A small number of de novo assembled human genomes have been reported to date, and few have been complemented with population-based genetic variation, which is particularly important for North Africa, a region underrepresented in current genome-wide references. Here, we combine long- and short-read whole-genome sequencing data with recent assembly approaches into a de novo assembly of an Egyptian genome. The assembly demonstrates well-balanced quality metrics and is complemented with variant phasing via linked reads into haploblocks, which we associate with gene expression changes in blood. To construct an Egyptian genome reference, we identify genome-wide genetic variation within a cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genome references. Thus, the Egyptian genome reference will be a valuable resource for precision medicine.

Background: Like its human counterpart, canine atopic dermatitis (cAD) is a chronic relapsing condition; thus, most cAD-affected dogs will require lifelong treatment to maintain an acceptable quality of life. A potential intervention is modulation of the composition of gut microbiota, and in fact, probiotic treatment has been proposed and tried in human atopic dermatitis (AD) patients. Since dogs are currently receiving intensive medical care, this will be the same option for dogs, while evidence of gut dysbiosis in cAD is still missing, although skin microbial profiling in cAD has been conducted in several studies. Therefore, we conducted a comprehensive analysis of both gut and skin microbiota in cAD in one specific cAD-predisposed breed, Shiba Inu. Additionally, we evaluated the impact of commonly used medical management on cAD (Janus kinase; JAK inhibitor, oclacitinib) on the gut and skin microbiota. Furthermore, we genotyped the Shiba Inu dogs according to the mitochondrial DNA haplogroup and assessed its association with the composition of the gut microbiota.Results: Staphylococcuswas the most predominant bacterial genus observed in the skin;Escherichia/ShigellaandClostridium sensu strictowere highly abundant in the gut of cAD-affected dogs. In the gut microbiota,FusobacteriaandMegamonaswere highly abundant in healthy dogs but significantly reduced in cAD-affected dogs. The abundance of these bacterial taxa was positively correlated with the effect of the treatment and state of the disease. Oclacitinib treatment on cAD-affected dogs shifted the composition of microbiota towards that in healthy dogs, and the latter brought it much closer to healthy microbiota, particularly in the gut. Additionally, even within the same dog breed, the mtDNA haplogroup varied, and there was an association between the mtDNA haplogroup and microbial composition in the gut and skin.Conclusions: Dysbiosis of both the skin and the gut was observed in cAD in Shiba Inu dogs. Our findings provide a basis for the potential treatment of cAD by manipulating the gut microbiota as well as the skin microbiota.

Autoimmune diseases share a general mechanism of auto-antigens harming tissues. Still. they are phenotypically diverse, with genetic as well as environmental factors contributing to their etiology at varying degrees. Associated genomic loci and variants have been identified in numerous genome-wide association studies (GWAS), whose results are increasingly used for polygenic scores (PGS) that are used to predict disease risk. At the same time, a technological shift from genotyping arrays to next generation sequencing (NGS) is ongoing. NGS allows the identification of virtually all - including rare - genetic variants, which in combination with methodological developments promises to improve the prediction of disease risk and elucidate molecular mechanisms underlying disease. Here we review current, publicly available autoimmune disease GWAS and PGS data based on information from the GWAS and PGS catalog, respectively. We summarize autoimmune diseases investigated, respective studies conducted and their results. Further, we review genetic data and autoimmune disease patients in the UK Biobank (UKB), the largest resource for genetic and phenotypic data available for academic research. We find that only comparably prevalent autoimmune diseases are covered by the UKB and at the same time assessed by both GWAS and PGS catalogs. These are systemic (systemic lupus erythematosus) as well as organ-specific, affecting the gastrointestinal tract (inflammatory bowel disease as well as specifically Crohn’s disease and ulcerative colitis), joints (juvenile ideopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), glands (Sjögren syndrome), the nervous system (multiple sclerosis), and the skin (vitiligo).

Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic (CCCTCT)_n domain that acts as a genetic modifier of disease onset and expressivity. Methods: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation. We used blood-derived DNA from 96 XDP patients for amplicon-based deep Nanopore sequencing and validated it with fragment analysis which was performed using fluorescence-based PCR. To detect methylation from blood- and brain-derived DNA, we used a Cas9-targeted approach. Results: High concordance was observed for hexanucleotide repeat numbers detected with Nanopore sequencing and fragment analysis. Within the SVA locus, there was no difference in genetic variability other than variations of the repeat motif between patients. We detected high CpG methylation frequency (MF) of the SVA and flanking regions (mean MF = 0.94, SD = ±0.12). Our preliminary results suggest only subtle differences between the XDP patient and the control in predicted enhancer sites directly flanking the SVA locus. Conclusions: Nanopore sequencing can reliably detect SVA hexanucleotide repeat numbers, methylation and, lastly, variation in the repeat motif.

Editorial: Long-read sequencing—Pitfalls, benefits and success stories

Exploration of genetic variant-to-gene relationships by quantitative trait loci such as expression QTLs is a frequently used tool in genome-wide association studies. However, the wide range of public QTL databases and the lack of batch annotation features complicate a comprehensive annotation of GWAS results. In this work, we introduce the tool “Qtlizer” for annotating lists of variants in human with associated changes in gene expression and protein abundance using an integrated database of published QTLs. Features include incorporation of variants in linkage disequilibrium and reverse search by gene names. Analyzing the database for base pair distances between best significant eQTLs and their affected genes suggests that the commonly used cis -distance limit of 1,000,000 base pairs might be too restrictive, implicating a substantial amount of wrongly and yet undetected eQTLs. We also ranked genes with respect to the maximum number of tissue-specific eQTL studies in which a most significant eQTL signal was consistent. For the top 100 genes we observed the strongest enrichment with housekeeping genes (P=2×10 ⁻⁶ ) and with the 10% highest expressed genes (P=0.005) after grouping eQTLs by r ² >0.95, underlining the relevance of LD information in eQTL analyses. Qtlizer can be accessed via http://genehopper.de/qtlizer or by using the respective Bioconductor R-package (DOI: 10.18129/B9.bioc.Qtlizer ).