We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form...We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.
Female individuals require greater autosomal genetic risk than male individuals to manifest autism, yet the biological basis of this 'female protective effect' (FPE) remains unknown. Based on insights into the human sex...Female individuals require greater autosomal genetic risk than male individuals to manifest autism, yet the biological basis of this 'female protective effect' (FPE) remains unknown. Based on insights into the human sex chromosomes, we propose that the FPE arises from higher expression of a subset of X-linked genes in females due to transcription from both the active (Xa) and inactive (Xi) X chromosomes. These higher expression levels enable females to buffer mutations in autosomal genes and in pathways regulated by Xi-expressed genes. This framework unifies epidemiological, genetic and mechanistic observations across autism and other male-biased congenital and developmental disorders, suggesting that the combined activity of Xa and Xi allows females to better tolerate autosomal genetic risk across many pediatric conditions. If correct, this reshapes our understanding of sex differences in human disease and positions Xi as a genetic suppressor of autosomal mutations in autism and beyond.
Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic loci and do not account for the global gen...Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic loci and do not account for the global genetic architecture. Here we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) with functional annotations and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods across several metrics, including error control, mapping power, resolution, precision, replication rate and trans-ancestry phenotype prediction. Across 48 complex traits, we identify credible sets that collectively explain 18% of the SNP-based heritability on average, with 30% credible sets located outside genome-wide significant loci. Leveraging the genetic architecture estimated from GWFM, we predict that fine-mapping over 50% of would require an average of 2 million samples. Finally, as proof-of-principle, we highlight a known causal variant at FTO influencing body mass index and identify new missense causal variants influencing schizophrenia and Crohn's disease risk.
Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LT...Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LTL from blood-derived whole-genome sequences in the All of Us research program (n = 242,494) with diverse ancestries across the USA. LTL was associated with lifestyle, socioeconomic status, biomarkers, cardiometabolic diseases and neoplasms, with heterogeneity across genetic ancestries and sexes. Geographical analysis revealed that significantly longer LTL clustered in the West Coast and Central Midwest, while significantly shorter LTL clustered in the Southeast in the USA. Genome-wide association studies and meta-analyses with the UK Biobank (n = 679,972) found 234 nonoverlapping loci, of which 37 were novel. We identified six novel loci unique to non-European-like populations and one specific to women. Rare variant analysis uncovered nine novel genes, providing new functional insights. Our study highlighted underappreciated contextual heterogeneities of phenomic and genomic associations with LTL.
Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a lar...Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene-phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function ('knockout') genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes.
Sequencing the human genome came with the promise of refined risk assessment for heritable diseases, drug responses and other applications of personalized genomics. Genome-wide association studies that linked thousands o...Sequencing the human genome came with the promise of refined risk assessment for heritable diseases, drug responses and other applications of personalized genomics. Genome-wide association studies that linked thousands of genetic alterations to heritable disorders have partially delivered on this promise. However, many patients with rare diseases remain undiagnosed after genome sequencing, in part because conventional sequencing studies struggle to characterize and phase all genomic variation. Chromosome-length phasing, enabled by the single-cell Strand-seq technique in combination with long-read data, has done much to improve the situation. For example, new diploid assembly analyses for personal genomes allow nearly complete descriptions of genomic variation. Moreover, a new Strand-seq-based phasing method can leverage DNA methylation to assign genetic variants not just to haplotypes but to maternally or paternally inherited homologous chromosomes, representing a new frontier in personalized genomics. Here we review the principles and application of Strand-seq, a key enabler of these developments.
