Volume 51 Issue 4, April 2019

More than one dozen hereditary ataxias are caused by repeat expansions. A newly discovered expansion may be the first known common genetic cause of late-onset ataxia.

Resolving variant-to-function relationships is a key challenge faced by human geneticists. A new study combining statistical fine-mapping with cell-type-specific functional annotations advances the understanding of the regulatory consequences of genetic variants associated with variations in blood-cell traits.

This Perspective discusses scientific and ethical considerations regarding the clinical use of polygenic risk scores, highlighting the pressing need to diversify cohorts for genetic studies beyond European-ancestry populations.

Transcriptome-wide association studies (TWAS) prioritize candidate causal genes at GWAS loci. This Perspective discusses the challenges to TWAS analysis, caveats to interpretation of results and opportunities for improvements to this class of methods.

Mendelian randomization analyses using genotyping data, gut metagenomic sequence and fecal short-chain-fatty-acid levels from 952 individuals combined with GWAS data show evidence of a causal effect of the gut microbiome on metabolic traits.

The authors transcriptionally profiled postmortem retinas from 453 age-related macular degeneration (AMD) cases and controls. Integration of AMD GWAS with eQTL analysis and TWAS identified several AMD-associated genes.

A pan-cancer analysis identifies 129 transposable-element-driven promoter-activation events involving 106 oncogenes. At the AluJb-LIN28B locus, deletion of the transposable element eliminates oncogene expression.

This study uses SMARCA2/4-mutant variants to define catalytic activity–dependent and catalytic activity–independent contributions of the ATPase module to the targeting of BAF and PBAF complexes genome-wide.

Generation of a library of 62,389 mapped insertion mutants for the unicellular alga Chlamydomonas reinhardtii enables screening for genes required for photosynthesis and the identification of 303 candidate genes.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

Biallelic expansion of an intronic AAGGG repeat in RFC1 is identified here as a common cause of late-onset ataxia. This expansion occurs in the poly(A) tail of an AluSx3 element and is observed at a carrier frequency of 0.7% in populations of European ancestry.

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

FOCUS (fine-mapping of causal gene sets) models correlation among TWAS signals to assign a probability for every gene in the risk region to explain the observed association signal while controlling for pleiotropic SNP effects and unmeasured causal expression.

Fine-mapping of blood cell traits in the UK Biobank identifies putative causal variants and enrichment of fine-mapped variants in accessible chromatin of hematopoietic progenitor cells. The study provides an analytical framework for single-variant and single-cell analyses of genetic associations.

Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

Cytogenetic and whole-genome-sequencing analyses using CEN-SELECT show that mitotic segregation errors generate a broad spectrum of chromosomal aberrations that recapitulate the complex structural features of cancer genomes.

Transcriptional and epigenomic profiling of osteoblast and adipocyte differentiation shows that adipogenesis is driven by de novo activation of enhancers, whereas osteogenesis involves preestablished enhancers and depends on the activation of pro-osteogenic and antiadipogenic transcription factors.

Fate-mapping and clonal analysis show that bronchioalveolar stem cells (BASCs) become activated and respond distinctly to different lung injuries and differentiate into multiple cell types. Single-cell RNA-seq analysis identifies new BASC markers.

High-quality de novo–assembled genomes of two cultivated allotetraploid cotton species and whole-genome comparative analyses provide insights into the evolution of cotton genomes and improvement of fiber quality and resilience to stress.

Linked-read analysis is a method for analyzing single-cell DNA-sequencing data that accurately identifies somatic single-nucleotide variants by using read-level phasing with nearby germline variants, enabling the characterization of mutational signatures and estimation of somatic mutation rates in single cells.

S-CAP is an RNA-splicing pathogenicity–prediction tool that can eliminate 41% of variants of unknown significance at 95% sensitivity.