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Article
| Open Access
Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI
Most polygenic risk score (PRS) methods focus only on individuals with distinct primary continental ancestry, without accommodating recently-admixed individuals. Here, the authors develop a novel penalized regression-based PRS method specifically designed for admixed individuals.
- Quan Sun
- , Bryce T. Rowland
- & Yun Li
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Article
| Open Access
Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
- Yun Soo Hong
- , Stephanie L. Battle
- & Dan E. Arking
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Article
| Open Access
Single-cell analysis of lizard blastema fibroblasts reveals phagocyte-dependent activation of Hedgehog-responsive chondrogenesis
Lizards are the closest known relatives of mammals capable of epimorphic tail regrowth. Here, single-cell analysis of regenerating lizard tails reveals a phagocyte-induced fibroblast population contributing to blastema formation and chondrogenesis.
- Ariel C. Vonk
- , Xiaofan Zhao
- & Thomas P. Lozito
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Article
| Open Access
Sequence variants affecting the genome-wide rate of germline microsatellite mutations
Microsatellites are tandem repeats of short DNA motifs and represent some of the most polymorphic sites in the genome. Here, the authors report that the human germline microsatellite mutation rate is, in part, under genetic control.
- Snaedis Kristmundsdottir
- , Hakon Jonsson
- & Kari Stefansson
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Article
| Open Access
Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups
Here, the authors assess performance and limitations to polygenic risk scores in different race/ethnic groups. They find that polygenic risk score performance improves with diverse training data, and a better understanding of varying genetic backgrounds, social and environmental factors, and gene-environment interactions, is needed to enhance PRS performance for all groups.
- Nuzulul Kurniansyah
- , Matthew O. Goodman
- & Tamar Sofer
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Article
| Open Access
Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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Article
| Open Access
Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
- William J. Young
- , Najim Lahrouchi
- & Patricia B. Munroe
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Article
| Open Access
A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood
Polygenic risk scores have potential to predict an individual’s risk of disease based on genetic markers. Here, the authors develop a polygenic risk score for hypertension and test it in a multi-ethnic cohort, finding that the score is associated with higher likelihood of hypertension development 4-6 years later.
- Nuzulul Kurniansyah
- , Matthew O. Goodman
- & Tamar Sofer
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Article
| Open Access
The architecture of assisted colonisation in sea turtles: building new populations in a biodiversity crisis
Empirical evidence on the process of founding new populations for assisted colonisations is limited. This work examined two wild populations of green turtles in the Cayman Islands following a reintroduction program started 50 years ago. They show both populations are highly related to the captive population and that philopatry may reinforce the success of new populations.
- Anna Barbanti
- , Janice M. Blumenthal
- & Carlos Carreras
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Article
| Open Access
A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
The underlying genetics of carpal tunnel syndrome is not well understood. Here, the authors perform a GWAS meta-analysis for carpal tunnel syndrome finding variants at 50 loci with connections to the extracellular matrix discovered through various functional analyses.
- Astros Th. Skuladottir
- , Gyda Bjornsdottir
- & Kari Stefansson
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Article
| Open Access
Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia
The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open Access
White pupae phenotype of tephritids is caused by parallel mutations of a MFS transporter
The white pupae (wp) phenotype has been used for decades to selectively remove females of tephritid species in genetic sexing, but the determining gene is unknown. Here, the authors show that wp phenotype is produced by parallel mutations in a Major Facilitator Superfamily domain containing gene across multiple species.
- Christopher M. Ward
- , Roswitha A. Aumann
- & Marc F. Schetelig
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Article
| Open Access
Diversity analysis of 80,000 wheat accessions reveals consequences and opportunities of selection footprints
Genebanks hold comprehensive collections of wild species, wild relatives, and landraces that are useful for genetic improvement. Here, the authors report the genotype of nearly 80,000 wheat accessions using DArTseq technology to show the less explored genetic diversity.
- Carolina Sansaloni
- , Jorge Franco
- & Kevin Pixley
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Article
| Open Access
Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk
Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.
- Mariana L. Stevens
- , Zhonghua Zhang
- & Gurjit K. Khurana Hershey
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Article
| Open Access
Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections
Disease prognosis after infection with Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission.
- Neneh Sallah
- , Wendell Miley
- & Inês Barroso
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Article
| Open Access
Integrating molecular markers into metabolic models improves genomic selection for Arabidopsis growth
An increase in genomic selection (GS) accuracy can accelerate genetic gain by shortening the breeding cycles. Here, the authors introduce a network-based GS method that uses metabolic models and improves the prediction accuracy of Arabidopsis growth within and across environments.
