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| Open AccessCopy number variation of the restorer Rf4 underlies human selection of three-line hybrid rice breeding
Ctyoplasmic male sterility gene WA352 and its fertility restorer Rf4 are widely used for commercial three-line hybrid rice production. Here, the authors investigate the origin, evolution, and variation of Rf4, and show that copy number variation of Rf4 contributes of fertility restoration in a dosage-dependent manner.
- Zhe Zhao
- , Zhi Ding
- & Letian Chen
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Article
| Open AccessAccurate haplotype construction and detection of selection signatures enabled by high quality pig genome sequences
Accurate haplotypes with abundant genomic variations benefit genetic research. Here, the authors accurately construct 1,874 pig haplotypes and demonstrate their applications in genome-wide association studies, prediction of breeding values and analyses of evolutionary selection.
- Xinkai Tong
- , Dong Chen
- & Lusheng Huang
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Article
| Open AccessImputation of ancient human genomes
For most ancient genomes, low sequencing depth restricts genotyping, limiting their study. Here, the authors test imputation performance of ancient human genomes by estimating error rates and potential bias introduced in downstream analyses.
- Bárbara Sousa da Mota
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open AccessA computational method for cell type-specific expression quantitative trait loci mapping using bulk RNA-seq data
Detecting cell type-specific genetic effects on gene expression is challenging in bulk RNA-seq data. Here, the authors develop a method to increase power which incorporates allele-specific expression and does not transform the gene expression data.
- Paul Little
- , Si Liu
- & Wei Sun
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Article
| Open AccessCRISPR-based targeted haplotype-resolved assembly of a megabase region
Low-cost targeted approach to construct haplotype-resolved assemblies is needed to facilitate population genetic studies. Here, the authors demonstrate assembling high-quality MHC haplotypes with CRISPR-based enrichment and long-read sequencings.
- Taotao Li
- , Duo Du
- & Yun Liu
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Article
| Open AccessWhole-genome sequencing of 1,171 elderly admixed individuals from Brazil
Whole genome sequencing (WGS) data on non-European and admixed individuals remains scarce. Here, the authors analyse WGS data from 1,171 admixed elderly Brazilians from a census cohort, characterising population-specific genetic variation and exploring the clinical utility of this expanded dataset.
- Michel S. Naslavsky
- , Marilia O. Scliar
- & Mayana Zatz
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Article
| Open AccessKL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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Article
| Open AccessEvidence of the interplay of genetics and culture in Ethiopia
Ethiopia is one of the most ethnically and culturally diverse countries. Here, the authors look at genetic and cultural variation in 1,214 Ethiopians to unravel the relationship between genetic admixture and cultural factors.
- Saioa López
- , Ayele Tarekegn
- & Garrett Hellenthal
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| Open AccessIdentity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations
Accurately measuring genetic relatedness by Identical-By-Descent (IBD) segments is challenging in biobank-level genome data. The authors present IBD method FastSMC, which when applied to the UK Biobank gives a detailed picture of genetic relatedness and evolutionary history in the UK over the past 2000 years.
- Juba Nait Saada
- , Georgios Kalantzis
- & Pier Francesco Palamara
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Article
| Open AccessDiscovery of beneficial haplotypes for complex traits in maize landraces
Genetic variations present in landraces are critical for crop genetic improvement. Here, the authors map haplotype-trait associations in ~1000 doubled haploid lines derived from three European maize landraces and identify beneficial haplotypes for quantitative traits that are not present in breeding lines.
- Manfred Mayer
- , Armin C. Hölker
- & Chris-Carolin Schön
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Article
| Open AccessA diploid assembly-based benchmark for variants in the major histocompatibility complex
Accurate, phased assemblies are a key tool in understanding the human genome, particularly in highly polymorphic regions like the medically important MHC. Here the authors provide an assembly-based benchmark for this difficult-to-characterize region.
- Chen-Shan Chin
- , Justin Wagner
- & Justin M. Zook
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Article
| Open AccessDutch population structure across space, time and GWAS design
Genetic variation in modern humans can reveal information about a population’s history and migration patterns. Here, the authors describe the ancestry and geospatial genetic structure of the Netherlands, and demonstrate the utility of haplotype-based covariates in genome-wide association studies.
