Exhibited Linkage Disequilibrium Research Articles

Positive selection in the genomes of two Papua New Guinean populations at distinct altitude levels.

Highlanders and lowlanders of Papua New Guinea have faced distinct environmental stress, such as hypoxia and environment-specific pathogen exposure, respectively. In this study, we explored the top genomics regions and the candidate driver SNPs for selection in these two populations using newly sequenced whole-genomes of 54 highlanders and 74 lowlanders. We identified two candidate SNPs under selection - one in highlanders, associated with red blood cell traits and another in lowlanders, which is associated with white blood cell count - both potentially influencing the heart rate of Papua New Guineans in opposite directions. We also observed four candidate driver SNPs that exhibit linkage disequilibrium with an introgressed haplotype, highlighting the need to explore the possibility of adaptive introgression within these populations. This study reveals that the signatures of positive selection in highlanders and lowlanders of Papua New Guinea align closely with the challenges they face, which are specific to their environments.

HLA-G 3'UTR polymorphism diplotypes and soluble HLA-G plasma levels impact cervical cancer susceptibility and prognosis.

Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with relevance in several cancers. The aim of this study was to evaluate the potential role of soluble HLA-G (sHLA-G), its genetic polymorphisms and its haplotype structure in the susceptibility and prognosis of primary cervical cancer in a Chinese Han population. We investigated sHLA-G plasma levels and 3' untranslated region (3'UTR) polymorphisms through ELISA and direct DNA sequencing, respectively, in cervical cancer patients (120 cases) and healthy control women (96 cases). The data were analyzed for associations using PowerMarker, Haploview, and GraphPad Prism. In this study, 8 polymorphic sites, 16 haplotypes and 23 diplotypes in the HLA-G 3'UTR were identified in our study population. We observed that each pair of 8 polymorphic sites exhibited linkage disequilibrium. The heterozygote CT genotype at position +3422 (rs17875408) was more common in cervical cancer patients than in healthy women (OR=5.285, P<0.05). Haplotypes UTR-1, UTR-3, and UTR-7 accounted for more than 85% of both groups, but no significant difference was found. The frequency of the UTR-1/UTR-3 diplotype in patients was significantly higher than that in controls (P<0.05). In addition, we further observed that HLA-G 3'UTR polymorphisms may influence the sHLA-G plasma level in patients' peripheral blood, especially 14 bp Ins/Del (rs371194629) and +3142 C/G (rs1063320). A receiver operating characteristic (ROC) curve analysis showed that the sHLA-G level had good diagnostic performance in differentiating patients with cervical cancer from healthy women (AUC>0.7). Among patients, mean sHLA-G levels increased with increasing FIGO stages but were not related to the overall survival time. The results of the present study enhance our understanding of how HLA-G 3'UTR polymorphisms can influence the peripheral sHLA-G plasma level and play a key role in cervical carcinogenesis. This study further confirmed that sHLA-G may represent a novel plasma biomarker for the prognosis and potential therapeutic target of cervical cancer.

Population genetic diversity and structure of the pecan scab pathogen, Venturia effusa, on cv. Desirable and native seedlings, and the impact of marker number

AbstractScab (Venturia effusa) is the major cause of economic loss in pecan in the south‐eastern USA. We explored population genetic diversity and structure among orchards of cv. Desirable and native seedlings, and within‐orchard variability among trees of all cultivars sampled. We compared the ability of 30, 15 and 7 previously developed microsatellites to characterize the population genetic diversity and structure of V. effusa. Analyses of molecular variance (AMOVA) provided little evidence of structure dependent on cultivar, but there was some evidence of structure between orchards of a cultivar based on distance. Individual orchard AMOVA showed that three of 11 orchards had between‐tree population structure. Among six populations from cv. Desirable, a Mantel test showed that geographic distance was related to the pairwise genetic divergence (R2 = 0.84). Among 11 orchards of various cultivars there was little difference in diversity using 30, 15 or 7 markers, or population structure based on AMOVA. Some minor differences in population structure were seen based on discriminant analysis of principal components, or dendrograms. Thus, depending on the objectives, future studies may use as few as 15 or 7 markers without losing ability to discern population genetic diversity or structure. More populations exhibited linkage disequilibrium when using 15 or 30 markers compared to when using seven markers. Knowledge of population genetics of V. effusa in relation to host genotype is needed to understand pathogen population interactions and gene flow, knowledge that will help underpin future breeding efforts to develop durable resistance in this long‐lived orchard tree.

