Retrotransposons can alter the regulation of genes both transcriptionally and post-transcriptionally, through mechanisms such as binding transcription factors and alternative splicing of transcripts. SINE-VNTR-Alu (SVA) retrotransposons are the most recently evolved class of retrotransposable elements, found solely in primates, including humans. SVAs are preferentially found at genic, high GC loci, and have been termed “mobile CpG islands”. We hypothesise that the ability of SVAs to mobilise, and their non-random distribution across the genome, may result in differential regulation of certain pathways. We analysed SVA distribution patterns across the human reference genome and identified over-representation of SVAs at zinc finger gene clusters. Zinc finger proteins are able to bind to and repress SVA function through transcriptional and epigenetic mechanisms, and the interplay between SVAs and zinc fingers has been proposed as a major feature of genome evolution. We describe observations relating to the clustering patterns of both reference SVAs and polymorphic SVA insertions at zinc finger gene loci, suggesting that the evolution of this network may be ongoing in humans. Further, we propose a mechanism to direct future research and validation efforts, in which the interplay between zinc fingers and their epigenetic modulation of SVAs may regulate a network of zinc finger genes, with the potential for wider transcriptional consequences.

Objective: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large‐scale characterization of SVs in PD.Methods: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short‐read whole genome sequencing samples. Using this set of SV variants, we performed a genome‐wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole‐genome long‐read sequencing data.Results: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long‐read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.Interpretation: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012–1022

Background: Parkin RBR E3 ubiquitin‐protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants.Objectives: To identify complex structural variants in PRKN using long‐read sequencing.Methods: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia‐parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long‐read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole‐genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP‐PD) and United Kingdom (UK)‐Biobank datasets.Results: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long‐read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK‐Biobank and 4941 participants of the AMP‐PD datasets. Nine inversions in the UK‐Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression.Conclusions: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long‐read sequencing for structural variant analysis in unresolved young‐onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Parkinson’s disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ‘’complex’’ PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants.

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson’s disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson’s Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.