Genome-wide Single Nucleotide Polymorphism Genotyping Research Articles

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.

Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer. A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death. Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancer‒specific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancer‒specific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancer‒specific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001). Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancer‒specific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.

Traditional multilocus phylogeny fails to fully resolve Palearctic ground squirrels (Spermophilus) relationships but reveals a new species endemic to West Siberia

Previous efforts to reconstruct evolutionary history of Palearctic ground squirrels within the genus Spermophilus have primarily relied on a single mitochondrial marker for phylogenetic data. In this study, we present the first phylogeny with comprehensive taxon sampling of Spermophilus via a conventional multilocus approach utilizing five mitochondrial and five nuclear markers. Through application of the multispecies coalescent model, we constructed a species tree revealing four distinct clades that diverged during the Late Miocene. These clades are 1) S. alaschanicus and S. dauricus from East Asia; 2) S. musicus and S. pygmaeus from East Europe and northwestern Central Asia; 3) the subgenus Colobotis found across Central Asia and its adjacent regions and encompassing S. brevicauda, S. erythrogenys, S. fulvus, S. major, S. pallidicauda, S. ralli, S. relictus, S. selevini, and S. vorontsovi sp. nov.; and 4) a Central/Eastern Europe and Asia Minor clade comprising S. citellus, S. taurensis, S. xanthoprymnus, S. suslicus, and S. odessanus. The latter clade lacked strong support owing to uncertainty of taxonomic placement of S. odessanus and S. suslicus. Resolving relationships within the subgenus Colobotis, which radiated rapidly, remains challenging likely because of incomplete lineage sorting and introgressive hybridization. Most of modern Spermophilus species diversified during the Early–Middle Pleistocene (2.2–1.0 million years ago). We propose a revised taxonomic classification for the genus Spermophilus by recognizing 18 species including a newly identified one (S. vorontsovi sp. nov.), which is found only in a limited area in the southeast of West Siberia. Employing genome-wide single-nucleotide polymorphism genotyping, we substantiated the role of the Ob River as a major barrier ensuring robust isolation of this taxon from S. erythrogenys. Despite its inherent limitations, the traditional multilocus approach remains a valuable tool for resolving relationships and can provide important insights into otherwise poorly understood groups. It is imperative to recognize that additional efforts are needed to definitively determine phylogenetic relationships between certain species of Palearctic ground squirrels.

Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals

BackgroundPlatelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown. ObjectivesWe aimed to investigate the nongenetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania. MethodsPlatelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analyzed the associations of platelet parameters with host genetic and nongenetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites. ResultsOnly a few associations were found between platelet reactivity parameters and plasma inflammatory markers and nongenetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism genotyping identified 2 novel single-nucleotide polymorphisms (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P < 5 × 10−8) as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity. ConclusionOur study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.

O-226 Is there a place for polygenic risk scoring in PGT (PGT-P)?

Abstract Preimplantation genetic testing (PGT), by embryo biopsy and genetic testing for inherited diseases and chromosome abnormalities following IVF, is now well established world-wide. PGT for monogenic conditions (PGT-M) is generally performed for childhood-onset, lethal disorders, but is increasingly accepted for certain adult-onset conditions, conditions with available treatment options or conditions with lower penetrance. Over recent years, machine learning methods applied to large genomic datasets, including genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) genotyping, has enabled polygenic risk scores (PRSs) to be calculated to identify individuals who are at elevated risk for a broad range of conditions including important common multifactorial diseases, such as coronary artery disease (CAD), diabetes, hypertension and various cancers. It is now possible to perform genome-wide SNP genotyping of embryo biopsy samples with the same accuracy as adult genomic DNA and the first live birth following PGT for polygenic risk scoring (PGT-P) was reported in 2019 (Treff et al (2019) Front Endocrinol 10, 845) . The clinical application of PGT-P is controversial and raises many practical, ethical and societal issues. To examine the question ‘is there a place for PRS in PGT’, the example of predisposition to breast cancer will be reviewed.