- Ross P. Byrne
- , Wouter van Rheenen
- & Russell L. McLaughlin
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Article
| Open AccessLandscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.
- Qingbo Wang
- , Emma Pierce-Hoffman
- & Daniel G. MacArthur
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Article
| Open AccessMulti-resolution localization of causal variants across the genome
GWAS analysis currently relies mostly on linear mixed models, which do not account for linkage disequilibrium (LD) between tested variants. Here, Sesia et al. propose KnockoffZoom, a non-parametric statistical method for the simultaneous discovery and fine-mapping of causal variants, assuming only that LD is described by hidden Markov models (HMMs).
- Matteo Sesia
- , Eugene Katsevich
- & Chiara Sabatti
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Article
| Open AccessHaplotyping the Vitis collinear core genome with rhAmpSeq improves marker transferability in a diverse genus
Trait introgression requires universal markers, but cross-species transferability of current SNP markers can be as low as 2%. Here, the authors use an AmpSeq haplotype strategy targeting the collinear core genome for marker development and show transferability increases to 91.4% in the Vitis genus.
- Cheng Zou
- , Avinash Karn
- & Lance Cadle-Davidson
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Article
| Open AccessUsing regulatory variants to detect gene–gene interactions identifies networks of genes linked to cell immortalisation
For most human genes nearby regulatory variants explain only a small proportion of their expression variation between individuals. Here the authors show how the impact of a gene’s set of nearby regulatory variant is often linked to the expression levels of distal genes, providing insights into gene networks.
- D. Wragg
- , Q. Liu
- & J. G. D. Prendergast
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Article
| Open AccessAccurate, scalable and integrative haplotype estimation
Haplotype information inferred by phasing is useful in genetic and genomic analysis. Here, the authors develop SHAPEIT4, a phasing method that exhibits sub-linear running time, provides accurate haplotypes and enables integration of external phasing information.
- Olivier Delaneau
- , Jean-François Zagury
- & Emmanouil T. Dermitzakis
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Article
| Open AccessPlatanus-allee is a de novo haplotype assembler enabling a comprehensive access to divergent heterozygous regions
Most phasing programmes for sequencing data work well for genomes with low heterozygosity but drop in performance in regions of high heterozygosity. Here, Kajitani et al. develop the assembler Platanus-allee and demonstrate its utility in de novo assemblies of various genomes and the human MHC region.
- Rei Kajitani
- , Dai Yoshimura
- & Takehiko Itoh
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Article
| Open AccessSubtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression
It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.
- William W. Greenwald
- , He Li
- & Kelly A. Frazer
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Article
| Open AccessGenome maps across 26 human populations reveal population-specific patterns of structural variation
Large structural variants (SV) are understudied in human genetics research because of the difficulty to detect them in the routinely generated short-read sequencing data. Here, the authors generate optical genome maps of 154 individuals from 26 populations that allow comprehensive examination of large SVs.
- Michal Levy-Sakin
- , Steven Pastor
- & Pui-Yan Kwok
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Article
| Open AccessMosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping
High-throughput sequencing and analyzes of antibody repertoire provide important information on immune responses, but current methodologies are limited in sequence assembly precision and haplotype inference validity. Here the authors propose a new Bayesian haplotyping method, and attest its broad application with a large, multi-individual dataset.
- Moriah Gidoni
- , Omri Snir
- & Gur Yaari
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Article
| Open AccessHaplosaurus computes protein haplotypes for use in precision drug design
Proteoforms arise as protein isoforms or as protein haplotypes, which are the result of genetic variation. Here, the authors develop Haplosaurus, a database that computes protein haplotypes genome-wide from existing genotype data and analyse protein haplotype variability in the 1000 Genomes dataset.
- William Spooner
- , William McLaren
- & Catherine Chaillan Huntington
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Article
| Open AccessGenetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease
Human APOBEC3H has several haplotypes and splice variants with distinct anti-HIV-1 activities, but the genetics underlying the expression of these variants are unclear. Here, the authors identify an intronic deletion in A3H haplotype II resulting in production of the most active splice variant, which is counteracted by HIV-1 protease.
