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DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event—the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation 1 – 3 . Here we analyse whole-genome sequences from 66,083 people—including 12,509 people with cancer—and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 10 4 births and once in every 10 3 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape. A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.

Mitochondrial disorders are challenging to diagnose because they can be caused by mutations of mitochondrial DNA (mtDNA) or one of over 300 different nuclear genes.1 They tend to affect tissues with high energy requirements, either in isolation (such as the eye in Leber hereditary optic neuropathy) or many different organs including the nervous system. The features can overlap with common disorders such as migraine, diabetes mellitus or other rare disorders such as Charcot-Marie-Tooth disease and myasthenia gravis.2 The traditional approach to diagnosis relies on specific genetic or metabolic testing for characteristic clinical syndromes. If this is not definitive, patients undergo an invasive tissue biopsy (usually skeletal muscle) enabling histochemistry and biochemical testing.3 This approach is complex and can lead to a prolonged ‘diagnostic odyssey’.4 One survey showed that patients saw an average of eight clinicians before reaching a correct diagnosis, with 70% having a muscle biopsy.4 The approach to diagnosis of mitochondrial disorders is, however, undergoing a transformation, driven by the introduction of whole-exome sequencing5–8 and whole genome sequencing.9–11 (Whole exome sequencing and whole genome sequencing are both next generation sequencing methods. Whole exome sequencing looks at all the protein coding parts of the genes (exons) together with intron-exon boundaries, 3’ and 5’ untranslated regions and non-coding RNAs. This makes up only 1–2% of the whole genome. Whole genome sequencing looks at all the DNA including both the protein coding genes and non-coding regions.)

Neuromuscular features are common in mitochondrial DNA (mtDNA) disorders. The genetic architecture of mtDNA disorders in diverse populations is poorly understood. We analysed mtDNA variants from whole‐exome sequencing data in neuromuscular patients from South Africa, Brazil, India, Turkey and Zambia. In 998 individuals, there were two definite diagnoses, two possible diagnoses and eight secondary findings. Surprisingly, common pathogenic mtDNA variants found in people of European ancestry were very rare. Whole‐exome or ‐genome sequencing from undiagnosed patients with neuromuscular symptoms should be re‐analysed for mtDNA variants, but the landscape of pathogenic mtDNA variants differs around the world.

AbstractObjectiveTo determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.DesignCohort study.SettingNational Health Service, England, including secondary and tertiary care.Participants345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.InterventionShort read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.Main outcome measureDefinite or probable genetic diagnosis.ResultsA definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.ConclusionWhole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

PurposeWith growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations.MethodsWe performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment.ResultsA total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making.ConclusionsThe use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children.

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first‐in‐class non‐cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR‐specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space. Synopsis This study demonstrates that microbial metabolite mimicry can expand the chemical space in drug discovery. Chemical mimics of microbial indoles interacting with a host nuclear receptor provides a novel and non‐toxic therapeutic approach for treating inflammatory conditions of the intestine. The hybrid structure based (HSB) method utilized the interactions of both IPA and indole in the ligand‐binding domain (LBD) of PXR. The resulting pharmacophore was screened, and ranking by individual docking score resulted in core indole structures that were simplified using intermediates of their synthetic pathway. The two identified lead molecules FKK5 and FKK6 directly bound the ligand‐binding pocket of human PXR and induced a PXR‐dependent gene expression profile in cells and tissues. Mice expressing the human PXR gene (hPXR) significantly expressed PXR target genes upon dosing with FKK6. FKK6 abrogated inflammation in a chemical model of murine colitis in a PXR‐ dependent manner. Graphical Abstract This study demonstrates that microbial metabolite mimicry can expand the chemical space in drug discovery. Chemical mimics of microbial indoles interacting with a host nuclear receptor provides a novel and non‐toxic therapeutic approach for treating inflammatory conditions of the intestine.

The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space. Footnotes * Data included at the request of reviewers