Genome-wide variant analyses reveal new patterns of admixture and population structure in Australian dingoes.

Admixture between species is a cause for concern in wildlife management. Canids are particularly vulnerable to interspecific hybridisation, and genetic admixture has shaped their evolutionary history. Microsatellite DNA testing, relying on a small number of genetic markers and geographically restricted reference populations, has identified extensive domestic dog admixture in Australian dingoes and driven conservation management policy. But there exists a concern that geographic variation in dingo genotypes could confound ancestry analyses that use a small number of genetic markers. Here, we apply genome-wide single-nucleotide polymorphism (SNP) genotyping to a set of 402 wild and captive dingoes collected from across Australia and then carry out comparisons to domestic dogs. We then perform ancestry modelling and biogeographic analyses to characterise population structure in dingoes and investigate the extent of admixture between dingoes and dogs in different regions of the continent. We show that there are at least five distinct dingo populations across Australia. We observed limited evidence of dog admixture in wild dingoes. Our work challenges previous reports regarding the occurrence and extent of dog admixture in dingoes, as our ancestry analyses show that previous assessments severely overestimate the degree of domestic dog admixture in dingo populations, particularly in south-eastern Australia. These findings strongly support the use of genome-wide SNP genotyping as a refined method for wildlife managers and policymakers to assess and inform dingo management policy and legislation moving forwards.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Genome-wide diversity analysis suggests divergence among Upper Guinea and the Dahomey Gap populations of the Sisrè berry (Syn: miracle fruit) plant (Synsepalum dulcificum [Schumach. & Thonn.] Daniell) in West Africa.

Although Synsepalum dulcificum is viewed as one of the most economically promising orphan tree crops worldwide, its genetic improvement and sustainable conservation are hindered by a lack of understanding of its evolutionary history and current population structure. Here, we report for the first time the application of genome-wide single nucleotide polymorphism genotyping to a diverse panel of S. dulcificum accessions to depict the genetic diversity and population structure of the species in the Dahomey Gap (DG) and Upper Guinea (UG) regions to infer its evolutionary history. Our findings suggest low overall genetic diversity but strong population divergence within the species. Neighbor-joining analysis detected two genetic groups in the UG and DG regions, while STRUCTURE distinguished three genetic groups, corresponding to the UG, Western DG, and Central DG regions. Application of Monmonier's algorithm revealed the existence of a barrier disrupting connectivity between the UG and DG groups. The Western DG group consistently exhibited the highest levels of nucleotide and haplotype diversities, while that of the Central DG exhibited the lowest. Analyses of Tajima's D, Fu's Fs, and Achaz Y* statistics suggest that while both UG and Central DG groups likely experienced recent expansions, the Western DG group is at equilibrium. These findings suggest a geographical structuring of genetic variation which supports the conclusion of differential evolutionary histories among West African groups of S. dulcificum. These results provide foundational insights to guide informed breeding population development and design sustainable conservation strategies for this species.

Genome-wide search reveals the uniqueness of DNA regions associated with coat color and innate immunity in Hokkaido Native Horse.

Hokkaido Native Horse (HKD) is a horse breed native to Hokkaido in Japan known for the traits such as coat color with no white spots and adaptability to the local cold climate. To examine whether those traits of HKD are conferred at the DNA level, we attempted to identify fixed DNA regions in HKD individuals, that is, the selection signatures of HKD. A comparison of genome-wide single nucleotide polymorphism genotypes in 58 HKD individuals by principal component analysis, and cluster analysis between breeds, including HKD, and within the HKD individuals indicated the genetic independence of HKD as a breed. Tajima's D analysis and runs of homozygosity analysis identified 23 selection signatures unique to HKD (P < 0.05), and following database search found 20 traits that were associated with those selection signatures; among these traits, coat color traits, face and body markings, showed the highest important value (0.50 and 0.46). Enrichment analysis of genes in the selection signatures identified six gene ontology terms (P < 0.05), and a term related to innate immunity (regulation of defense response; GO:0031347) showed the highest positive fold enrichment value (7.13). These results provide the first scientific evidence of a genetic basis for the traits of HKD.

