Genomic complexity of the variable region-containing chitin-binding proteins in amphioxus

Background

Genetic isolates such as the Ashkenazi Jews (AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap (CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups.

Results

A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean F _ST of 0.009 (P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium (LD) statistics (Haploview) as well as by expectation-maximization haplotype phase inference (HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview (50,397 vs. 44,169) or by HAP (59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU (e.g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ.

Conclusion

LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure.     

htSNPer1.0: software for haplotype block partition and htSNPs selection

Background  

There is recently great interest in haplotype block structure and haplotype tagging SNPs (htSNPs) in the human genome for its implication on htSNPs-based association mapping strategy for complex disease. Different definitions have been used to characterize the haplotype block structure in the human genome, and several different performance criteria and algorithms have been suggested on htSNPs selection.     

Genetic determinants of hair and eye colours in the Scottish and Danish populations

Background

The Bovine HapMap Consortium has generated assay panels to genotype ~30,000 single nucleotide polymorphisms (SNPs) from 501 animals sampled from 19 worldwide taurine and indicine breeds, plus two outgroup species (Anoa and Water Buffalo). Within the larger set of SNPs we targeted 101 high density regions spanning up to 7.6 Mb with an average density of approximately one SNP per 4 kb, and characterized the linkage disequilibrium (LD) and haplotype block structure within individual breeds and groups of breeds in relation to their geographic origin and use.

Results

From the 101 targeted high-density regions on bovine chromosomes 6, 14, and 25, between 57 and 95% of the SNPs were informative in the individual breeds. The regions of high LD extend up to ~100 kb and the size of haplotype blocks ranges between 30 bases and 75 kb (10.3 kb average). On the scale from 1–100 kb the extent of LD and haplotype block structure in cattle has high similarity to humans. The estimation of effective population sizes over the previous 10,000 generations conforms to two main events in cattle history: the initiation of cattle domestication (~12,000 years ago), and the intensification of population isolation and current population bottleneck that breeds have experienced worldwide within the last ~700 years. Haplotype block density correlation, block boundary discordances, and haplotype sharing analyses were consistent in revealing unexpected similarities between some beef and dairy breeds, making them non-differentiable. Clustering techniques permitted grouping of breeds into different clades given their similarities and dissimilarities in genetic structure.

Conclusion

This work presents the first high-resolution analysis of haplotype block structure in worldwide cattle samples. Several novel results were obtained. First, cattle and human share a high similarity in LD and haplotype block structure on the scale of 1–100 kb. Second, unexpected similarities in haplotype block structure between dairy and beef breeds make them non-differentiable. Finally, our findings suggest that ~30,000 uniformly distributed SNPs would be necessary to construct a complete genome LD map in Bos taurus breeds, and ~580,000 SNPs would be necessary to characterize the haplotype block structure across the complete cattle genome.     

A mitochondrial mutator plasmid that causes senescence under dietary restricted conditions

Background

The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.

Results

Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments.

Conclusion

We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques.     

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.     

Efficient haplotype block recognition of very long and dense genetic sequences

Background

The new sequencing technologies enable to scan very long and dense genetic sequences, obtaining datasets of genetic markers that are an order of magnitude larger than previously available. Such genetic sequences are characterized by common alleles interspersed with multiple rarer alleles. This situation has renewed the interest for the identification of haplotypes carrying the rare risk alleles. However, large scale explorations of the linkage-disequilibrium (LD) pattern to identify haplotype blocks are not easy to perform, because traditional algorithms have at least Θ(n ²) time and memory complexity.

Results

We derived three incremental optimizations of the widely used haplotype block recognition algorithm proposed by Gabriel et al. in 2002. Our most efficient solution, called MIG ⁺⁺, has only Θ(n) memory complexity and, on a genome-wide scale, it omits >80% of the calculations, which makes it an order of magnitude faster than the original algorithm. Differently from the existing software, the MIG ⁺⁺ analyzes the LD between SNPs at any distance, avoiding restrictions on the maximal block length. The haplotype block partition of the entire HapMap II CEPH dataset was obtained in 457 hours. By replacing the standard likelihood-based D ^′ variance estimator with an approximated estimator, the runtime was further improved. While producing a coarser partition, the approximate method allowed to obtain the full-genome haplotype block partition of the entire 1000 Genomes Project CEPH dataset in 44 hours, with no restrictions on allele frequency or long-range correlations. These experiments showed that LD-based haplotype blocks can span more than one million base-pairs in both HapMap II and 1000 Genomes datasets. An application to the North American Rheumatoid Arthritis Consortium (NARAC) dataset shows how the MIG ⁺⁺ can support genome-wide haplotype association studies.