Zhang H, Windhorst A, Bornhofen E
… +18 more, Tulpova Z, Novak P, Macas J, Simkova H, Nadzieja M, Kim JM, Cram D, Cao Y, Konkin DJF, Sass O, Welna G, Himmelbach A, Mascher M, Link W, Kwon SJ, Yang TJ, Andersen SU, Jayakodi M
Zhang M, Wu Z, Huang L
… +17 more, Shen X, Wang K, Hu Y, Wubulikasimu B, Qin Y, Fu J, Luo Z, Yang B, Zhao X, Wang X, Qin F, Bian C, Zhao H, Chen J, Song W, Wang Y, Lai J
Restrepo P, Wilder A, Houser A
… +22 more, Sandhu HS, Ramirez A, Grace Hren M, Gill R, Kazmi A, Chen L, Nigro A, Imanishi I, Demircioglu D, Hasson D, Soto A, McQuillan S, Gonzalez-Kozlova E, Brody R, Ungar B, Kasper M, Lu CP, Torina P, Lewin JM, Gnjatic S, Ma S, Ji AL
The skin is the largest human organ and a site of substantial disease burden, yet its cellular and molecular organization across the body is largely undefined. Here we construct an organ-wide single-cell spatial atlas of...The skin is the largest human organ and a site of substantial disease burden, yet its cellular and molecular organization across the body is largely undefined. Here we construct an organ-wide single-cell spatial atlas of ~1.2 million cells from normal adult human skin, resolving the location of 45 cell types across 114 samples encompassing 15 anatomic sites. We uncover site-specific stereotypic cell-type composition and their organization into ten multicellular neighborhoods, most notably a perivascular neighborhood reminiscent of skin-associated lymphoid tissue. Within this neighborhood, ligand-receptor (L-R) analyses identify a central role for tumor necrosis factor in maintaining CCL19 perivascular fibroblasts, highlighting homeostatic immune-stromal crosstalk. Finally, comparing neighborhood dynamics in spatial transcriptomics of skin disease, we find pan-disease immune alterations in this perivascular neighborhood, suggesting spatial compartmentalization of pathogenic activity. Thus, multicellular neighborhoods underlie the skin's multiscale molecular to macroanatomic organization, orchestrate cell-cell interactions and anatomic site specialization and exhibit architectural disruption in disease.
Zhang Y, Sun Z, Tian S
… +35 more, Wu L, Gu Q, Ke H, Zhang G, Chen B, Wang Z, Zhang J, Zhang X, Li Z, Yang J, Li X, Jiang Y, Zhang K, Wu J, Wang G, Zhang D, Wang X, Meng C, Li Y, Zhang Z, Chen W, Jiao M, Jia H, Li J, Zuo H, Wang Y, Gu M, Xie M, Wu L, Li Z, Yan Y, Cui Y, Liu J, Wang X, Ma Z
Limited pangenome and ambiguous genomic architecture constrain comprehensive genetic variation discovery and cotton improvement. Here we assembled a telomere-to-telomere (T2T) genome for elite cultivar NDM13 and near-T2T...Limited pangenome and ambiguous genomic architecture constrain comprehensive genetic variation discovery and cotton improvement. Here we assembled a telomere-to-telomere (T2T) genome for elite cultivar NDM13 and near-T2T genomes for 27 additional representatives of Gossypium hirsutum over the recent century, with transcriptomic profiling of 15 distinct tissues from each. We uncovered 51,551 one-to-one conserved orthologs across all genomes and landscapes of telomere, centromere, 45S rDNA, segmental duplication and copy number variant. We revealed hotspots of structural variation (SV) and impacts of SV, segmental duplication and copy number variant on gene expression or content alteration, as well as adversity resistances. We identified thousands of divergent SVs and genes implicated in modern breeding evolution. Combining T2T-reference-based pangenome construction and 761,536 SVs identified across 1,671 worldwide accessions with phenotypic data from 22 environments, we captured a number of hidden SVs that potentially influence critical breeding traits. These will boost genetic study and biotechnological improvement of the crop.
Essential tremor, a movement disorder characterized by an upper-limb postural and action tremor, is among the most common neurological disorders, affecting 1% of the population worldwide. Despite strong evidence for gene...Essential tremor, a movement disorder characterized by an upper-limb postural and action tremor, is among the most common neurological disorders, affecting 1% of the population worldwide. Despite strong evidence for genetic factors driving the etiology of essential tremor, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in essential tremor on the cerebellum, the brain region suspected to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprising more than 1 million cells from 109 individuals. Here, using single-cell expression quantitative trait loci and Mendelian randomization, we show that essential-tremor-associated variants in the BACE2 locus are causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also identify dysfunctional processes affecting interactions between neuronal populations and oligodendrocytes in essential tremor. Our findings suggest a crucial role for cerebellar oligodendrocytes in the pathogenesis of essential tremor.