Genome-Wide Associative Study of Phenotypic Parameters of the 3D Body Model of Aberdeen Angus Cattle with Multiple Depth Cameras.

Simple SummaryThis article aims to develop a new approach to the lifetime evaluation of cattle by 3-D visualization of economic-biological and genetic features. The following indicators were selected as phenotypic features: chest width and chest girth retrieved by 3-D model and meat output on the bones. Correlation analysis showed a reliable positive relationship between chest width and meat output on the bones, which can potentially be used for lifetime evaluation of meat productivity of animals. Genome-wide associations analysis revealed the following potential loci of quantitative traits on cattle chromosomes for chest width, chest girth, and meat output on bones.In beef cattle breeding, genome-wide association studies (GWAS) using single nucleotide polymorphisms (SNPs) arrays can reveal many loci of various production traits, such as growth, productivity, and meat quality. With the development of genome sequencing technologies, new opportunities are opening up for more accurate identification of areas associated with these traits. This article aims to develop a novel approach to the lifetime evaluation of cattle by 3-D visualization of economic-biological and genetic features. The purpose of this study was to identify significant variants underlying differences in the qualitative characteristics of meat, using imputed data on the sequence of the entire genome. Samples of biomaterial of young Aberdeen-Angus breed cattle (n = 96) were the material for carrying out genome-wide SNP genotyping. Genotyping was performed using a high-density DNA chip Bovine GPU HD BeadChip (Illumina Inc., San Diego, CA, USA), containing ~150 thousand SNPs. The following indicators were selected as phenotypic features: chest width and chest girth retrieved by 3-D model and meat output on the bones. Correlation analysis showed a reliable positive relationship between chest width and meat output on the bones, which can potentially be used for lifetime evaluation of meat productivity of animals.

Clinical application of genome-wide single nucleotide polymorphism genotyping and karyomapping for preimplantation genetic testing of Charcot–Marie–Tooth disease

Clinical application of genome-wide single nucleotide polymorphism genotyping and karyomapping for preimplantation genetic testing of Charcot–Marie–Tooth disease

MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER Florian Rumpf, Anna Plym, Jane Vaselkiv, Mark Preston, Adam Kibel, Lorelei Mucci, and Keyan Salari Florian RumpfFlorian Rumpf More articles by this author , Anna PlymAnna Plym More articles by this author , Jane VaselkivJane Vaselkiv More articles by this author , Mark PrestonMark Preston More articles by this author , Adam KibelAdam Kibel More articles by this author , Lorelei MucciLorelei Mucci More articles by this author , and Keyan SalariKeyan Salari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002609.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A family history of prostate cancer (PCa) and BRCA/DNA repair gene-associated cancers are risk factors for developing prostate cancer. In the last decade, >260 PCa-associated single nucleotide polymorphisms (SNPs) have been identified through large-scale genome-wide association studies that strongly stratify lifetime risk of prostate cancer. Few studies have examined the prognostic value of family history or PCa germline risk variants in patients with favorable-risk PCa eligible for active surveillance (AS). Here, we evaluate the impact of a positive family history and germline risk SNPs on outcomes on AS-eligible patients. METHODS: In a prospective cohort of 39,427 U.S. men in the Health Professionals Follow-up Study, 1,367 were diagnosed with clinically favorable-risk (NCCN very low-, low-, or favorable intermediate-risk) PCa from 1986 to 2016 and underwent genome-wide SNP genotyping. During the 30-year follow-up, 263 patients experienced disease recurrence and 52 patients died of PCa. A polygenic risk score was derived from 269 SNPs associated with development of PCa. Two loci associated with PCa survival were also assessed. Multivariable Cox proportional hazards models were used to estimate the association between family history of prostate, breast, or pancreatic cancer, germline risk SNPs, and PCa recurrence or death through 2019. RESULTS: The median follow up time from diagnosis was 14.1 years. A family history of prostate, breast, or pancreatic cancer was observed in 494 (36%) patients. Men with a positive family history had an 83% greater risk of PCa-specific death (95% CI 1.06-3.17, p=0.03), and greater than that of men with a family history of PCa alone. The polygenic risk score was not associated with either PCa recurrence or death. However, focusing on 2 loci on 8q24 and 19q13 with the strongest evidence in the literature for association with PCa aggressiveness, we observed a significant association between rs2735839 on 19q13 and PCa-specific death (HR 1.81, 95% CI 1.04-3.17, p=0.037). Using a risk score giving one point each to a positive family history and rs2735839 risk allele, each point of the heritable risk score was associated with a 72% increased risk of PCa-specific death (95% CI 1.16-2.54, p=0.006). CONCLUSIONS: Our study found that patients with AS-eligible PCa with a family history of prostate, breast, or pancreatic cancer or a 19q13 germline risk allele had elevated risks of PCa-specific death. These findings have implications for how germline genetic risk should be factored into AS selection criteria. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e744 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florian Rumpf More articles by this author Anna Plym More articles by this author Jane Vaselkiv More articles by this author Mark Preston More articles by this author Adam Kibel More articles by this author Lorelei Mucci More articles by this author Keyan Salari More articles by this author Expand All Advertisement PDF DownloadLoading ...

