Research articles

Characterizing the essentiality of human genes provides insights into gene function and genome evolution and facilitates the clinical interpretation of genetic variants. This article analyses essentiality metrics based on the statistical intolerance to loss-of-function mutations in human population sequencing studies and discusses commonalities and distinctions relative to data sets from knockout mice and functional genomics screens in human cell culture. Implications for disease genetics and extrapolation to non-coding regions are also discussed.

Recent large-scale genome-wide association studies have identified numerous variants that are associated with obesity-relevant traits such as body mass index or body fat percentage. Here, the authors explore to what extent this genomic evidence matches the evidence from functional and mechanistic studies.

Evidence is emerging that transcription factors (TFs) lacking methyl-CpG binding domains can interact with methylated DNA. This Analysis article reviews thein vitro and in vivoevidence for methylation-mediated interactions between TFs and DNA, and their functional consequences.

This Analysis provides a statistical evaluation of the core structure inherent to all gene-set analyses. The authors examine current implementations in available tools and show which factors affect valid and successful detection of gene sets.

Copy number variation (CNV) accounts for much of the variability across genomes and can influence phenotypes. In this Analysis, the authors construct a CNV map using high-quality data from published studies to provide more detailed insights into CNV, which will be useful for both clinical and research applications in the future.

Increasing evidence suggests that competition between transcripts for binding of microRNAs and RNA-binding proteins might be a fundamental principle of post-transcriptional gene regulation. The authors use a simple steady-state model to quantitatively assess competition effects under physiological conditions and review the role of endogenous 'sponges' in light of the key features that emerge.

Analyses of post-transcriptional gene regulation and the protein factors involved have been substantially driven forward by technological advances such as next-generation sequencing and modern protein mass spectrometry. This Analysis provides a census of 1,542 manually curated RNA-binding proteins, for which the authors have investigated interactions with different classes of RNA, evolutionary conservation, abundance and tissue-specific expression.

There are various measures to quantify the contribution of genetic variants to disease risk, but differing terminology and assumptions obfuscate their use and interpretation. In this Analysis, the authors consider and contrast six commonly used measures that assess disease risk of individual variants, and provide numerical examples in breast cancer, Crohn's disease, rheumatoid arthritis and schizophrenia.

Research into the genetics of immune and inflammatory disease has experienced major recent advances owing to the availability of a custom single-nucleotide polymorphism (SNP) genotyping array — the Immunochip — developed specifically to investigate these disorders. In this Analysis, the authors assess findings from studies that have used this platform, and explore the shared and phenotype-specific genetic associations among several immune-mediated diseases.

Transcription factors (TFs) are essential for gene expression, but very little is known about the majority of human TFs. This Analysis article provides a manually curated repertoire of sequence-specific human TFs as a foundation for future research, and examines patterns of TF expression and conservation.

Hox clusters, which confer axial patterning on bilaterian embryos, also contain microRNAs. This analysis suggests that these microRNAs specifically target the Hox genes that lie to their 3′ side, thereby reinforcing the dominance of posterior Hox genes over anterior ones.

To what extent is the architecture of genetic networks the product of natural selection? A population-genetic analysis of such networks shows that many of their features can arise through the neutral processes of genetic drift, mutation and recombination.

Chromatin modifications affect many aspects of epigenetic inheritance and cell biology. The authors focus on evolutionary relationships among proteins containing the Jumonji C domain — the largest class of histone demethylases — and discuss their functions in relation to potential enzymatic activities.