scholarly journals Evidence for stabilizing selection at pleiotropic loci for human complex traits

2017 ◽  
Author(s):  
Emily S Wong ◽  
Steve Chenoweth ◽  
Mark Blows ◽  
Joseph E Powell
Keyword(s):  
Complex Traits ◽  
Allelic Diversity ◽  
Complex Trait ◽  
Stabilizing Selection ◽  
Single Nucleotide ◽  
Risk Alleles ◽  
History Of ◽  
Genetic Constraint ◽  
Disease Risks ◽  
Disease Loci

AbstractHow genetic variation contributes to phenotypic variation is a central question in genetics. Association signals for a complex trait are found throughout the majority of the genome suggesting much of the genome is under some degree of genetic constraint. Here, we develop a intraspecific population genetics approach to define a measure of population structure for each single nucleotide polymorphism (SNP). Using this approach, we test for evidence of stabilizing selection at complex traits and pleiotropic loci arising from the evolutionary history of 47 complex traits and common diseases. Our approach allowed us to identify traits and regions under stabilizing selection towards both global and subpopulation optima. Strongest depletion of allelic diversity was found at disease loci, indicating stabilizing selection has acted on these phenotypes in all subpopulations. Pleiotropic loci predominantly displayed evidence of stabilizing selection, often contributed to multiple disease risks, and sometimes also affected non-disease traits such as height. Risk alleles at pleiotropic disease loci displayed a more consistent direction of effect than expected by chance suggesting that stabilizing selection acting on pleiotropic loci is amplified through multiple disease phenotypes.

Single Nucleotide Polymorphism and its Application in Mapping Loci Involved in Developing Human Diseases and Traits

2011 ◽  
pp. 113-127
Author(s):  
Rui-Ru Ji
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Complex Traits ◽  
Single Gene ◽  
Complex Trait ◽  
Human Diseases ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Systematic Analysis ◽  
Success Stories ◽  
Mapping Process

Common diseases or traits in humans are often influenced by complex interactions among multiple genes as well as environmental and lifestyle factors rather than being attributable to a genetic variation within a single gene. Identification of genes that confer disease susceptibility can be facilitated by studying DNA markers such as single nucleotide polymorphism (SNP) associated with a disease trait. Genome-wide association approaches offers a systematic analysis of the association of hundreds of thousands of SNPs with a quantitative complex trait. This method has been successfully applied to a wide variety of common human diseases and traits, and has generated valuable findings that have improved the understanding of the genetic basis of many complex traits. This chapter outlines the general mapping process and methods, highlights the success stories, and describes some limitations and challenges that lie ahead.

scholarly journals Risk Model for Colorectal Cancer in Spanish Population Using Environmental and Genetic Factors: Results from the MCC-Spain study

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Gemma Ibáñez-Sanz ◽  
Anna Díez-Villanueva ◽  
M. Henar Alonso ◽  
Francisco Rodríguez-Moranta ◽  
Beatriz Pérez-Gómez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Model ◽  
Vegetable Consumption ◽  
Environmental Data ◽  
Average Risk ◽  
Nucleotide Polymorphisms ◽  
Genetic Score ◽  
Single Nucleotide ◽  
Risk Alleles ◽  
History Of

Abstract Colorectal cancer (CRC) screening of the average risk population is only indicated according to age. We aim to elaborate a model to stratify the risk of CRC by incorporating environmental data and single nucleotide polymorphisms (SNP). The MCC-Spain case-control study included 1336 CRC cases and 2744 controls. Subjects were interviewed on lifestyle factors, family and medical history. Twenty-one CRC susceptibility SNPs were genotyped. The environmental risk model, which included alcohol consumption, obesity, physical activity, red meat and vegetable consumption, and nonsteroidal anti-inflammatory drug use, contributed to CRC with an average per factor OR of 1.36 (95% CI 1.27 to 1.45). Family history of CRC contributed an OR of 2.25 (95% CI 1.87 to 2.72), and each additional SNP contributed an OR of 1.07 (95% CI 1.04 to 1.10). The risk of subjects with more than 25 risk alleles (5th quintile) was 82% higher (OR 1.82, 95% CI 1.11 to 2.98) than subjects with less than 19 alleles (1st quintile). This risk model, with an AUROC curve of 0.63 (95% CI 0.60 to 0.66), could be useful to stratify individuals. Environmental factors had more weight than the genetic score, which should be considered to encourage patients to achieve a healthier lifestyle.