Targeted genome-wide SNP genotyping in feral horses using non-invasive fecal swabs

The development of high-throughput sequencing has prompted a transition in wildlife genetics from using microsatellites toward sets of single nucleotide polymorphisms (SNPs). However, genotyping large numbers of targeted SNPs using non-invasive samples remains challenging due to relatively large DNA input requirements. Recently, target enrichment has emerged as a promising approach requiring little template DNA. We assessed the efficacy of Tecan Genomics’ Allegro Targeted Genotyping (ATG) for generating genome-wide SNP data in feral horses using DNA isolated from fecal swabs. Total and host-specific DNA were quantified for 989 samples collected as part of a long-term individual-based study of feral horses on Sable Island, Nova Scotia, Canada, using dsDNA fluorescence and a host-specific qPCR assay, respectively. Forty-eight samples representing 44 individuals containing at least 10 ng of host DNA (ATG’s recommended minimum input) were genotyped using a custom multiplex panel targeting 279 SNPs. Genotyping accuracy and consistency were assessed by contrasting ATG genotypes with those obtained from the same individuals with SNP microarrays, and from multiple samples from the same horse, respectively. 62% of swabs yielded the minimum recommended amount of host DNA for ATG. Ignoring samples that failed to amplify, ATG recovered an average of 88.8% targeted sites per sample, while genotype concordance between ATG and SNP microarrays was 98.5%. The repeatability of genotypes from the same individual approached unity with an average of 99.9%. This study demonstrates the suitability of ATG for genome-wide, non-invasive targeted SNP genotyping, and will facilitate further ecological and conservation genetics research in equids and related species.

Non-invasive DNA collection for parentage analysis for bivalves: A case study from the silver-lipped pearl oyster (Pinctada maxima)