- Hao Tong
- , Anika Küken
- & Zoran Nikoloski
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Article
| Open Access
Associations of autozygosity with a broad range of human phenotypes
Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
- David W Clark
- , Yukinori Okada
- & James F Wilson
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Article
| Open Access
Cis-regulatory CYP6P9b P450 variants associated with loss of insecticide-treated bed net efficacy against Anopheles funestus
Bed nets treated with insecticides have been instrumental in reducing malaria mortality, but insecticide resistance is on the rise. Here, Mugenzi et al. identify genetic variants in the P450 gene CYP6P9b of Anopheles funestus that associate with insecticide resistance and develop a PCR-based diagnostic assay to help identify pyrethroid-resistant strains.
- Leon M. J. Mugenzi
- , Benjamin D. Menze
- & Charles S. Wondji
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Article
| Open Access
Functional disease architectures reveal unique biological role of transposable elements
Transposable elements (TE) make up a large component of the human genome and have been shown to contribute to human diseases. Here, Hormozdiari
et al . estimate the contribution of TEs to the heritability of 41 complex traits and diseases and find enrichment of SINEs in blood traits.- Farhad Hormozdiari
- , Bryce van de Geijn
- & Alkes L. Price
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Article
| Open Access
Biological relevance of computationally predicted pathogenicity of noncoding variants
Researchers can make use of a variety of computational tools to prioritize genetic variants and predict their pathogenicity. Here, the authors evaluate the performance of six of these tools in three typical biological tasks and find generally low concordance of predictions and experimental confirmation.
- Li Liu
- , Maxwell D. Sanderford
- & Sudhir Kumar
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Article
| Open Access
Dissection of genetic variation and evidence for pleiotropy in male pattern baldness
Male pattern baldness (MPB) is a polygenic trait that affects the majority of European men. Here, Yap et al. estimate heritability, partitioned by autosomes and the X-chromosome, of MPB in the UK Biobank cohort, perform GWAS for MPB and find genetic correlation with other sex-specific traits.
- Chloe X. Yap
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open Access
High prevalence of focal and multi-focal somatic genetic variants in the human brain
Similar to cancers, somatic mutations might lead to neurodegenerative diseases. Here, the authors perform ultra-deep sequencing of 102 genes in 173 adult human brains, detect somatic mutations in 54 brains, and develop a mathematical model to estimate the frequency of mutated foci in human brains.
- Michael J. Keogh
- , Wei Wei
- & Patrick F. Chinnery
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Article
| Open Access
A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers
Biomarker identification requires prohibitively large cohorts with gene expression and phenotype data. The approach introduced here learns polygenic predictors of expression from genetic and expression data, used to infer biomarker levels in patients with genetic and disease information.
- Jonathan D. Mosley
- , QiPing Feng
- & Dan M. Roden
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Article
| Open Access
CRISPR–Cas9-targeted fragmentation and selective sequencing enable massively parallel microsatellite analysis
Microsatellite genotyping is a common molecular method of for identification but current methods have restricted throughput. The authors demonstrate STR-Seq, which combines next generation sequencing with targetedin vitroCRISPR-Cas9 fragmentation to enable massively parallel analysis in the thousands.
- GiWon Shin
- , Susan M. Grimes
- & Hanlee P. Ji
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Article
| Open Access
The K526R substitution in viral protein PB2 enhances the effects of E627K on influenza virus replication
Mutations in the viral polymerase, such as PB2-E627K, contribute to adaptation of avian influenza strains to mammalian hosts. Here the authors show that another mutation, PB2-K526R, is found in seasonal H3N2 and avian-origin human influenza isolates, and facilitates replication of these viruses in mammals.
- Wenjun Song
- , Pui Wang
- & Honglin Chen
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Article
| Open Access
A visible dominant marker for insect transgenesis
Genetic modification in insects mostly involves the use of fluorescent markers to identify successful transformation. Here Osanai-Futahashi et al.report a marker system based on changes in melanin pigmentation that allows the identification of genetically modified insects with the naked eye.
- Mizuko Osanai-Futahashi
- , Takahiro Ohde
- & Hideki Sezutsu
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Article
| Open Access
Gene-associated markers provide tools for tackling illegal fishing and false eco-certification
Catch certificates and eco-labels are used to control illegal fishing worldwide, however, independent control methods are needed. Here, gene-associated SNPs are used to assign individual marine fish back to their population of origin with high precision, with potential application for illegal fishing control.
- Einar E. Nielsen
- , Alessia Cariani
- & Gary R. Carvalho
Intrauterine growth and the tangential expansion of the human cerebral cortex in times of food scarcity and abundance