Perspectives

Extraordinary advances in genomic science have defined the twenty-first century, transforming our understanding of human biology in both health and disease. This timeline Perspective charts two decades of genomic innovation since the human genome reference sequence became available, highlighting the evolution of sequencing technologies and how they, combined with computational advances, paved the way for genomic medicine.

Synonymous mutations, once deemed neutral, have been shown to influence gene expression and organismal fitness by affecting transcription, mRNA processing, translation and protein folding. In this Perspective, the authors highlight evidence for fitness effects of synonymous mutations and discuss resulting implications for evolutionary and disease genetics.

Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner. The authors review this recently described phenomenon of X-linked competition and map out the implications for X-linked human diseases.

Transcriptional condensates are membraneless organelles that concentrate molecules involved in gene regulation. In this Perspective, the authors outline how transcriptional condensates could serve as temporal signal decoders that transmit information through gene regulatory networks governing cellular responses.

Intrinsically disordered domains (IDRs) are increasingly appreciated as important components of protein function. This Perspective discusses the emerging evidence for IDRs from transcription factors as contributors to the transcription factor target search process, as well as the challenges associated with studying these regions.

Recent advances in genome engineering are enabling the recording of cellular histories into genomes, with single-cell and spatial omics technologies enabling their reconstruction into cellular lineages, states and exposures. This Perspective explores the rationale and technical basis of DNA recording, what aspects of cellular biology can be recorded and how, and the types of discovery that DNA recording will enable when studying development and disease.

In this Perspective, Werner and colleagues discuss the many potential mechanisms by which natural antisense transcripts (NATs) can regulate expression of their complementary sense transcripts, the biological implications of their regulatory effects and the potential of NATs for therapeutic applications.

Multiple mechanisms have evolved to prevent or trap deleterious unwanted transcripts. The unwanted transcript hypothesis proposes that selection at synonymous sites favours mutations that prevent the generation of unwanted transcripts or that make native transcripts appear ‘wanted’ by being GC-rich.

This Perspective reviews large-scale genomics and longitudinal phenomics efforts and the insights they can provide into wellness. The authors describe their vision for the transformation of the current health care from disease-oriented to data-driven, wellness-oriented and personalized population health.

In this Perspective, Carolyn Hogg discusses the utility of genomic data to conservation and the importance of adopting a translational mindset to ensure that genomics is used to its full potential to protect Earths’ declining biodiversity.

Commemorating the 40th anniversary of Barbara McClintock’s Nobel Prize in Physiology or Medicine for her discovery of transposable elements, Cédric Feschotte reflects on McClintock’s life and legacy and how her work has shaped and defined the field of genetics.

In this Perspective, Lim et al. discuss the potential benefits of, and the challenges associated with, translating single-cell genomic approaches from research to clinical settings.

In this Perspective, Harden reviews the terms genetic determinism, genetic essentialism and genetic reductionism to provide consensus and clarity about the meaning of these terms. She discusses common misconceptions, illustrates examples and concludes with recommendations for science communication.

In this Perspective, the authors discuss how regulated alternative splicing can generate phenotypic diversity and outline emerging evidence that alternative splicing contributes to adaptation and species divergence.

Commemorating the 200th birthday of Gregor Mendel, Kim Nasmyth reflects on Mendel’s life and legacy and how his work has shaped and defined the field of modern genetics.

In this Perspective, Pecori et al. provide an overview of the AID/APOBEC cytidine deaminase family, discussing key structural features, how they contribute to viral and tumour evolution and how they can be harnessed for (potentially therapeutic) base-editing purposes.

This Perspective highlights privacy issues related to the sharing of functional genomics data, including genotype and phenotype information leakage from different functional genomics data types and their summarization steps. The authors also review the techniques that will enable broad sharing and analysis while maintaining privacy.

In this Perspective article, Oh and Petronis discuss emerging evidence of time-dependent patterns of DNA modification and describe how incorporating this ‘chrono-epigenetic’ perspective could add value and interpretability in human disease studies.

In this Perspective, Teschendorff and Feinberg describe how single-cell analysis methods based on statistical mechanics can provide valuable insights into developmental phenomena, such as differentiation potency and lineage trajectories, as well as disruption of these processes in cancer.

Although cancer genetics analyses have often focused on individual mutations of classic cancer genes, a wealth of cancer sequencing data are allowing a more comprehensive understanding of the cumulative effects of mutations genome-wide. In this Perspective article, the authors propose how the burden of different types of mutation — from point mutations to large-scale chromosomal aberrations — has distinct and compensatory effects on tumour fitness and selection during different stages of cancer evolution.