Due to the high revenues generated by the pearl industry, interest in developing breeding programs is increasing. The traditional approach for collecting DNA for pedigree analyses in breeding programs for the silver-lipped pearl oyster (Pinctada maxima) involves tissue excision from the muscular foot and/or mantle. Tissue excision causes injury and stress to the animal, and can lead to reduced growth efficiency, bacterial infection and subsequent mortality when oysters are returned to the non-sterile marine environment. The approach of swabbing tissue to collect cells for DNA analyses offers a potential non-invasive and rapid method but has not been reported previously for pearl oysters; particularly where DNA is destined for a high-throughput genotype-by-sequencing (GBS) single nucleotide polymorphism (SNP) genotyping platform. To evaluate the potential of swabbing as a method to collect DNA for downstream GBS SNP genotyping under commercial farming conditions, 29 broodstock pearl oysters were swabbed with two different swab brushes (a stiff and soft brush). Concentration of the extracted DNA from swabs was found to meet requirements for genotyping (44 to 59 ng/μL) and 260/280 ratios were in the acceptable range for DNA purity (1.9–2.2). SNP genotype calls derived from swab samples were highly correlated with those derived from tissue excised from the same oyster (mean of 0.97 ± 0.04 for soft bristle – mean of 0.98 ± 0.02 for stiff bristle). Finally, we evaluated the performance of swabbing under a commercial breeding program scenario, whereby 923 spat were genotyped and 18 months later 1927 pearl oysters from the same commercial cohort were swabbed to determine parental contributions for the cohort at the two time periods. Results demonstrated that the swab method is reliable for collecting sufficient quantity and quality of DNA for genome-wide SNP genotyping enabling accurate pedigree reconstruction. This study validated the efficiency of the use of the swab technique to collect DNA for routine parentage assignment, while limiting the adverse effects of destructive tissue sampling for commercial use and/or for the development of breeding programs.

Kinship genomics approach to study mating systems in a depleted sea turtle rookery

Knowledge of demographic processes and life history strategies is necessary for the conservation and management of endangered sea turtle populations, but it is difficult to ascertain because of the limited accessibility to marine environments that sea turtles use during the different stages of their life cycle. In such cases, molecular genetics and genomic approaches are useful to assess mating systems and operational sex ratios (OSR), which ultimately influence demography. This pilot study used genome-wide single nucleotide polymorphism (SNP) genetic markers for exploring kinship and mating systems in sea turtles where major obstacles prevent a comprehensive assessment in the wild. We sampled 217 young hawksbill turtles (Eretmochelys imbricata) of unknown parentage that had originally been collected locally from seven nests and were being temporarily kept in captivity by Treasure Island Ltd as part of its captive rearing conservation project at Bounty and Treasure Islands, Fiji, in the South Pacific. The raw dataset comprised 13,573 SNPs, of which we retained 639 SNPs for parentage and relatedness analyses. Our findings from seven different pairs of parents suggest a 1:1 male:female OSR and demonstrate that genome-wide SNP genotyping approaches can be used to infer OSR. Knowledge of OSR can help evaluate the magnitude of the impact of warming temperatures and consequent feminisation in sea turtles. Our approach can complement or substitute field observation of breeding males and nesting females when logistical or budgetary constraints prevent observation of OSR in wild sea turtle populations. This approach allows inference of OSR. Protection of beaches with a higher number of pairs of parents should be prioritised to increase genetic resilience. Conservation actions in rookeries with a female-skewed OSR should be prioritised to address population declines in the long run.

Genetic inference of the mating system of free-ranging domestic dogs.

Domestication has greatly changed the social and reproductive behavior of dogs relative to that of wild members of the genus Canis, which typically exhibit social monogamy and extended parental care. Unlike a typical gray wolf pack that consists of a single breeding pair and their offspring from multiple seasons, a group of free-ranging dogs (FRDs) can include multiple breeding individuals of both sexes. To understand the consequences of this shift in reproductive behavior, we reconstructed the genetic pedigree of an FRD population and assessed the kinship patterns in social groups, based on genome-wide single-nucleotide polymorphism genotypes. Consistent with behavioral observations, the mating system of the study population was characterized by polygynandry. Instead of the discreet family units observed in wolves, FRDs were linked by a network of kinship relationships that spread across packs. However, we also observed reproduction of the same male–female pairs in multiple seasons, retention of adult offspring in natal packs, and dispersal between neighboring packs—patterns in common with wolves. Although monogamy is the predominant mating system in wolves, polygyny and polyandry are occasionally observed in response to increased food availability. Thus, polygynandry of domestic dogs was likely influenced by the shift in ecological niche from an apex predator to a human commensal.