Conclusions

The MIG ⁺⁺ enables to perform LD-based haplotype block recognition on genetic sequences of any length and density. In the new generation sequencing era, this can help identify haplotypes that carry rare variants of interest. The low computational requirements open the possibility to include the haplotype block structure into genome-wide association scans, downstream analyses, and visual interfaces for online genome browsers.     

Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes

Background

The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers.

Results

We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen α1 (COL1A1), estrogen receptor-α (ER-α), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-β1 (TGF-β1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D₃) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r², were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r² was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene.

Conclusion

The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.     

Depauperate genetic variability detected in the American and European bison using genomic techniques

 

A total of 929 polymorphic SNPs in EB (out of 54, 000 SNPs screened using a BovineSNP50 Illumina Genotyping BeadChip), and 1, 524 and 1, 403 polymorphic SNPs in WB and PB, respectively, were analysed. EB, WB and PB have all undergone recent drastic reductions in population size. Accordingly, they exhibited extremely depauperate genomes, deviations from genetic equilibrium and a genome organization consisting of a mosaic of haplotype blocks: regions with low haplotype diversity and high levels of linkage disequilibrium. No evidence for positive or stabilizing selection was found in EB, WB and PB, likely reflecting drift overwhelming selection. We suggest that utilization of genome-wide screening technologies, followed by utilization of less expensive techniques (e.g. VeraCode and Fluidigm EP1), holds large potential for genetic monitoring of populations. Additionally, these techniques will allow radical improvements of breeding practices in captive or managed populations, otherwise hampered by the limited availability of polymorphic markers. This result in improved possibilities for 1) estimating genetic relationships among individuals and 2) designing breeding strategies which attempt to preserve or reduce polymorphism in ecologically relevant genes and/or entire blocks.

Reviewers

This article was reviewed by: Fyodor Kondrashov and Shamil Sunyaev     

Finding haplotype tagging SNPs by use of principal components analysis

The immense volume and rapid growth of human genomic data, especially single nucleotide polymorphisms (SNPs), present special challenges for both biomedical researchers and automatic algorithms. One such challenge is to select an optimal subset of SNPs, commonly referred as "haplotype tagging SNPs" (htSNPs), to capture most of the haplotype diversity of each haplotype block or gene-specific region. This information-reduction process facilitates cost-effective genotyping and, subsequently, genotype-phenotype association studies. It also has implications for assessing the risk of identifying research subjects on the basis of SNP information deposited in public domain databases. We have investigated methods for selecting htSNPs by use of principal components analysis (PCA). These methods first identify eigenSNPs and then map them to actual SNPs. We evaluated two mapping strategies, greedy discard and varimax rotation, by assessing the ability of the selected htSNPs to reconstruct genotypes of non-htSNPs. We also compared these methods with two other htSNP finders, one of which is PCA based. We applied these methods to three experimental data sets and found that the PCA-based methods tend to select the smallest set of htSNPs to achieve a 90% reconstruction precision.     

Single-nucleotide polymorphism,linkage disequilibrium and geographic structure in the malaria parasite <Emphasis Type="Italic">Plasmodium vivax</Emphasis>: prospects for genome-wide association studies

Background

The ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite P. vivax remain little characterized.

Results

We examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of P. vivax in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of P. vivax. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the pvmdr-1 locus, putatively associated with drug resistance.

Conclusion

These findings support the feasibility of genome-wide association studies in carefully selected populations of P. vivax, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.See commentary: http://www.biomedcentral.com/1741-7007/8/90

     

Large-scale single-nucleotide polymorphism (SNP) and haplotype analyses, using dense SNP Maps, of 199 drug-related genes in 752 subjects: the analysis of the association between uncommon SNPs within haplotype blocks and the haplotypes constructed with haplotype-tagging SNPs

