Nature Reviews Genetics

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Publishing reviews and commentaries across the fields of genetics and genomics. Part of Springer Nature and Nature Portfolio. https://www.nature.com/nrg/

Illustrated cover image inspired by next-generation programmable cell therapies. A dark blue computer-chip-like circuit board is overlaid with red-filled test tubes and gold DNA-like segments. Large dome-shaped structures resemble engineered cells integrated into electronic networks, symbolising the convergence of synthetic biology, genetic programming and precision medicine.
Red cable car moving up icy blue-ringed 'fitness' peaks
How to do science that matters: Computational biologist @casey.greenelab.com on purpose-driven open science practices
Open science, altruism and impact: An interview with clinical geneticist @zornitza.bsky.social
A, To detect resistance in host genomes, studies use association tests in living populations to identify candidate disease susceptibility or resistance alleles (Aa), and then selection on hosts can be tracked by the change in frequency of candidate alleles through time53 (Ab). B, To detect adaptation in pathogen genomes, studies can quantify pseudogenization, which implies host tropism compared with generalist lineages (Ba); the emergence of host tropism can be inferred through molecular clock calibration by the dates of ancient pathogen genomes67,68 (Bb). C, Functional palaeogenomics can reveal differences in virulence, which can be compared with human behaviour, social organization and treatment of animals as evidenced in the historical and archaeological records12.
Blue and red train carriages on tracks reminiscent of exon/intron structure of genes
Pinball machine with DNA as launcher and cells as balls
A DNA helix on a bed and in front of differently shaped clouds (proteoforms)
4 cocktail glasses of different shapes and colours on a background of little tiles
Summary of germ cell development in various model organisms
Illustrated night sky with planets (cells), a shooting star, and star constellations against a blue grid background reminiscent of architectural drawings.
Proteoform-resolved therapeutic strategies across molecular and network scales
Proteoform-resolved networks reveal functional rewiring beyond gene-level models
The map–perturb–predict conceptual framework for proteoform medicine
Combinatorial complexity of protein variation
Overview of proteoform diversity, molecular ontogeny and functional examples of reference and alternative proteoforms from five well-characterized examples
Human figure wrapped in DNA, surrounded by viruses, bacteria, and other microorganisms, with a globe in the background, symbolizing global health and genetics.
a, Next-generation sequencing (NGS)-based methods require pretreatment or pre-labelling of the nucleic acid with antibodies (left), restriction enzymes or endonucleases (middle), or chemicals (right) before sequencing, so that modified and unmodified bases can be distinguished during NGS sequencing. b, Long-read sequencing (LRS)-based methods can directly detect modified bases. In single-molecule, real-time (SMRT) sequencing (left), a DNA polymerase (or reverse transcriptase for RNA) is bound within the zero-mode waveguide (ZMW). When a dNTP is incorporated at the polymerase active site, it will emit a fluorescent pulse in the corresponding colour channel. The order of pulses provides the read sequence and inter-pulse duration (IPD) between base incorporation events indicates the presence of a covalent modification in the DNA or RNA template. Nanopore sequencing (right) relies on engineered biological nanopores embedded in a lipid membrane to sequence single-stranded DNA (ssDNA) or RNA. The ionic current measured as DNA or RNA gets ratcheted through the nanopore depends on the precise set of nucleotides occupying the constriction point. Modified nucleotides in the ssDNA or RNA introduce distinct current patterns, making it possible to detect the existence of modified bases relative to non-modified nucleotides.
Schematic of a generic primary cilium showing the main ciliary subcompartments
a, Early models built sequence motifs to describe the consensus sequences of individual core splicing elements, such as splice sites (SSs) and intronic and/or exonic enhancers and silencers. Statistical and machine-learning models were built to output the probability of a novel sequence acting as a core splicing element. The sequence logos shown for 5′SS and 3′SS were generated from Human hg38 RefSeq annotations (code available at https://www.github.com/ulelab/splicelogos). b, As our understanding of splicing mechanisms progressed, expert-selected features were extracted from sequences and used to train integrative models to predict splicing outcomes. c, With the advent of deep-learning, models could jointly learn features directly from raw sequence input. Although theoretically, sequence context could be as large as shown in part d, in practice smaller windows of up to 30 kb have been used. d, Supervised models with convolutional and transformer layers produce multimodal genome-wide data. These models use a much larger sequence context and can predict genome-wide data including RNA sequencing coverage, which can be further processed to evaluate splicing. e, By learning how to reconstruct partially masked genomic sequences across multiple species, self-supervised masked language models capture evolutionarily conserved sequence elements and their functional context in a very generic and flexible fashion. The informative numerical representations obtained by large language models can be used for splicing prediction tasks. Here 3′SS within different sequence contexts from multiple species are shown aligned for easier interpretation, but in practice sequences do not have to be aligned. Current masked language models with application to splicing use variable context windows from 1,000 to 1 million base pairs; however, it is currently unclear whether larger context windows confer better performance
Magnified view of partially methylated domains or highly methylated domains over CpG islands and DNA methylation valleys (DMVs)
RNA ribbon that is being cut and re-stitched together, representing pre-mRNA splicing of introns and exon ligation
A landscape of red and transparent lollipops (reminiscent of typical DNA methylation schematics that show a filled or empty circle to denote methylated and unmethylated cytosines, respectively)
Distinct nomenclature for reproductive hybrids and composite cell lines
Mutations that accrue in single cells during development and postnatal life reflect cell states and exposures and mark cellular lineages
Methods of error correction in single-cell whole-genome sequencing
Methods of single-cell whole-genome amplification and sources of error in single-cell whole-genome sequencing
Abundant genetic variation is revealed by single-cell sequencing
4 cranes surrounding and building a DNA helix
Bidirectional regulators of height
Height-associated genes cluster into common processes and pathways that affect activity in the growth plate
Examples of genes with both monogenic and polygenic links to height
The determinants of height