Jang B, Bp K, Tokolyi A
… +14 more, Dredge WH, Ravi A, Jung SH, Naito T, Kim B, Kim MS, Cho M, Park MS, Rosen M, Blanchard J, Humphrey J, Knowles DA, Won HH, Raj T
Most genetic risk variants for neurological diseases are located in noncoding regulatory regions, where they often act as expression quantitative trait loci (eQTLs), modulating gene expression and influencing disease sus...Most genetic risk variants for neurological diseases are located in noncoding regulatory regions, where they often act as expression quantitative trait loci (eQTLs), modulating gene expression and influencing disease susceptibility. However, eQTL studies in bulk brain tissue or cell lines fail to capture the brain's cellular diversity. Single-nucleus RNA sequencing (snRNA-seq) allows high-resolution mapping of eQTLs across diverse brain cell types. Here we performed a meta-analysis by integrating snRNA-seq and genotype data from four cohorts, totaling 5.8 million nuclei from 983 individuals of European ancestry. We mapped cis-eQTLs and trans-eQTLs across major brain cell types and subtypes, including disease-specific and sex-specific eQTLs, and applied colocalization and Mendelian randomization to identify genes that mediate neurological disease risk. We observed up to tenfold more cis-eQTLs and uncovered cell-type-specific genes linked to neurological disease. SingleBrain is a comprehensive single-cell eQTL resource that provides insights into the genetic mechanism of brain disorders.
Yao W, Ku L, Wang B
… +18 more, Ren Z, Su H, Li C, Liu H, Zeng H, Liu Z, Zhang D, Wang Y, Zhu X, Zhao Q, Hu X, Sun C, Han S, Chen J, Bao M, Li T, Wang H, Chen Y
Breeding ideotype maize for high-density planting is crucial for increasing yield but is hindered by a limited understanding of plant architecture regulation. Here we uncover a prominent role for the accumulation of homo...Breeding ideotype maize for high-density planting is crucial for increasing yield but is hindered by a limited understanding of plant architecture regulation. Here we uncover a prominent role for the accumulation of homozygous favorable alleles in genes regulating four principal shoot traits constituting a maize ideotype, and we identify and functionally validate eight architecture-regulating genes. Guided by genomics, we selected the elite hybrid Yufeng303 as a chassis to develop five improved parental lines by pyramiding favorable alleles of these eight genes together with genome-wide loci associated with these traits. These improved parental lines led to the creation of four new hybrids better suited for high-density planting, achieving 4.1-9.2% higher plot yields than Yufeng303 across eight environments. This study exemplifies the power of genomics-guided breeding of ideotype maize for high densities and serves as a template for informed hybrid improvement of other appropriate crops.
Zhang M, Wu Z, Huang L
… +17 more, Shen X, Wang K, Hu Y, Wubulikasimu B, Qin Y, Fu J, Luo Z, Yang B, Zhao X, Wang X, Qin F, Bian C, Zhao H, Chen J, Song W, Wang Y, Lai J
Although nitrogen fertilizer use has boosted crop yields, excessive application diminishes crop nitrogen use efficiency (NUE) and causes environmental problems. Therefore, increasing crop NUE is urgently needed for agric...Although nitrogen fertilizer use has boosted crop yields, excessive application diminishes crop nitrogen use efficiency (NUE) and causes environmental problems. Therefore, increasing crop NUE is urgently needed for agricultural sustainability. Through a genome-wide association study, we identified a locus, NCR1 (Nitrate Concentration Regulator 1), that correlates with nitrate concentrations in maize root xylem. NCR1 encodes a MYB transcription factor that positively regulates the transcription of nitrate transporter NRT2.3 expressed predominantly in root xylem parenchyma cells. The NCR1-NRT2.3 transcription module responds to external nitrogen and controls nitrate translocation from roots to shoots. The superior NCR1 allele with a 123-bp promoter deletion has decreased in frequency as nitrogen fertilizer use in China has increased. Overexpression of NCR1 or NRT2.3, or introgression of NCR1, increases grain yield and nitrogen content in the shoot and seed. This study uncovers a crucial genetic module for improving grain yield and NUE in maize.