Medical genomics articles within Nature Communications

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  • Article
    | Open Access

    The contribution of rare variants to complex traits has not been well studied. Here, the authors present RARity, a method to assess rare variant heritability without assuming a particular genetic architecture and enabling both gene-level and exome-wide heritability estimation of continuous traits.

    • Nazia Pathan
    • , Wei Q. Deng
    •  & Guillaume Paré
  • Article
    | Open Access

    Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.

    • Taryn D. Treger
    • , John E. G. Lawrence
    •  & Tanzina Chowdhury
  • Article
    | Open Access

    Haplotype-resolved long, complex tandem repeats remain largely hidden despite their potential relevance to disease. Here, the authors reveal and analyze the genome-wide landscape of these repeats using a high-precision algorithm.

    • Kazuki Ichikawa
    • , Riki Kawahara
    •  & Shinichi Morishita
  • Article
    | Open Access

    The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.

    • Liina Nagirnaja
    • , Alexandra M. Lopes
    •  & Donald F. Conrad
  • Article
    | Open Access

    While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.

    • Jacob Joseph
    • , Chang Liu
    •  & Yan V. Sun
  • Article
    | Open Access

    Immune genes under selection can shed light on phenotypes contributing to survival and modern inflammatory conditions. Here, the authors prioritize adaptive disease variants in 535 risk loci for 21 inflammatory conditions and report promising SNPs for functional studies with predictions of cell context and function.

    • Vasili Pankratov
    • , Milyausha Yunusbaeva
    •  & Bayazit Yunusbayev
  • Article
    | Open Access

    By comprehensively mapping the impact that different classes of mutations (substitutions, insertions, deletions) have on the ability of the amyloid beta peptide to nucleate amyloids, the authors identify a large set of likely pathogenic variants of amyloid beta that are specifically enriched at its polar N-terminal region.

    • Mireia Seuma
    • , Ben Lehner
    •  & Benedetta Bolognesi
  • Article
    | Open Access

    Staphylococcus capitis is a common causative agent of bloodstream infections in neonatal intensive care units, with multidrug resistant isolates complicating treatment. Authors aimed to establish a core genome multilocus sequence typing (cgMLST) scheme to document the transmission and dissemination of multidrug-resistant S. capitis isolates.

    • Zhengan Wang
    • , Chao Gu
    •  & Yunsong Yu
  • Article
    | Open Access

    Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.

    • Yoshitaka Sakamoto
    • , Shuhei Miyake
    •  & Ayako Suzuki
  • Article
    | Open Access

    Obtaining accurate variant calls from multiple displacement amplified single cell DNA sequencing data needs dedicated models that account for amplification bias and copy errors. Here, the authors describe ProSolo, a model for calling single nucleotide variants with control over the false discovery rate.

    • David Lähnemann
    • , Johannes Köster
    •  & Alexander Schönhuth
  • Comment
    | Open Access

    More and more clinical studies include potentially sensitive human proteomics or metabolomics datasets, but bioinformatics resources for managing the access to these data are not yet available. This commentary discusses current best practices and future perspectives for the responsible handling of clinical proteomics and metabolomics data.

    • Thomas M. Keane
    • , Claire O’Donovan
    •  & Juan Antonio Vizcaíno
  • Article
    | Open Access

    Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.

    • Andrew T. Timberlake
    • , Casey Griffin
    •  & Daniela V. Luquetti
  • Article
    | Open Access

    Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

    • Julia K. Goodrich
    • , Moriel Singer-Berk
    •  & Miriam S. Udler
  • Article
    | Open Access

    Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.

    • Alyssa L. Kennedy
    • , Kasiani C. Myers
    •  & R. Coleman Lindsley
  • Article
    | Open Access

    Developing machine learning models that work equally well for all ethnic groups is of crucial importance to health disparity prevention and reduction. Here, using an extensive set of machine learning experiments on cancer omics data, the authors find that transfer learning can improve model performance for data-disadvantaged ethnic groups.

    • Yan Gao
    •  & Yan Cui
  • Article
    | Open Access

    Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.