scholarly journals Social Network Analysis of the Genealogy of Strawberry: Retracing the Wild Roots of Heirloom and Modern Cultivars

2021 ◽  
Author(s):  
Dominique D A Pincot ◽  
Mirko Ledda ◽  
Mitchell J Feldmann ◽  
Michael A Hardigan ◽  
Thomas J Poorten ◽  
...  
Keyword(s):  
Overlapping Generations ◽  
Phenotypic Diversity ◽  
Allelic Diversity ◽  
Nucleotide Polymorphisms ◽  
Fragaria Ananassa ◽  
Single Nucleotide ◽  
Day Range ◽  
History Of ◽  
Cycle Lengths ◽  
Shed Light

Abstract The widely recounted story of the origin of cultivated strawberry (Fragaria × ananassa) oversimplifies the complex interspecific hybrid ancestry of the highly admixed populations from which heirloom and modern cultivars have emerged. To develop deeper insights into the three century long domestication history of strawberry, we reconstructed the genealogy as deeply as possible—pedigree records were assembled for 8,851 individuals, including 2,656 cultivars developed since 1775. The parents of individuals with unverified or missing pedigree records were accurately identified by applying exclusion analysis to array-genotyped single nucleotide polymorphisms. We identified 187 wild octoploid and 1,171 F. × ananassa founders in the genealogy, from the earliest hybrids to modern cultivars. The pedigree networks for cultivated strawberry are exceedingly complex labyrinths of ancestral interconnections formed by diverse hybrid ancestry, directional selection, migration, admixture, bottlenecks, overlapping generations, and recurrent hybridization with common ancestors that have unequally contributed allelic diversity to heirloom and modern cultivars. Fifteen to 333 ancestors were predicted to have transmitted 90% of the alleles found in country-, region-, and continent-specific populations. Using parent-offspring edges in the global pedigree network, we found that selection cycle lengths over the last 200 years of breeding have been extraordinarily long (16.0-16.9 years/generation) but decreased to a present-day range of 6.0-10.0 years/generation. Our analyses uncovered conspicuous differences in the ancestry and structure of North American and European populations and shed light on forces that have shaped phenotypic diversity in F. × ananassa.

scholarly journals Social Network Analysis of the Genealogy of Strawberry: Retracing the Wild Roots of Heirloom and Modern Cultivars

2020 ◽  
Author(s):  
Dominique D.A. Pincot ◽  
Mirko Ledda ◽  
Mitchell J. Feldmann ◽  
Michael A. Hardigan ◽  
Thomas J. Poorten ◽  
...  
Keyword(s):  
Overlapping Generations ◽  
Phenotypic Diversity ◽  
Allelic Diversity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Day Range ◽  
History Of ◽  
Cycle Lengths ◽  
Shed Light ◽  
European Populations

