Volume 55 Issue 11, November 2023

The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.

Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.

Genome-wide association analyses of placental weight identify 40 association signals, partially overlapping with birth weight genetics. We find parent-of-origin effects and connections to placental development and morphology, and transport of amino acids and antibodies. Mendelian randomization reveals a fetal contribution to preeclampsia and implicates fetal insulin in the regulation of placental growth.

We developed a computational, age-dependent topic model to identify longitudinal comorbidity patterns from hospital diagnosis data. The inferred comorbidity patterns are robust across UK and US populations and identify disease subtypes with distinct genetic profiles.

Whole-exome and genome sequencing in consanguineous families with unsolved lipodystrophy identified biallelic pathogenic loss-of-function variants in the phospholipase gene PLAAT3. Multi-omics and functional analyses in human and mouse PLAAT3-deficient adipose tissue and adipose stem cells revealed an adipocyte differentiation defect that is mediated by an altered gene network downstream of the adipogenesis master regulator PPARγ.

This Review discusses how embryonic transcriptional programs, such as epithelial–mesenchymal plasticity and stemness, may be harnessed in adult tissues to drive processes and diseases such as regeneration and cancer.

Genome-wide analyses using fetal and parental genotypes identify 40 independent associations influencing placental weight and highlight the role of the fetus in preeclampsia risk and placental growth regulation via insulin signaling.

Genome-wide analyses identify 43 loci associated with forearm fracture, including some influencing bone quality parameters. Follow-up work shows that Tac4 knockout mice exhibit reduced mechanical bone strength with no effect on bone mineral density.

Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).

Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.

Age-dependent topic modeling provides a low-rank representation of longitudinal disease records and identifies diseases with heterogeneous comorbidity profiles, defining subtypes that exhibit distinct genome-wide and locus-specific association patterns.

This study seeks to explain the poor overlap of genome-wide association study and cis-expression quantitative trait locus variants using a model of differential selective constraint, suggesting that these two study types have biases towards different functional classes of variants.

Epigenomic profiling and massively parallel reporter assays identify 892 functional differentially-active single-nucleotide variants (daSNVs) linked to ten neuropsychiatric diseases. CRISPRi and gene editing approaches show magnesium transport dysfunction as a common genetic pathomechanism.

Analysis of the somatic mutations landscape of 111 patients with psoriasis vulgaris shows that the disease is unlikely to be driven by clonal expansions caused by somatic mutations in keratinocytes. A mutational footprint associated with psoralen treatment was observed and characterized.

Analysis of GTEx RNA-seq samples identifies hundreds of mosaic chromosomal alterations (mCAs). Considerable inter-tissue variability and excess incidence of mCAs across malignancies suggest a complex relationship with tumorigenesis.

A method that allows for the detection of mosaic chromosomal alterations from blood whole-genome sequencing data highlights ancestry-specific differences in the distribution of common and rare germline susceptibility variants.

Mosaic copy number gains arising from an extra parentally derived chromosome 1q allele are found in brain tissue from five individuals with focal epilepsy. These copy number gains are strongly enriched in astrocytes, indicating somatic rescue in other tissues during development.

Homozygous loss-of-function variants in phospholipase A/acyltransferase 3 (PLAAT3) underlie a new lipodystrophy syndrome. Functional studies link PLAAT3 loss with peroxisome proliferator-activated receptor gamma (PPARγ)-mediated defects in white adipose tissue differentiation and function.

Mouse lineage tracing in regenerating bone marrow after myeloablation shows a dynamic dedifferentiation of mature adipocytes into bone marrow stromal cells. Lipolysis disruption obstructs adipocyte dedifferentiation and hematopoietic stem cell regeneration.

Single-haplotype genome assemblies from five cat species shed light on the dynamics of structural variations during felid radiation and resolve sensory gene repertoires associated with adaptation and domestication.

De novo genome assemblies of 12 species from Aurantioideae and pangenome analyses provide insights into the origin and evolution of the orange subfamily and the genetic basis of flavor in citrus fruits.

Chromosome-level genome assemblies of three Allium crops (onion, garlic and Welsh onion) and spatial RNA sequencing provide insights into Allium trait evolution and gene expression patterns during onion bulb formation.

Genome and transcriptome analyses of 376 Gossypium hirsutum accessions uncover the regulation of gene expression during fiber development in allotetraploid cotton and highlight the potential for fiber quality improvement.

In single-cell studies, combining healthy reference atlases and designed control datasets allows more precise identification of disease-associated cell states.