Network Analysis of Linkage Disequilibrium Reveals Genome Architecture in Chum Salmon.

Many studies exclude loci that exhibit linkage disequilibrium (LD); however, high LD can signal reduced recombination around genomic features such as chromosome inversions or sex-determining regions. Chromosome inversions and sex-determining regions are often involved in adaptation, allowing for the inheritance of co-adapted gene complexes and for the resolution of sexually antagonistic selection through sex-specific partitioning of genetic variants. Genomic features such as these can escape detection when loci with LD are removed; in addition, failing to account for these features can introduce bias to analyses. We examined patterns of LD using network analysis to identify an overlapping chromosome inversion and sex-determining region in chum salmon. The signal of the inversion was strong enough to show up as false population substructure when the entire dataset was analyzed, while the effect of the sex-determining region on population structure was only obvious after restricting analysis to the sex chromosome. Understanding the extent and geographic distribution of inversions is now a critically important part of genetic analyses of natural populations. Our results highlight the importance of analyzing and understanding patterns of LD in genomic dataset and the perils of excluding or ignoring loci exhibiting LD. Blindly excluding loci in LD would have prevented detection of the sex-determining region and chromosome inversion while failing to understand the genomic features leading to high-LD could have resulted in false interpretations of population structure.

Recombination contributes to population diversification in the polyploid intestinal symbiont Epulopiscium sp. type B.

Epulopiscium sp. type B (Lachnospiraceae) is an exceptionally large, highly polyploid, intestinal symbiont of the coral reef dwelling surgeonfish Naso tonganus. These obligate anaerobes do not form mature endospores and reproduce solely through the production of multiple intracellular offspring. This likely makes them dependent on immediate transfer to a receptive host for dispersal. During reproduction, only a small proportion of Epulopiscium mother-cell DNA is inherited. To explore the impact of this unusual viviparous lifestyle on symbiont population dynamics, we investigated Epulopiscium sp. type B and their fish hosts collected over the course of two decades, at island and reef habitats near Lizard Island, Australia. Using multi-locus sequence analysis, we found that recombination plays an important role in maintaining diversity of these symbionts and yet populations exhibit linkage disequilibrium (LD). Symbiont populations showed spatial but not temporal partitioning. Surgeonfish are long-lived and capable of traveling long distances, yet the population structures of Epulopiscium suggest that adult fish tend to not roam beyond a limited locale. Codiversification analyses and traits of this partnership suggest that while symbionts are obligately dependent on their host, the host has a facultative association with Epulopiscium. We suggest that congression of unlinked markers contributes to LD estimates in this and other recombinant populations of bacteria. The findings here inform our understanding of evolutionary processes within intestinal Lachnospiraceae populations.

Development of 12 Microsatellite Markers in Dorcus titanus castanicolor (Motschulsky, 1861) (Lucanidae, Coleoptera) from Korea Using Next-Generation Sequencing.

In the present study, we used next-generation sequencing to develop 12 novel microsatellite markers for genetic structural analysis of Dorcus titanus castanicolor (Lucanidae; Coleoptera), a popular pet insect in China, Korea, and Japan. We identified 52,357 microsatellite loci in 339,287,381 bp of genomic sequence and selected 19 of the loci based on their PCR amplification efficiency and polymorphism. The 19 selected markers were then tested for the presence of null alleles and linkage disequilibrium. We did not detect any evidence of null alleles; however, four pairs of loci (DT03 and DT11, DT05 and DT26, DT08 and DT26, DT26 and DT35) exhibited linkage disequilibrium. Thus, we assessed the genetic diversity of a D. titanus castanicolor population from the Daejeon region of Korea (n = 22) using 13 markers. Among them, one marker (DT17) deviated from Hardy-Weinberg equilibrium. Therefore, 12 markers may be useful for further analyzing the genetic diversity of D. titanus castanicolor.

