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Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.

Background COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain. Subjects/methods In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry. Results Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) (P = 9.14 × 10−6), obesity status (P = 4.81 × 10−5), higher serum fasting insulin (P = 5.32 × 10−4), BMI (P = 3.94 × 10−4), and lower serum HDL levels (P = 1.92 × 10−7). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells (P = 4.25 × 10−4) and higher proportion of macrophages (P = 2.74 × 10−5). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression. Conclusions Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remains unclear. To study the origins and functional consequences of PZMs, we generated a multi-tissue atlas of PZMs from 948 donors using the final major release of the Genotype-Tissue Expression (GTEx) project. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, while 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we find that their type and predicted functional impact varies during prenatal development, across tissues, and the germ cell lifecycle. Remarkably, a class of prenatal mutations was predicted to be more deleterious than any other category of genetic variation investigated and under positive selection as strong as somatic mutations in cancers. In total, the data indicate that PZMs can contribute to phenotypic variation throughout the human lifespan, and, to better understand the relationship between genotype and phenotype, we must broaden the long-held assumption of one genome per individual to multiple, dynamic genomes per individual.One-Sentence SummaryThe predicted rates, functional effects and selection pressure of postzygotic mutations vary through the human lifecycle.

COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue ACE2 expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P-4). ACE2 expression levels were also associated with estimated proportions of cell types in adipose tissue; lower ACE2 expression was associated with a lower proportion of microvascular endothelial cells (P=4.25×10-4) and higher macrophage proportion (P=2.74×10-5), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue ACE2 expression. Our results demonstrate that at-risk individuals have lower background ACE2 levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.

Autism Spectrum Disorder (ASD) is a complex neuropsychiatric syndrome whose etiology includes genetic and environmental components. Since epigenetic marks are sensitive to environmental insult, they may be involved in the development of ASD. Initial brain studies have suggested a dysregulation of epigenetic marks in ASD. However, due to cellular heterogeneity in the brain, these studies have not determined if there is a true change in the neuronal epigenetic signature. Here, we report a genome-wide methylation study on fluorescence-activated cell sorting-sorted neuronal nuclei from the frontal cortex of 16 male ASD and 15 male control subjects. Using the 450 K BeadArray, we identified 58 differentially methylated regions (DMRs) that included loci associated to GABAergic system genes, particularly ABAT and GABBR1, and brain-specific MicroRNAs. Selected DMRs were validated by targeted Next Generation Bisulfite Sequencing. Weighted gene correlation network analysis detected 3 co-methylation modules which are significantly correlated to ASD that were enriched for genomic regions underlying neuronal, GABAergic, and immune system genes. Finally, we determined an overlap of the 58 ASD-related DMRs with neurodevelopment associated DMRs. This investigation identifies alterations in the DNA methylation pattern in ASD cortical neurons, providing further evidence that epigenetic alterations in disorder-relevant tissues may be involved in the biology of ASD.

Human organoids have been proposed to be powerful tools mimicking the physiopathological processes of the organs of origin. Recently, human pancreatic organoids (hPOs) have gained increasing attention due to potential regenerative medicine applications. However, the cellular components of these three-dimensional structures have not been defined precisely. In this work, we finely characterized hPOs, focusing first on morphology and identity-defining molecular features under long-term culture conditions. We observed consistent cell growth, accompanied by genetic stability, expression of pancreatic markers, and epithelial organization. Next, we identified hPO cell types using single-cell RNA sequencing. Exploiting cutting-edge bioinformatics pipelines, we reshaped the conventional theory of the univocal ductal nature of hPOs into a ductal and acinar bipotentiality. Finally, we proposed a new definition of the multipotent pancreatic hPO progenitors using a refined sorting strategy, with demonstration of self-renewal and differentiation capabilities, thus providing a strong foundation for future studies of pancreatic health and disease.

To balance the X-linked transcriptional dosages between the sexes, one of the two X-chromosomes is randomly selected to be inactivated in somatic tissues of female placental mammals. Non-random, or skewed X-chromosome inactivation (XCI) toward one parental X has been observed in female somatic tissues, and this skewing effect has been associated with several complex human traits. However, the extent of the influence of genetic and environmental factors on XCI skewing is largely unknown. Here, we use RNA-seq and DNA-seq data taken from a large cohort of female twins to quantify the degree of skewing of XCI (DS) in multiple tissues and to study the relationship of XCI with age, genetic factors and complex traits. We show that the XCI patterns are highly tissue-specific with a higher prevalence of skewed XCI in blood-derived tissues than in fat or skin tissue. We also show that the DS in blood-derived tissues is associated with age and that the acquired DS occurs uniquely in blood-derived tissues with an inflection point at approximately 55 years of age. Heritability analysis indicates that the heritability of DS is both age and tissue specific; DS is heritable in blood tissue of females >55 years-old (h2= 0.34) but is not heritable in blood tissues of females 2= 0), nor in skin and fat tissues at any age. We find a positive association between the DS and smoking status in blood tissues of older females (P= 0.02). The high tissue specificity of XCI patterns in human indicates the existence of tissue-specific mechanisms influencing XCI patterns, including genetic and environmental factors. We conclude that the heritability of XCI skewing in blood-derived tissues is dependent on age, representing a Gene x Age interaction that can shift the functional allelic dosage of an entire chromosome in a tissue-restricted manner.

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3′-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner., Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.