    • Akl C. Fahed
    • , Minxian Wang
    •  & Amit V. Khera
  • Article
    | Open Access

    Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

    • Nicola Whiffin
    • , Konrad J. Karczewski
    •  & James S. Ware
  • Article
    | Open Access

    Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

    • Shimin Shuai
    • , Federico Abascal
    •  & Christian von Mering
  • Article
    | Open Access

    Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.

    • Mark Pinese
    • , Paul Lacaze
    •  & David M. Thomas
  • Article
    | Open Access

    Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.

    • Gavin Band
    • , Quang Si Le
    •  & Dominic P. Kwiatkowski
  • Article
    | Open Access

    Whole genome sequencing (WGS) holds promise to solve a subset of Mendelian disease cases for which exome sequencing did not provide a genetic diagnosis. Here, Wells et al. report a supervised machine learning model trained on functional, mutational and structural features for rank-scoring and interpreting variants in non-coding regions from WGS.

    • Alex Wells
    • , David Heckerman
    •  & Julia di Iulio
  • Article
    | Open Access

    Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

    • Eugene J. Gardner
    • , Elena Prigmore
    •  & Matthew E. Hurles
  • Article
    | Open Access

    A number of computational methods have been developed for calling structural variants (SVs) using short read sequencing data. Here, the authors perform a comprehensive benchmarking analysis comparing 10 general-purpose callers and provide recommendations for both users and methods developers.

    • Daniel L. Cameron
    • , Leon Di Stefano
    •  & Anthony T. Papenfuss
  • Article
    | Open Access

    Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.

    • C. F. Wright
    • , E. Prigmore
    •  & M. E. Hurles
  • Article
    | Open Access

    Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.

    • Konstantinos Nikopoulos
    • , Katarina Cisarova
    •  & Carlo Rivolta
  • Article
    | Open Access

    Nanopore sequencing technology generates longer reads than current technologies, but with more errors. Here, the authors develop new analytical tools to improve accuracy and evaluate the potential of nanopore sequencing for clinical human genomics.

    • Rory Bowden
    • , Robert W. Davies
    •  & Peter Donnelly
  • Perspective
    | Open Access

    Indigenous peoples are still underrepresented in genetic research. Here, the authors propose an ethical framework consisting of six major principles that encourages researchers and Indigenous communities to build strong and equal partnerships to increase trust, engagement and diversity in genomic studies.

    • Katrina G. Claw
    • , Matthew Z. Anderson
    •  & Joseph M. Yracheta
  • Article
    | Open Access

    As melanoma progresses, it evolves. Here, in advanced melanoma the authors study genomic evolution, highlighting trunk mutations dominated by the ultraviolet damage signature, common late truncal whole-genome duplication events, as well as selective copy number gain of mutant BRAF.

    • E. Birkeland
    • , S. Zhang
    •  & P. E. Lønning
  • Article
    | Open Access

    The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.

    • Janani Iyer
    • , Mayanglambam Dhruba Singh
    •  & Santhosh Girirajan
  • Article
    | Open Access

    Urinary tract infections are one of the most common infections in humans. Here, the authors use urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections, and show that it is a versatile analyte for monitoring urinary tract infections.

    • Philip Burnham
    • , Darshana Dadhania
    •  & Iwijn De Vlaminck
  • Article
    | Open Access

    A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.

    • Mafalda Barbosa
    • , Ricky S. Joshi
    •  & Andrew J. Sharp
  • Article
    | Open Access

    The detection of structural variants can be difficult with short-read sequencing technology, especially when variants are highly complex. Here, the authors use a MinION nanopore sequencer to analyse two patient genomes and develop NanoSV to map known and novel structural variants in long read data.

    • Mircea Cretu Stancu
    • , Markus J. van Roosmalen
    •  & Wigard P. Kloosterman
  • Article
    | Open Access

    Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.

    • Kashyap A. Patel
    • , Jarno Kettunen
    •  & Michael N. Weedon
  • Article
    | Open Access

    Enteropathy associated T-cell lymphoma -EATL- affects the intestine and there are two different subtypes. In this study, the authors carry out exome sequencing of the type II variant and find that it is characterized by recurrent mutations in the histone methyltransferase SETD2 that are accompanied by altered H3K6 methylation.

    • Annalisa Roberti
    • , Maria Pamela Dobay
    •  & Laurence de Leval