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Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Although the number of participants is important for phenotypic prediction accuracy in brain-wide association studies using functional MRI, scanning for at least 30 min offers the greatest cost effectiveness.

FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

This work introduces a pedigree-derived benchmark for single-nucleotide variants, indels, structural variants and tandem repeats, offering a variant map to validate sequencing workflows or to support the development and evaluation of new variant callers.

Evan Eichler and colleagues report an expanded copy number variation (CNV) morbidity map of developmental delay, with additional resequencing of candidate genes in regions implicated by large CNVs. They identify several new disease-associated CNVs and show how their combined approach facilitates discovery of new developmental syndromes and disease genes.

Evan Eichler and colleagues identify a recurrent microdeletion on 16p12.1 associated with developmental, cognitive and neuropsychiatric phenotypes. They also show that more severe phenotypes are frequently correlated with the presence of a second large genomic rearrangement, supporting a complex model of pathogenesis that may underlie the variable expressivity typical of many microdeletion syndromes.

About 15,000 pairwise interactions within S. epidermidis from 18 people in 6 families reveal the antagonism and molecular trade-offs that shape the skin microbiota.

Evan Eichler and colleagues have developed an algorithm called mrFAST to map short, next-generation sequence reads across the genome that allows for the accurate prediction of copy-number variation.

TiO₂ and other metal oxides were interfaced with molecular boron clusters to form a hybrid material. This modifies the electrochemical and photocatalytic properties, enabling fast electron transfer and dye degradation under red light.

Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, developmental delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.

Sepsis may promptly develop into lethal organ failure, so early diagnosis and treatment planning are essential. Here the authors use machine learning to develop a six-gene signature, termed Sepset, for initial diagnosis, and integrate Sepset into a microfluidic-based bench-side platform for predicting the prognosis of suspected sepsis suitable for the clinic.

Ultrasound neuromodulation overcomes limitations of electrode-based stimulation through improved

targeting and long-term stability for treating neurological disorders. Here, authors present a hair-thin, implantable piezoelectric stimulator that selectively modulates neurons in the deep brain.

Evan Eichler and colleagues analyze the relative impact of de novo and rare, inherited variants on autism risk. They show a statistically independent role for rare, inherited mutations and implicate several new candidate genes likely contributing to autism risk.

Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.

Nature Biotechnology asks a selection of faculty about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

DPANN archaea are a group of microorganisms that require direct cell contact with other archaeal host species for growth. Here, Hamm et al. show that a DPANN archaeon engages in parasitic interactions with its host leading to host cell lysis, thus providing experimental evidence of a predatory-like lifestyle for an archaeon.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

The complete assembly of human chromosome 8 resolves previous gaps and reveals hidden complex forms of genetic variation, enabling functional and evolutionary characterization of primate centromeres.

This study presents results from a SARS-CoV-2 genomic surveillance study at a university campus in which ~2,000 samples were sequenced over five months. The authors document the replacement of Delta with Omicron as the dominant variant, and describe clinical characteristics and transmission dynamics.

A high-quality bonobo genome assembly provides insights into incomplete lineage sorting in hominids and its relevance to gene evolution and the genetic relationship among living hominids.

A comparative segmental duplication map of four primate genomes that allows the evolutionary history of all human segmental duplications to be reconstructed is presented. It reveals a fourfold acceleration of segmental duplication accumulation during the speciation of human, chimpanzee and gorilla at a time when other mutational processes were slowing, and also provides a detailed evolutionary history of all human segmental duplications as a resource to the human genetics community.

Evan Eichler, Jay Shendure and colleagues sequenced the exomes of 20 sporadic cases of autism spectrum disorder and their unaffected parents. They identified potentially causative de novo mutations in four cases, including a frameshift in FOXP1, a splice-site mutation in GRIN2B and missense variants in SCN1A and LAMC3.

Reconstruction of the evolutionary history of the chromosome 16p11.2 locus and identification of bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens.

Segmental duplications in the genome are regions with the potential for the evolution of phenotypic novelties, but their cataloguing has been technically difficult. Here, the evolution and function of human duplications is characterized.

A study comparing the pattern of single-nucleotide variation between unique and duplicated regions of the human genome shows that mutation rate and interlocus gene conversion are elevated in duplicated regions.

Thomas Sander and colleagues identify 15q13.3 microdeletions in 1% of individuals with idiopathic generalized epilepsy (IGE). The majority of these individuals do not show intellectual disability, schizophrenia or other neuropsychiatric phenotypes, thus extending the phenotypic spectrum associated with 15q13.3 microdeletions.

Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

Typhoidal Salmonella is a major pathogen, but there is still a lack of knowledge about suitable vaccine antigens. Cerundolo and colleagues deep-phenotype bacteria-specific CD4⁺ T cells of Salmonella-infected volunteers to define cross-reactive and serovar-specific responses.

Comparisons within the human pangenome establish that homologous regions on short arms of heterologous human acrocentric chromosomes actively recombine, leading to the high rate of Robertsonian translocation breakpoints in these regions.

Duplications of gene segments can allow novel physiological adaptations to evolve. A detailed analysis of the TCAF gene family in primates and archaic humans suggest rapid duplication and diversification in this gene family is associated with cold or dietary adaptations.

The genome of the gibbon, a tree-dwelling ape from Asia positioned between Old World monkeys and the great apes, is presented, providing insights into the evolutionary history of gibbon species and their accelerated karyotypes, as well as evidence for selection of genes such as those for forelimb development and connective tissue that may be important for locomotion through trees.

Constructing genome graphs directly from genome assemblies overcomes single-reference bias.

The molecular and cellular underpinnings of cribriform prostate cancer aggressiveness remain to be explored. Here, the authors perform single-cell RNA-sequencing, TCR sequencing and histology and reveal cancer cell intrinsic pathways and an immunosuppressive tumour microenvironment.

Carbapenem β-lactam antibiotics target non-classical transpeptidases, the L,D-transpeptidases, which act in an alternative Mycobacterium tuberculosis peptidoglycan synthesis pathway, informing the design of evolved carbapenems with improved antibacterial activity.

Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

A new assembly of the sea lamprey germline genome identifies genomic regions that are systematically eliminated from somatic tissue during early development. Comparative analysis gives new insight into vertebrate evolution.

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles.

The genome of the grey short-tailed opossum Monodelphis domestica has been sequenced and analyzed, giving a first peek at a marsupial's genetic code. Of particular interest are the genetics of the immune system, which has been studied as a model for humans, and of the X chromosome for historical reasons.

Sequencing of the bonobo genome shows that more than three per cent of the human genome is more closely related to either the bonobo genome or the chimpanzee genome than those genomes are to each other.

Understanding the neural processes governing the human gut-brain connection has been challenging. Here, the authors investigate the perceptual response and neural correlates of gastrointestinal sensation using a minimally invasive mechanosensory probe.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.