To optimize the strategies for population-based pharmacogenetic studies, we extensively analyzed single-nucleotide polymorphisms (SNPs) and haplotypes in 199 drug-related genes, through use of 4,190 SNPs in 752 control subjects. Drug-related genes, like other genes, have a haplotype-block structure, and a few haplotype-tagging SNPs (htSNPs) could represent most of the major haplotypes constructed with common SNPs in a block. Because our data included 860 uncommon (frequency <0.1) SNPs with frequencies that were accurately estimated, we analyzed the relationship between haplotypes and uncommon SNPs within the blocks (549 SNPs). We inferred haplotype frequencies through use of the data from all htSNPs and one of the uncommon SNPs within a block and calculated four joint probabilities for the haplotypes. We show that, irrespective of the minor-allele frequency of an uncommon SNP, the majority (mean +/- SD frequency 0.943+/-0.117) of the minor alleles were assigned to a single haplotype tagged by htSNPs if the uncommon SNP was within the block. These results support the hypothesis that recombinations occur only infrequently within blocks. The proportion of a single haplotype tagged by htSNPs to which the minor alleles of an uncommon SNP were assigned was positively correlated with the minor-allele frequency when the frequency was <0.03 (P<.000001; n=233 [Spearman's rank correlation coefficient]). The results of simulation studies suggested that haplotype analysis using htSNPs may be useful in the detection of uncommon SNPs associated with phenotypes if the frequencies of the SNPs are higher in affected than in control populations, the SNPs are within the blocks, and the frequencies of the SNPs are >0.03.     

Evaluation of LD decay and various LD-decay estimators in simulated and SNP-array data of tetraploid potato

Key message

The number of SNPs required for QTL discovery is justified by the distance at which linkage disequilibrium has decayed. Simulations and real potato SNP data showed how to estimate and interpret LD decay.

Abstract

The magnitude of linkage disequilibrium (LD) and its decay with genetic distance determine the resolution of association mapping, and are useful for assessing the desired numbers of SNPs on arrays. To study LD and LD decay in tetraploid potato, we simulated autotetraploid genotypes and used it to explore the dependence on: (1) the number of haplotypes in the population (the amount of genetic variation) and (2) the percentage of haplotype specific SNPs (hs-SNPs). Several estimators for short-range LD were explored, such as the average r ², median r ², and other percentiles of r ² (80, 90, and 95 %). For LD decay, we looked at LD_½,90, the distance at which the short-range LD is halved when using the 90 % percentile of r ² at short range, as estimator for LD. Simulations showed that the performance of various estimators for LD decay strongly depended on the number of haplotypes, although the real value of LD decay was not influenced very much by this number. The estimator LD_½,90 was chosen to evaluate LD decay in 537 tetraploid varieties. LD_½,90 values were 1.5 Mb for varieties released before 1945 and 0.6 Mb in varieties released after 2005. LD_½,90 values within three different subpopulations ranged from 0.7 to 0.9 Mb. LD_½,90 was 2.5 Mb for introgressed regions, indicating large haplotype blocks. In pericentromeric heterochromatin, LD decay was negligible. This study demonstrates that several related factors influencing LD decay could be disentangled, that no universal approach can be suggested, and that the estimation of LD decay has to be performed with great care and knowledge of the sampled material.

     

Haplotype frequencies at the DRD2 locus in populations of the East European Plain

Background

A key to increasing the power of multilocus association tests is to reduce the number of degrees of freedom by suppressing noise from data. One of the difficulties is to decide how much noise to suppress. An often overlooked problem is that commonly used association tests based on genotype data cannot utilize the genetic information contained in spatial ordering of SNPs (see proof in the Appendix), which may prevent them from achieving higher power.

Results

We develop a score test based on wavelet transform with empirical Bayesian thresholding. Extensive simulation studies are carried out under various LD structures as well as using HapMap data from many different chromosomes for both qualitative and quantitative traits. Simulation results show that the proposed test automatically adjusts the level of noise suppression according to LD structures, and it is able to consistently achieve higher or similar powers than many commonly used association tests including the principle component regression method (PCReg).

Conclusion

The wavelet-based score test automatically suppresses the right amount of noise and uses the information contained in spatial ordering of SNPs to achieve higher power.     

Genetic diversity and linkage disequilibrium analysis in elite sugar beet breeding lines and wild beet accessions

Key message

Linkage disequilibrium decay in sugar beet is strongly affected by the breeding history, and varies extensively between and along chromosomes, allowing identification of known and unknown signatures of selection.

