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Evan Eichler and colleagues assess copy number variation of the C57BL/6J duplicated regions in 15 mouse strains used for genetic association studies. They report that mice show comparable copy number polymorphism when compared to humans, but that it is more locally restricted, specifically to regions containing gene families associated with spermatogenesis, pregnancy, viviparity, pheromone signaling and the immune response.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a truth set to understand the most fundamental processes underlying human genetic variation.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

MaizeCODE maps active regulatory regions tied to maize domestication traits in a diverse panel of tissues and inbreds. It reveals bi-directional enhancer RNAs and the molecular conflicts between activity and silencing of non-coding regions.

Evan Eichler and colleagues present a detailed characterization of the chromosome 15q13.3 microdeletion region. They identify complex structural polymorphisms and find that the rearrangement breakpoints cluster in palindromic GOLGA8 core duplicons, providing evidence that this repeat and its palindromic architecture underlie the evolutionary and disease-related instability of this region.

Generation and analysis of high-quality, genome assemblies from Middle Eastern trios demonstrate the utility of ancestry-matched data and assembly-based variation analysis.

The aging immune system is characterized by changes in immune cell frequencies and functionality. Here the authors report dynamics of age-related divergence of circulating immune responses in patients with solid tumors treated with immune checkpoint inhibitors

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Methods to produce haplotype-resolved genome assemblies often rely on access to family trios. The authors present FALCON-Phase, a tool that combines ultra-long range Hi-C chromatin interaction data with a long read de novo assembly to extend haplotype phasing to the contig or scaffold level.

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.

The authors show that the deletion of ultraconserved TAD boundaries affects gene expression and phenotype, highlighting TAD evolution’s function. Human-specific TAD boundaries reveal a role in brain development and disease.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Locityper is a general-purpose genotyper that can efficiently genotype and analyze a diverse set of genes, such as hyperpolymorphic HLA genes, using both short-read and long-read whole-genome sequencing data.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

A complete genome sequence is presented of a female Neanderthal from Siberia, providing information about interbreeding between close relatives and uncovering gene flow events among Neanderthals, Denisovans and early modern humans, as well as establishing substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

Reference assemblies of great ape sex chromosomes show that Y chromosomes are more variable in size and sequence than X chromosomes and provide a resource for studies on human evolution and conservation genetics of non-human apes.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

MRP4 is an ATP-binding cassette transporter that transports prostanoids, a group of signaling molecules. The authors use cryo-EM to visualize the transport cycle and characterize its substrate selectivity.

Here, the authors show that SARS-CoV-2 infection causes gut microbiome dysbiosis and gut epithelial cell alterations in a mouse model, and correlate dysbiosis observed in COVID-19 patients with blood stream infections, matching reads of bacterial sequences from stool samples to organisms found in the blood.

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.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

A comparison of two complete sets of human centromeres reveals that the centromeres show at least a 4.1-fold increase in single-nucleotide variation compared with their unique flanks, and up to 3-fold variation in size, resulting from an accelerated mutation rate.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Doppler spectroscopic measurements of the mass of the Earth-sized planet Kepler-78b reveal that its mean density is similar to Earth’s, suggesting a composition of rock and iron.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Analysis of chromatin state at a single-cell level in samples of developing human forebrain demonstrate both cell-type-specific and region-specific changes during neurogenesis.

Cytoplasmic, amyloid-like oligomeric assemblies that contain TDP-43 are increased in damaged tissues with elevated regeneration, thereby enhancing the possibility of amyloid fibre formation and/or aggregation of TDP-43 in disease.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

We present the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference.

Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

Zong et al. reveal that genetic and pharmacologic inhibition of TRPM7 channel function prevents the activation of Ca²⁺–CaM–calcineurin–KLF4 signaling, the phenotypic switch of vascular smooth muscle cells and the formation of abdominal aortic aneurysms.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

An example of hybrid incompatibility between maize and teosinte reveals a selfish toxin–antidote system mediated by small RNAs that may have contributed to the origin of maize.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

The Structural Variation Analysis Group of The 1000 Genomes Project reports an integrated structural variation map based on discovery and genotyping of eight major structural variation classes in 2,504 unrelated individuals from across 26 populations; structural variation is compared within and between populations and its functional impact is quantified.

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.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

In neurons the membrane-associated periodic skeleton (MPS) consists of actin, spectrin, and associated molecules. Here the authors use proteomic analysis and super-resolution imaging to provide insight into the molecular composition and organization of the MPS, and its functions in axon-diameter regulation and neurite-neurite interactions.

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.

Integration of long and ultra-long reads results in improved phased, diploid assemblies.