Volume 54 Issue 7, July 2022

Thirty years ago, I had the privilege of launching Nature Genetics, the first spin-off journal bearing the famous Nature logo. Spurred on by the Human Genome Project, there were high hopes for the new journal and indeed the future of human genetics. But there was little expectation that we would launch a science publishing franchise of more than 30 sister journals — or be able to therapeutically rewrite the faulty genomes of patients. Here, I reflect on the humble beginnings of Nature Genetics and 30 years of progress in genetics.

Building on the fundamental discoveries of Mendel, plant genomics has had a major role in advancing the genetic improvement of crops worldwide, particularly in developed economies where the technologies are easily accessible. From cumbersome to more miniaturized high-throughput sequencing technologies, the field continues to evolve, providing vast opportunities for studying plant genomes with varying levels of complexity and potential real-life applications.

The boundaries of chromatin domains have an important role in genome organization and regulation. A comprehensive genetic dissection of a domain boundary in vivo provides insights into how boundary elements function and cooperate to mediate insulation between chromatin domains.

A machine-learning model produces summarized sequence representations of genomic regulatory activity, and provides a functional view of regulatory DNA variation in the human genome, with the aim of better understanding the role of sequence variation in health and disease.

A large-scale collaborative effort now provides a comprehensive annotation of functional non-coding elements in the zebrafish genome. This work serves as an essential foundation for future studies to understand how gene regulatory circuits control embryonic development.

The use of association studies to identify candidate genes for complex biological traits in plants has been challenging due to a reliance on single reference genomes, leading to missing heritability. Graphical pangenomes and the identification of causal variants help overcome this and provide an important advance for crop breeding.

The largest GWAS for kidney function so far provided the starting point for integrated multi-stage annotation of genetic loci. Whole kidney and single-cell epigenomic information is crucial for translating GWAS information to the identification of causal genes and pathogenetic (and potentially targetable) cellular and molecular mechanisms of kidney disease.

By integrating single-cell and bulk transcriptomic analyses, we found that malignant cells belong to two major intrinsic epithelial subtypes. We propose a refined, three-tiered classification of colorectal cancer subtypes based on intrinsic epithelial subtypes, microsatellite instability status and the presence of fibrosis.

In celebration of the 200th anniversary of Gregor Mendel’s birth, this Perspective discusses the historical context of Mendel’s discoveries and the importance of these insights in shaping the field of genetics.

This Perspective celebrates the scientific legacy of W. G. Hill and highlights his various important contributions to the field of genetics.

Sei is a new framework for integrating human genetics data with a sequence-based mapping of predicted regulatory activities to elucidate mechanisms contributing to complex traits and diseases.

Genome-wide analyses identify hundreds of loci associated with kidney function. Integrated analyses of expression, methylation and single-cell open chromatin and expression data derived from human kidney samples prioritize genes and mechanisms underlying renal disease.

A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis.

A modified fluctuation test applied to colorectal cancer cells shows that EGFR/BRAF inhibitor-induced persisters slowly proliferate and have an increased mutation rate. Error-prone DNA polymerases are identified as potential targets to avoid tumor recurrence following treatment with these drugs.

Single-cell ATAC-seq and RNA-seq profiling traces the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC). A large proportion of polyp and CRC cells show a stem-like phenotype.

An analysis of POLE and POLD1 mutations distinguishes driver mutations from passengers and explores their functionality. Driver mutations are associated with specific mutational signatures and correlate with immune checkpoint blockage response.

DeepLoop is a modular Hi-C processing workflow that enables kilobase-resolution analysis of sparse data. Reanalysis of published data demonstrates that DeepLoop can identify allele-specific chromatin loops and large heterozygous structural variants.

Genetically dissecting the Epha4–Pax3 topological boundary in mice shows that divergent CTCF binding sites (CBSs) are not essential for insulation and that chromatin loops in nonconvergently oriented CBSs can be driven by a loop interference mechanism.

The DANIO-CODE consortium leverages a large-scale multiomic dataset to improve zebrafish genome annotation. They identify ~140,000 cis-regulatory elements throughout development and perform a comparison with the mouse regulatory landscape.

Single-cell RNA-sequencing of seven mouse developmental stages identifies lineage-specific and shared regulatory programs controlling cell-fate decisions. Cross-species analysis associates differentiation potency with ribosomal protein gene expression.