Abstract

Genetic diversity and linkage disequilibrium (LD) patterns were investigated in 233 elite sugar beet breeding lines and 91 wild beet accessions, using 454 single nucleotide polymorphisms (SNPs) and 418 SNPs, respectively. Principal coordinate analysis suggested the existence of three groups of germplasm, corresponding to the wild beets, the seed parent and the pollen parent breeding pool. LD was investigated in each of these groups, with and without correction for genetic relatedness. Without correction for genetic relatedness, in the pollen as well as the seed parent pool, LD persisted beyond 50 centiMorgan (cM) on four (2, 3, 4 and 5) and three chromosomes (2, 4 and 6), respectively; after correction for genetic relatedness, LD decayed after <6 cM on all chromosomes in both pools. In the wild beet accessions, there was a strong LD decay: on average LD disappeared after 1 cM when LD was calculated with a correction for genetic relatedness. Persistence of LD was not only observed between distant SNPs on the same chromosome, but also between SNPs on different chromosomes. Regions on chromosomes 3 and 4 that harbor disease resistance and monogermy loci showed strong genetic differentiation between the pollen and seed parent pools. Other regions, on chromosomes 8 and 9, for which no a priori information was available with respect to their contribution to the phenotype, still contributed to clustering of lines in the elite breeding material.     

A multilocus linkage disequilibrium measure based on mutual information theory and its applications

Evaluating the patterns of linkage disequilibrium (LD) is important for association mapping study as well as for studying the genomic architecture of human genome (e.g., haplotype block structures). Commonly used bi-allelic pairwise measures for assessing LD between two loci, such as r ² and D′, may not make full and efficient use of modern multilocus data. Though extended to multilocus scenarios, their performance is still questionable. Meanwhile, most existing measures for an entire multilocus region, such as normalized entropy difference, do not consider existence of LD heterogeneity across the region under investigation. Additionally, these existing multilocus measures cannot handle distant regions where long-range LD patterns may exist. In this study, we proposed a novel multilocus LD measure developed based on mutual information theory. Our proposed measure described LD pattern between two chromosome regions each of which may consist of multiple loci (including multi-allele loci). As such, the proposed measure can better characterize LD patterns between two arbitrary regions. As potential applications, we developed algorithms on the proposed measure for partitioning haplotype blocks and for selecting haplotype tagging SNPs (htSNPs), which were helpful for follow-up association tests. The results on both simulated and empirical data showed that our LD measure had distinct advantages over pairwise and other multilocus measures. First, our measure was more robust, and can capture comprehensively the LD information between neighboring as well as disjointed regions. Second, haplotype blocks were better described via our proposed measure. Furthermore, association tests with htSNPs from the proposed algorithm had improved power over tests on single markers and on haplotypes.     

A genome-wide association study of seed protein and oil content in soybean

Background

Association analysis is an alternative to conventional family-based methods to detect the location of gene(s) or quantitative trait loci (QTL) and provides relatively high resolution in terms of defining the genome position of a gene or QTL. Seed protein and oil concentration are quantitative traits which are determined by the interaction among many genes with small to moderate genetic effects and their interaction with the environment. In this study, a genome-wide association study (GWAS) was performed to identify quantitative trait loci (QTL) controlling seed protein and oil concentration in 298 soybean germplasm accessions exhibiting a wide range of seed protein and oil content.

Results

A total of 55,159 single nucleotide polymorphisms (SNPs) were genotyped using various methods including Illumina Infinium and GoldenGate assays and 31,954 markers with minor allele frequency >0.10 were used to estimate linkage disequilibrium (LD) in heterochromatic and euchromatic regions. In euchromatic regions, the mean LD (r ² ) rapidly declined to 0.2 within 360 Kbp, whereas the mean LD declined to 0.2 at 9,600 Kbp in heterochromatic regions. The GWAS results identified 40 SNPs in 17 different genomic regions significantly associated with seed protein. Of these, the five SNPs with the highest associations and seven adjacent SNPs were located in the 27.6-30.0 Mbp region of Gm20. A major seed protein QTL has been previously mapped to the same location and potential candidate genes have recently been identified in this region. The GWAS results also detected 25 SNPs in 13 different genomic regions associated with seed oil. Of these markers, seven SNPs had a significant association with both protein and oil.

Conclusions

This research indicated that GWAS not only identified most of the previously reported QTL controlling seed protein and oil, but also resulted in narrower genomic regions than the regions reported as containing these QTL. The narrower GWAS-defined genome regions will allow more precise marker-assisted allele selection and will expedite positional cloning of the causal gene(s).     

CrypticIBDcheck: an R package for checking cryptic relatedness in nominally unrelated individuals

Background

In population association studies, standard methods of statistical inference assume that study subjects are independent samples. In genetic association studies, it is therefore of interest to diagnose undocumented close relationships in nominally unrelated study samples.