ABSTRACTThe widely recounted story of the origin of cultivated strawberry (Fragaria × ananassa) oversimplifies the complex interspecific hybrid ancestry of the highly admixed populations from which heirloom and modern cultivars have emerged. To develop deeper insights into the three century long domestication history of strawberry, we reconstructed the genealogy as deeply as possible—pedigree records were assembled for 8,851 individuals, including 2,656 cultivars developed since 1775. The parents of individuals with unverified or missing pedigree records were accurately identified by applying exclusion analysis to array-genotyped single nucleotide polymorphisms. We identified 187 wild octoploid and 1,171 F. × ananassa founders in the genealogy, from the earliest hybrids to modern cultivars. The pedigree networks for cultivated strawberry are exceedingly complex labyrinths of ancestral interconnections formed by diverse hybrid ancestry, directional selection, migration, admixture, bottlenecks, overlapping generations, and recurrent hybridization with common ancestors that have unequally contributed allelic diversity to heirloom and modern cultivars. Fifteen to 333 ancestors were predicted to have transmitted 90% of the alleles found in country-, region-, and continent-specific populations. Using parent-offspring edges in the global pedigree network, we found that selection cycle lengths over the last 200 years of breeding have been extraordinarily long (16.0-16.9 years/generation) but decreased to a present-day range of 6.0-10.0 years/generation. Our analyses uncovered conspicuous differences in the ancestry and structure of North American and European populations and shed light on forces that have shaped phenotypic diversity in F. × ananassa.

scholarly journals The overdue promise of short tandem repeat variation for heritability.

2014 ◽  
Author(s):  
Maximilian Press ◽  
Keisha D. Carlson ◽  
Christine Queitsch
Keyword(s):  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Complex Traits ◽  
Association Studies ◽  
Complex Trait ◽  
Model Organisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Repetitive Nature ◽  
Short Tandem

Short tandem repeat (STR) variation has been proposed as a major explanatory factor in the heritability of complex traits in humans and model organisms. However, we still struggle to incorporate STR variation into genotype-phenotype maps. Here, we review the promise of STRs in contributing to complex trait heritability, and highlight the challenges that STRs pose due to their repetitive nature. We argue that STR variants are more likely than single nucleotide variants to have epistatic interactions, reiterate the need for targeted assays to accurately genotype STRs, and call for more appropriate statistical methods in detecting STR-phenotype associations. Lastly, somatic STR variation within individuals may serve as a read-out of disease susceptibility, and is thus potentially a valuable covariate for future association studies.

Single Nucleotide Polymorphism and its Application in Mapping Loci Involved in Developing Human Diseases and Traits

2012 ◽  
Vol 3 (4) ◽  
pp. 61-75
Author(s):  
Rui-Ru Ji
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Complex Traits ◽  
Single Gene ◽  
Complex Trait ◽  
Human Diseases ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Systematic Analysis ◽  
Success Stories ◽  
Mapping Process

Common diseases or traits in humans are often influenced by complex interactions among multiple genes as well as environmental and lifestyle factors rather than being attributable to a genetic variation within a single gene. Identification of genes that confer disease susceptibility can be facilitated by studying DNA markers such as single nucleotide polymorphism (SNP) associated with a disease trait. Genome-wide association approaches offers a systematic analysis of the association of hundreds of thousands of SNPs with a quantitative complex trait. This method has been successfully applied to a wide variety of common human diseases and traits, and has generated valuable findings that have improved the understanding of the genetic basis of many complex traits. This article outlines the general mapping process and methods, highlights the success stories, and describes some limitations and challenges that lie ahead.

scholarly journals Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 808
Author(s):  
Laura Pérez-Lago ◽  
Teresa Aldámiz-Echevarría ◽  
Rita García-Martínez ◽  
Leire Pérez-Latorre ◽  
Marta Herranz ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Evolutionary Dynamics ◽  
Viral Evolution ◽  
Special Focus ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
New Variant ◽  
History Of ◽  
Evolution Dynamics ◽  
The Uk

A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma specimen, and was only observed in one bronchoaspirate specimen, although viral viability was still considered based on constant low Ct values throughout the disease and recovery of the virus in cell cultures. The acquired viral diversity in Cases A and B followed different dynamics. For Case A, new single nucleotide polymorphisms were quickly fixed (13–15 days) after emerging as minority variants, while for Case B, higher diversity was observed at a slower emergence: fixation pace (1–2 months). Slower SARS-CoV-2 evolutionary pace was observed for Case A following the administration of hyperimmune plasma. This work adds knowledge on SARS-CoV-2 prolonged shedding in severely immunocompromised patients and demonstrates viral viability, noteworthy acquired intra-patient diversity, and different SARS-CoV-2 evolutionary dynamics in persistent cases.