ASSOCIATION STUDY BETWEEN OLIGODENDROCYTE TRANSCRIPTION FACTOR 2 GENE AND OBSESSIVE-COMPULSIVE DISORDER IN A CHINESE HAN POPULATION.

Oligodendrocyte transcription factor 2 (OLIG2) is primarily concentrated in the brain and spinal cord ventricular zone, where this protein stimulates oligodendrocytes and specific neurons, determines motor neuron and oligodendrocyte differentiation, and sustains replication in early development. Recent studies have demonstrated that OLIG2 gene is associated with mental disorders, such as schizophrenia, mood disorder, and obsessive-compulsive disorder (OCD). The aim of the present study was to explore whether OLIG2 gene is associated with OCD in a Chinese Han population through the assessment and analysis of three single nucleotide polymorphisms (SNPs), namely, rs762178, rs1059004, and rs9653711, selected from OLIG2 gene sequences from 400 OCD samples and 459 healthy controls in a case-controlled association study. We demonstrated three principal results. First, SNP rs762178 was associated with OCD, female OCD, and early-onset OCD; rs1059004 was associated with OCD and early-onset OCD; and rs9653711 was also associated with OCD and early-onset OCD. Second, the pairs of loci rs762178 and rs1059004, rs1059004 and rs9653711, and rs762178 and rs9653711 exhibited linkage disequilibrium. Third, the three-locus A-C-G haplotype was associated with early-onset OCD. The present study is the first to verify the associations of SNPs rs762178, rs1059004, and rs9653711 of the OLIG2 gene with OCD in a Chinese Han population. Thus, OLIG2 might serve as a potential target for OCD treatment in future studies. Further studies should verify the current findings.

Genetic analysis of Cheirostylis species based on microsatellite markers

Microsatellite markers specific to Cheirostylis yunnanensis Rolfe were developed using an enriched genomic DNA library technique. The library was constructed using (AG)20 and (CAG)20 oligonucleotide repeats. A total of 48 primer pairs were designed and tested with 48 C. yunnanensis Rolfe samples, resulting in 11 polymorphic loci. The number of alleles per locus ranged from 2 to 12, with an average of six alleles. The observed and expected heterozygosity ranged from 0.0426 to 0.8085 and 0.0421 to 0.9078, respectively. Of the 11 polymorphic loci, three showed a significant deviation from Hardy–Weinberg equilibrium and one exhibited linkage disequilibrium. Cross-species amplification was tested with five samples of Cheirostylis of unknown species resulting in eight loci that could be amplified, with the number of alleles ranging from one to two. The microsatellite markers developed in this study will be useful for the genetic analysis of C. yunnanensis in order to differentiate species as well as to establish a conservation plan for this species.

Development and characterization of microsatellite loci in the sub-canopy tree Chengiopanax sciadophylloides (Araliaceae) using next-generation sequencing technology

Chengiopanax sciadophylloides is a deciduous broad-leaved sub-canopy tree species that is endemic to Japan and widely distributed in its temperate forests. Recent analyses indicate that climate change will reduce its distributional range and cause habitat fragmentation, leading to a loss of genetic variation. Here we describe the development of 15 microsatellite markers for this species using next-generation sequencing techniques. A total of 44 individuals from two populations were genotyped at each marker. The number of alleles per locus ranged from two to 13 with a mean of 4.8, and the expected heterozygosity ranged from 0.215 to 0.895 with a mean of 0.560. None of the loci exhibited linkage disequilibrium or any deviation from Hardy–Weinberg equilibrium. Because these 15 microsatellite markers exhibit high degrees of genetic variation, they should be useful tools for studying the conservation genetics of C. sciadophylloides.

