Whole genome resequencing of a laboratory-adapted population sample.

As part of a study into the molecular genetics of sexually dimorphic complex traits, we used high-throughput sequencing to obtain data on genomic variation in an outbred laboratory-adapted fruit fly ( ) population. We successfully resequenced the whole genome of 220 hemiclonal females that were heterozygous for the same Berkeley reference line genome (BDGP6/dm6), and a unique haplotype from the outbred base population (LH ). The use of a static and known genetic background enabled us to obtain sequences from whole-genome phased haplotypes.

Sex differences in disease genetics: evidence, evolution, and detection.

Understanding the genetic architecture of disease is an enormous challenge, and should be guided by evolutionary principles. Recent studies in evolutionary genetics show that sexual selection can have a profound influence on the genetic architecture of complex traits. Here, we summarise data from heritability studies and genome-wide association studies (GWASs) showing that common genetic variation influences many diseases and medically relevant traits in a sex-dependent manner.

Functional investigation of a schizophrenia GWAS signal at the CDC42 gene.

Objectives: SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported. Our objective was to test whether the associated SNP affected CDC42 expression.

Multiplex target enrichment using DNA indexing for ultra-high throughput SNP detection.

Screening large numbers of target regions in multiple DNA samples for sequence variation is an important application of next-generation sequencing but an efficient method to enrich the samples in parallel has yet to be reported. We describe an advanced method that combines DNA samples using indexes or barcodes prior to target enrichment to facilitate this type of experiment. Sequencing libraries for multiple individual DNA samples, each incorporating a unique 6-bp index, are combined in equal quantities, enriched using a single in-solution target enrichment assay and sequenced in a single reaction.

Replicated genetic evidence supports a role for HOMER2 in schizophrenia.

Schizophrenia is a heritable mental disorder with a complex genetic aetiology potentially implicating glutamatergic dysfunction. Following a search for functionally relevant genes with evidence of linkage to schizophrenia, we selected HOMER2 for as a candidate gene for investigation using a multi-stage association design. Twenty-six tagging SNPs were genotyped in 401 cases and 812 controls and associated SNPs were analysed in an independent sample of 408 cases and 804 controls, all from Ireland.

Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress.

Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria.

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report.

A common LRRK2 mutation in idiopathic Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease.

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.

Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process.

Hereditary early-onset Parkinson's disease caused by mutations in PINK1.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6.