Understanding the genetic architecture of the metabolically unhealthy normal weight and metabolically healthy obese phenotypes in a Korean population

Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. Here, we conducted genome-wide association studies (GWASs) to identify the MUHNW and MHO genetic indices. The study dataset comprised genome-wide single-nucleotide polymorphism genotypes and epidemiological data from 49,915 subjects categorised into four phenotypes—metabolically healthy normal weight (MHNW), MUHNW, MHO, and metabolically unhealthy obese (MUHO). We conducted two GWASs using logistic regression analyses and adjustments for confounding variables (model 1: MHNW versus MUHNW and model 2: MHO versus MUHO). GCKR, ABCB11, CDKAL1, LPL, CDKN2B, NT5C2, APOA5, CETP, and APOC1 were associated with metabolically unhealthy phenotypes among normal weight individuals (model 1). LPL, APOA5, and CETP were associated with metabolically unhealthy phenotypes among obese individuals (model 2). The genes common to both models are related to lipid metabolism (LPL, APOA5, and CETP), and those associated with model 1 are related to insulin or glucose metabolism (GCKR, CDKAL1, and CDKN2B). This study reveals the genetic architecture of the MUHNW and MHO phenotypes in a Korean population-based cohort. These findings could help identify individuals at a high metabolic risk in normal weight and obese populations and provide potential novel targets for the management of metabolically unhealthy phenotypes.

The number of SNPs required for distinguishing Japanese from other East Asians.

In some cases, it is necessary to estimate the national origin of an unknown subject in forensic medicine. The use of single nucleotide polymorphism (SNP) markers appears to be very effective for this purpose, since genome-wide SNP genotype data of many human populations are publicly available. In this study, we examined the number of SNPs that could objectively and accurately distinguish Japanese subjects (1KG-JPT) from the other East Asians (1KG-CDX, -CHB, -CHS, and -KHV) using the combination of principal component analysis and hierarchical cluster analysis. A computer simulation showed that approximately 3000 randomly selected SNPs were enough for the discrimination. Our results suggest that at least a 0.024% coverage is needed in the next generation sequencing experiment to objectively determine whether an unknown person is Japanese or not if the amount of DNA sample from him/her is insufficient or the quality is low.

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci.

Background & AimsThe association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource.MethodsWe collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses.ResultsWe provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application.ConclusionsWe provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.

Common Susceptibility Loci for Male Breast Cancer.

BackgroundThe etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10–06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.ResultsThe genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10–08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10–30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Forensic validation of a panel of 12 SNPs for identification of Mongolian wolf and dog

Wolf (Canis lupus) is a species included in appendices of CITES and is often encountered in cases of alleged poaching and trafficking of their products. When such crimes are suspected, those involved may attempt to evade legal action by claiming that the animals involved are domestic dogs (C. l. familiaris). To respond effectively to such claims, law enforcement agencies require reliable and robust methods to distinguish wolves from dogs. Reported molecular genetic methods are either unreliable (mitogenome sequence based), or operationally cumbersome and require much DNA (un-multiplexed microsatellites), or financially expensive (genome wide SNP genotyping). We report on the validation of a panel of 12 ancestral informative single nucleotide polymorphism (SNP) markers for discriminating wolves from dogs. A SNaPshot multiplex genotyping system was developed for the panel, and 97 Mongolian wolves (C. l. chanco) and 108 domestic dogs were used for validation. Results showed this panel had high genotyping success (0.991), reproducibility (1.00) and origin assignment accuracy (0.97 ± 0.05 for dogs and 1.00 ± 0.03 for wolves). Species-specificity testing suggested strong tolerance to DNA contamination across species, except for Canidae. The minimum DNA required for reliable genotyping was 6.25 pg/μl. The method and established gene frequency database are available to support identification of wolves and dogs by law enforcement agencies.