Selection pressures have driven population differentiation of domesticated and wild common carp (Cyprinus carpio L.)

Selection pressures are the principle evolutionary forces for the genetic differentiation of populations. Recent changes in selection pressures on mitochondrial DNA and microsatellite have been described in a wide variety of organisms. The common carp (Cyprinus carpio) has experienced strong selection pressure, in particular artificial selection, during its domestication. However, the contribution and extent of artificial selection in driving genome-wide population differentiation remain unclear. We investigated the genetic differentiation of 4 domesticated strains (Xingguo red common carp, Glass red common carp, Purse red common carp, and Jian common carp, which have been generated by artificial selection since 1970s) and 2 wild populations (Shishou section in Hubei and Yangzhou section in Jiangsu of the Yangtze River) of common carp in China by sequencing the mitochondrial DNA D-loop and by genotyping 10 microsatellite loci. It was found that the domesticated strains exhibited linkage disequilibrium within the population and less genetic variability, higher inbreeding coefficients (F(IS) = 0.101 vs 0.038), and higher genetic differentiation (F(ST) = 0.087 vs 0.001) than the wild populations, which indicates strong selection pressures in the process of domestication. Of the 10 loci, 5 appeared to be under positive directional selection in the domesticated strains, and all 10 loci in wild populations were potentially under balancing selection. We conclude that strong selection pressures, artificial selection in particular, have caused genetic differentiation between populations of domesticated and wild common carp.

New tetranucleotide microsatellite loci in pink abalone (Haliotis corrugata) isolated via 454 pyrosequencing

Microsatellite loci were developed for the pink abalone (Haliotis corrugata) via 454 high-throughput sequencing. From 193 tetranucleotide repeats identified from 77.5 Mb of sequence, we tested 80 loci and successfully amplified and scored 18 microsatellite markers. All loci were polymorphic with number of alleles ranging from 5 to 21. Average observed and expected heterozygosities were 0.745 and 0.844, respectively. Three loci deviated from Hardy–Weinberg equilibrium, two of which had significant deficits of heterozygotes and only one displayed statistical evidence of a null allele. None of the loci exhibited linkage disequilibrium. These loci are a valuable asset for fine-scale population genetic and paternity studies centered on the conservation and management of pink abalone.

Pathogenic copy number variants (pCNVs) in individuals diagnosed on the autism spectrum disorder (ASD): A closer look at candidate genes

&#x0D; &#x0D; &#x0D; Introduction: The genetic basis for autism spectrum disorders (Asds) is well established and its heterogenetic nature provides us with substantial evidence for the many chromosomal aberrations associated with this complex disorder (5). however, little is known about the genes that occupy the different chromosomal regions and the gene networks they participate in as they relate to phenotypes associated with Asds. Methods: here, the author reports pathogenic copy number variants (pcnVs) validated through array-comparative genomic hybridization (cgh) and the candidate genes found on these affected regions that may be implicated in the observed clinical phenotypes in 9 patients diagnosed with an Asd. formal clinical assessments, which include a full physical examination, a medical history report, and a family history, were administered by a clinical geneticist unaware of the array-cgh results. results: The author’s findings suggest a number of genes involved in neurodevelopment as well as craniofacial and systemic features that may account for the observed phenotypes in the nine affected patients. discussion: Among the candidate genes found, the CYFIP1 gene, which is involved in maturation and maintenance of dendrites, the gamma acid receptor family (GABA) which exhibit linkage disequilibrium with autistic disorders, and the PHF8 and WNK3 genes, which have been shown to be associated with X-linked mental retardation (XlMr), present the most interesting findings as they may account for most of the neurodevelopmental pathogenesis observed in the affected patients. future studies need to be conducted in order to precisely determine the networks these genes participate in and how they are regulated to gain a deeper understanding in the roles they play in the clinical presentations of affected individuals with Asds.&#x0D; &#x0D; &#x0D;