scholarly journals Leveraging Multiple Layers of Data To Predict Drosophila Complex Traits

2020 ◽  
Vol 10 (12) ◽  
pp. 4599-4613
Author(s):  
Fabio Morgante ◽  
Wen Huang ◽  
Peter Sørensen ◽  
Christian Maltecca ◽  
Trudy F. C. Mackay
Keyword(s):  
Precision Agriculture ◽  
Complex Traits ◽  
Prediction Accuracy ◽  
Cellular Response ◽  
Complex Trait ◽  
Sources Of Information ◽  
Starvation Resistance ◽  
Expression Levels ◽  
Chill Coma ◽  
Additional Layer

The ability to accurately predict complex trait phenotypes from genetic and genomic data are critical for the implementation of personalized medicine and precision agriculture; however, prediction accuracy for most complex traits is currently low. Here, we used data on whole genome sequences, deep RNA sequencing, and high quality phenotypes for three quantitative traits in the ∼200 inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) to compare the prediction accuracies of gene expression and genotypes for three complex traits. We found that expression levels (r = 0.28 and 0.38, for females and males, respectively) provided higher prediction accuracy than genotypes (r = 0.07 and 0.15, for females and males, respectively) for starvation resistance, similar prediction accuracy for chill coma recovery (null for both models and sexes), and lower prediction accuracy for startle response (r = 0.15 and 0.14 for female and male genotypes, respectively; and r = 0.12 and 0.11, for females and male transcripts, respectively). Models including both genotype and expression levels did not outperform the best single component model. However, accuracy increased considerably for all the three traits when we included gene ontology (GO) category as an additional layer of information for both genomic variants and transcripts. We found strongly predictive GO terms for each of the three traits, some of which had a clear plausible biological interpretation. For example, for starvation resistance in females, GO:0033500 (r = 0.39 for transcripts) and GO:0032870 (r = 0.40 for transcripts), have been implicated in carbohydrate homeostasis and cellular response to hormone stimulus (including the insulin receptor signaling pathway), respectively. In summary, this study shows that integrating different sources of information improved prediction accuracy and helped elucidate the genetic architecture of three Drosophila complex phenotypes.

scholarly journals Bayesian reassessment of the epigenetic architecture of complex traits

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Trejo Banos ◽  
Daniel L. McCartney ◽  
Marion Patxot ◽  
Lucas Anchieri ◽  
Thomas Battram ◽  
...  
Keyword(s):  
Complex Traits ◽  
Complex Disease ◽  
Target Identification ◽  
Blood Cholesterol ◽  
Methylation Array ◽  
Single Nucleotide ◽  
Epigenetic Effects ◽  
Probability Prediction ◽  
Stimuli Response ◽  
Insight Into

Abstract Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70–79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.

scholarly journals Temporal fluctuations of Y-chromosomal variation in Bos taurus

2008 ◽  
Vol 4 (6) ◽  
pp. 752-754 ◽  
Author(s):  
Emma Svensson ◽  
Anders Götherström
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Bos Taurus ◽  
Demographic History ◽  
Northern Europe ◽  
Chromosomal Gene ◽  
Chromosomal Variation ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Domestic Species ◽  
History Of

Phylogeography has recently become more abundant in studies of demographic history of both wild and domestic species. A single nucleotide polymorphism (SNP) in the intron of the Y-chromosomal gene UTY19 displays a north–south gradient in modern cattle. Support for this geographical distribution of haplogroups has previously also been seen in ancient cattle from Germany. However, when analysing 38 historic remains of domestic bulls and three aurochs from northern Europe for this SNP we found no such association. Instead, we noted extensive amounts of temporal variation that can be attributed to transportation of cattle and late breed formation.

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