- Diako Ebrahimi
- , Christopher M. Richards
- & Reuben S. Harris
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Article
| Open AccessDe novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations
The majority of the human reference genome assembly is represented as a single consensus haplotype. Here, Wong et al. analyze de novo assemblies of 17 diverse, haplotype-resolved genomes to gain insights into the structure of genetic diversity and compile a list of alternative haplotypes across populations.
- Karen H. Y. Wong
- , Michal Levy-Sakin
- & Pui-Yan Kwok
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Article
| Open AccessA high-quality human reference panel reveals the complexity and distribution of genomic structural variants
Structural variants (SVs) are prevalent in genomes of the general population. Here, Guryev and The Genome of the Netherlands Consortium describe the reference panel of haplotype-resolved SVs from 769 individuals from 250 Dutch families and show its utility for studying heritable traits.
- Jayne Y. Hehir-Kwa
- , Tobias Marschall
- & Victor Guryev
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Article
| Open AccessRare variant phasing and haplotypic expression from RNA sequencing with phASER
Genome interpretation and analysis of allelic activity requires appropriate haplotype phasing. Here the authors present phASER, a fast and accurate method for variant phrasing from RNA-seq and genome sequencing data.
- Stephane E. Castel
- , Pejman Mohammadi
- & Tuuli Lappalainen
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Article
| Open AccessImproved imputation of low-frequency and rare variants using the UK10K haplotype reference panel
Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.
- Jie Huang
- , Bryan Howie
- & Nicole Soranzo
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Article
| Open AccessSingle-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes
The spatial organization of the genome within the nucleus impacts many processes. Here the authors combine oligo-based DNA FISH with single-molecule super-resolution microscopy to image single-copy genomic regions and, taking advantage of SNPs, distinguish allelic regions of homologous chromosomes.
- Brian J. Beliveau
- , Alistair N. Boettiger
- & Chao-ting Wu
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Article |
Human gephyrin is encompassed within giant functional noncoding yin–yang sequences
Yin–yang haplotypes are stretches of DNA that differ at multiple markers and exhibit two disparate forms. Here, the authors identify a pair of 284-nucleotide-long yin–yang haplotypes that encompass the gephyringene, and show that these human-specific haplotypes evolved rapidly and bear functional implications.
- Sharlee Climer
- , Alan R. Templeton
- & Weixiong Zhang
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Article
| Open AccessUnravelling the hidden ancestry of American admixed populations
The genetic make-up of people living in the Americas has been shaped heavily by migration. Here the authors use a haplotype-based approach to reconstruct American genomic ancestry using genotype data from 2,500 individuals, revealing a previously unrecognized genetic contribution from European and African populations.
- Francesco Montinaro
- , George B.J. Busby
- & Cristian Capelli
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| Open AccessGenomic analysis reveals selection for Asian genes in European pigs following human-mediated introgression
Domestication of wild boar populations has led to phenotypically distinct European and Asian pig breeds. Here, the authors show that Asian haplotypes that have introgressed into European pig breeds harbour genes that control economically important traits such as meat quality, development and fertility.
- Mirte Bosse
- , Hendrik-Jan Megens
- & Martien A. M. Groenen
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Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel
1000 Genomes imputation can increase the power of genome-wide association studies to detect genetic variants associated with human traits and diseases. Here, the authors develop a method to integrate and analyse low-coverage sequence data and SNP array data, and show that it improves imputation performance.
- Olivier Delaneau
- , Jonathan Marchini
- & Leena Peltonenz
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Neolithic mitochondrial haplogroup H genomes and the genetic origins of Europeans
Here, Brotherton and colleagues sequence 39 mitochondrial genomes from ancient human remains. They track population changes across Central Europe and find that the foundations of the European mitochondrial DNA pool were formed during the Neolithic rather than the post-glacial period.
- Paul Brotherton
- , Wolfgang Haak
- & Janet S. Ziegle