined linkage disequilibrium and linkage information. In a simulation study where there are complex epistatic interactions between QTL, it is possible to simultaneously map interacting QTL into a small region using the proposed approach. The estimated variance components are accurate and less biased with the proposed approach compared with traditional models.

Inheritance of grain protein content upon crossing covered and hulless barley biological varieties

In a study of F1 diallel hybrids from crossing covered and hulless barley biological varieties, intralocus overdominance and interlocus interaction of nonallelic genes of the complementary (recessive) epistasis type are revealed in genetic control of grain protein content. It is shown that recessive genes increase protein content. Selection of hulless productive genotypes is preferable in later hybrid generations, starting with F4–F6.