RUNX2 Polymorphisms Associated with OPLL and OLF in the Han Population

Runt-related transcription factor 2 (RUNX2), BMP-2, COL6A1, and VDR are four genes that may be related to ossification of the spinal ligament. However, their pathogenetic relevance remains unclear. Most cases of ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) have been reported in Asian populations, but the polymorphic loci in these genes may vary among people of different races. We identified (1) polymorphic loci in four genes (RUNX2, BMP-2, COL6A1, and VDR) in OPLL and OLF in Chinese Han patients and (2) identified loci related to these diseases. We analyzed 19 single nucleotide polymorphisms (SNPs) in four candidate genes in 200 Han individuals (82 patients and 118 control subjects) by the Sequenom system. The genotype distribution and allele frequency of each SNP in the control and patient groups were compared. We then determined the relationships between the loci and the occurrence of OPLL and OLF. Genotyping showed RS1321075 and RS12333172 in RUNX2 differed between the patients and the control subjects. Both loci were located on chromosome 6 and exhibited linkage disequilibrium. One of the two blocks was a haplotype, thus suggesting a link between this block and increased incidence of OPLL and OLF. Although the detailed mechanism of the SNP is unclear, our data suggest RUNX2 could be responsible for ectopic bone formation in the spinal ligament in the Chinese Han population. However, we found no obvious connection between polymorphic loci of COLA1, BMP-2, and VDR and the diseases. Molecular genetic studies have identified several candidate genes that may be responsible for increased susceptibility to the diseases. Information regarding SNPs among the certain candidate genes may improve understanding of the disease and assist in developing new diagnostic gene tools during early episodes of the disease.

Isolation and characterization of microsatellite loci for mountain mullet (Agonostomus monticola)

We report on the isolation of 15 polymorphic microsatellite loci from mountain mullet (Agonostomus monticola). In the two populations sampled, loci exhibited two to 21 alleles and observed heterozygosity values ranged from 0.222 to 1.000. All loci conformed to Hardy-Weinberg equilibrium expectations, and none exhibited linkage disequilibrium. Although A. monticola is an important subsistence fishery in parts of its range, little is known about its ecology and many populations appear to be experiencing declines. These microsatellite loci should prove useful in the study of population structure of A. monticola and aid in other potential conservation efforts such as the management of hatchery broodstock.

Isolation and characterization of microsatellite loci for alligator gar (Atractosteus spatula) and their variability in two other species (Lepisosteus oculatus and L. osseus) of Lepisosteidae

We report on the isolation of 17 polymorphic microsatellite loci from alligator gar (Atractosteus spatula), a large-bodied species that has experienced population declines across much of its range. These loci possessed 2-19 alleles and observed heterozygosities of 0-0.974. All loci conformed to Hardy-Weinberg equilibrium expectations, and none exhibited linkage disequilibrium. Nine and eight of these loci were found to be polymorphic in the related species Lepisosteus oculatus and L. osseus, respectively. These microsatellite loci should prove useful in conservation efforts of A. spatula through the study of population structure and hatchery broodstock management.

Microsatellite loci isolated from the tropical tree Hymenaea courbaril L. (Fabaceae)

We developed 11 microsatellite markers for Hymenaea courbaril for the purpose of studying spatial genetic structure and gene flow. The microsatellite loci were screened in 44 trees from two populations. All loci were polymorphic, exhibiting between two and 16 alleles, and levels of expected heterozygosity from 0.174 to 0.909. Departures from Hardy-Weinberg equilibrium were detected for all loci in one population. The estimated null allele frequency is low or moderate. No locus combinations exhibited linkage disequilibrium.

Development of highly polymorphic tetranucleotide microsatellite markers in Austrocedrus chilensis

An enriched genomic library was constructed and 9 novel polymorphic tetranucleotide microsatellite markers developed for Austrocedrus chilensis, the most economically important native conifer in the Andean Patagonian region. Polymorphism was investigated for these markers in 48 individuals from two populations. Numbers of alleles ranged from 3 to 19 and levels of observed heterozygosity among the 9 loci ranged from 0.32 to 0.95. No locus combinations exhibited linkage disequilibrium. These polymorphic markers will be useful tools for the study of demography and gene flow and more in general for population and conservation genetics of this species.

Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

BackgroundThe TP53 polymorphisms Arg72Pro (Ex4+199 G>C) and Ins16 (IVS3+24 ins16) have been proposed to modify risk of breast cancer associated with germline BRCA1 and BRCA2 mutations. Allele frequencies of these polymorphisms were investigated to determine if they modify risk in BRCA mutation carriers in breast cancer cases drawn from French Canadian cancer families, a population shown to exhibit strong founder effects.MethodsThe frequencies of the TP53 alleles, genotypes and haplotypes of 157 index breast cancer cases comprised of 42 BRCA1 mutation carriers, 57 BRCA2 mutation carriers, and 58 BRCA mutation-negative cases, where each case was drawn from independently ascertained families were compared. The effect of TP53 variants on the age of diagnosis was also investigated for these groups. The TP53 polymorphisms were also investigated in 112 women of French Canadian descent with no personal history of cancer.ResultsThe BRCA mutation-positive groups had the highest frequency of homozygous carriers of the 72Pro allele compared with mutation-negative group. The TP53 polymorphisms exhibited linkage disequilibrium (p < 0.001), where the 72Arg and Ins16minus alleles occurred in strong disequilibrium. The highest frequency of carriers of Ins16minus-72Arg haplotype occurred in the BRCA mutation-negative groups. The BRCA1 mutation carriers homozygous for the 72Pro allele had the youngest ages of diagnosis of breast cancer. However none of these observations were statistically significant. In contrast, the BRCA2 mutation carriers homozygous for the 72Pro allele had a significantly older age of diagnosis of breast cancer (p = 0.018). Moreover, in this group, the mean age of diagnosis of breast cancer in carriers of the Ins16minus-72Arg haplotype was significantly younger than that of the individuals who did not this carry this haplotype (p = 0.009).ConclusionWe observed no significant association of breast cancer risk with TP53 genetic variants based on BRCA1/2 mutation carrier status. Although the small sample size did not permit analysis of all possible haplotypes, we observed that BRCA2 mutation carriers harboring the Ins16minus-72Arg haplotype had a significantly younger mean age of diagnosis of breast cancer. These observations suggest that investigations in a larger French Canadian sample are warranted to further elucidate the effects of TP53 variants on age of diagnosis of breast cancer among BRCA1 and BRCA2 mutation carriers.

A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms

Multiple testing is a challenging issue in genetic association studies using large numbers of single nucleotide polymorphism (SNP) markers, many of which exhibit linkage disequilibrium (LD). Failure to adjust for multiple testing appropriately may produce excessive false positives or overlook true positive signals. The Bonferroni method of adjusting for multiple comparisons is easy to compute, but is well known to be conservative in the presence of LD. On the other hand, permutation-based corrections can correctly account for LD among SNPs, but are computationally intensive. In this work, we propose a new multiple testing correction method for association studies using SNP markers. We show that it is simple, fast and more accurate than the recently developed methods and is comparable to permutation-based corrections using both simulated and real data. We also demonstrate how it might be used in whole-genome association studies to control type I error. The efficiency and accuracy of the proposed method make it an attractive choice for multiple testing adjustment when there is high intermarker LD in the SNP data set.

Isolation and characterisation of microsatellite loci in the papillose woolly bat, Kerivoula papillosa (Chiroptera: Vespertilionidae)

The papillose woolly bat (Kerivoula papillosa) is one of the most well known species of an understudied bat genus that may be particularly vulnerable to disturbance and fragmentation events. We describe 22 novel microsa tellite loci, 17 of which are polymorphic in K. papillosa, and one of which is polymorphic in a related species K. pellucida. When tested in a single population, none of the markers significantly deviated from Hardy-Weinberg expectations, showed the presence of null alleles or exhibited linkage disequilibrium. These markers will be useful in determining impacts of forest fragmentation on this species.