Results

We describe the R package CrypticIBDcheck to identify pairs of closely-related subjects based on genetic marker data from single-nucleotide polymorphisms (SNPs). The package is able to accommodate SNPs in linkage disequibrium (LD), without the need to thin the markers so that they are approximately independent in the population. Sample pairs are identified by superposing their estimated identity-by-descent (IBD) coefficients on plots of IBD coefficients for pairs of simulated subjects from one of several common close relationships.

Conclusions

The methods implemented in CrypticIBDcheck are particularly relevant to candidate-gene association studies, in which dependent SNPs cluster in a relatively small number of genes spread throughout the genome. The accommodation of LD allows the use of all available genetic data, a desirable property when working with a modest number of dependent SNPs within candidate genes. CrypticIBDcheck is available from the Comprehensive R Archive Network (CRAN).

     

Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study

Background

Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of neuroserpin polymorphisms with risk for ischemic stroke among young women.

Methods

A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke.

Results

Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only.

Conclusion

This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among Caucasian women.     

Extent and consistency of linkage disequilibrium and identification of DNA markers for production and egg quality traits in commercial layer chicken populations

Background

The genome sequence and a high-density SNP map are now available for the chicken and can be used to identify genetic markers for use in marker-assisted selection (MAS). Effective MAS requires high linkage disequilibrium (LD) between markers and quantitative trait loci (QTL), and sustained marker-QTL LD over generations. This study used data from a 3,000 SNP panel to assess the level and consistency of LD between single nucleotide polymorphisms (SNPs) over consecutive years in two egg-layer chicken lines, and analyzed one line by two methods (SNP-wise association and genome-wise Bayesian analysis) to identify markers associated with egg-quality and egg-production phenotypes.

Results

The LD between markers pairs was high at short distances (r² > 0.2 at < 2 Mb) and remained high after one generation (correlations of 0.80 to 0.92 at < 5 Mb) in both lines. Single- and 3-SNP regression analyses using a mixed model with SNP as fixed effect resulted in 159 and 76 significant tests (P < 0.01), respectively, across 12 traits. A Bayesian analysis called BayesB, that fits all SNPs simultaneously as random effects and uses model averaging procedures, identified 33 SNPs that were included in the model >20% of the time (φ > 0.2) and an additional ten 3-SNP windows that had a sum of φ greater than 0.35. Generally, SNPs included in the Bayesian model also had a small P-value in the 1-SNP analyses.

Conclusion

High LD correlations between markers at short distances across two generations indicate that such markers will retain high LD with linked QTL and be effective for MAS. The different association analysis methods used provided consistent results. Multiple single SNPs and 3-SNP windows were significantly associated with egg-related traits, providing genomic positions of QTL that can be useful for both MAS and to identify causal mutations.

     

Haplotype distribution and association of candidate genes with salt tolerance in Indian wild rice germplasm

Key message

The association of natural genetic variations of salt-responsive candidate genes belonging to different gene families with salt-tolerance phenotype and their haplotype variation in different geographic regions.

Abstract

Soil salinity covers a large part of the arable land of the world and is a major factor for yield losses in salt-sensitive crops, such as rice. Different gene families that respond to salinity have been identified in rice, but limited success has been achieved in developing salt-tolerant cultivars. Therefore, 21 salt stress-responsive candidate genes belonging to different gene families were re-sequenced to analyse their genetic variation and association with salt tolerance. The average single nucleotide polymorphism (SNP) density was 16 SNPs per kbp amongst these genes. The identified nucleotide and haplotype diversity showed comparatively higher genetic variation in the transporter family genes. Linkage disequilibrium (LD) analysis showed significant associations of SNPs in BADH2, HsfC1B, MIPS1, MIPS2, MYB2, NHX1, NHX2, NHX3, P5CS1, P5CS2, PIP1, SIK1, SOS1, and SOS2 genes with the salt-tolerant phenotype. A combined analysis of SNPs in the 21 candidate genes and eight other HKT transporter genes produced two separate clusters of tolerant genotypes, carrying unique SNPs in the ion transporter and osmoticum-related genes. Haplotype network analysis showed all the major and few minor alleles distributed over distant geographic regions. Minor haplotypes may be recently evolved alleles which migrated to distant geographic regions and may represent recent expansion of Indian wild rice. The analysis of genetic variation in different gene families identified the relationship between adaptive variations and functional significance of the genes. Introgression of the identified alleles from wild relatives may enhance the salt tolerance and consequently rice production in the salinity-affected areas.