Biology subjects

Koks, S.

Publications and source records attributed to Koks, S..

6 recordsLinked to original sources

bioRxiv2024

Whole blood transcriptome profile identifies motor neurone disease (MND) RNA biomarker signatures

Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.

genomics↗

bioRxiv2022

Mitochondrial function determines severity but not risk of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Selective vulnerability of energy-intensive motor neurons (MNs) has fostered speculation that mitochondrial function is a determinant of ALS. Previously, the position of mitochondrial function in the pathogenic cascade leading to neurotoxicity has been unclear. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial copy number (mtCN) and MN gene expression. We discovered that functionally validated mitochondrial haplotypes are a determinant of ALS survival but not ALS risk. Loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to shorter ALS survival; both genes impact mitochondrial function. MtCN responds dynamically to the onset of ALS independent of mitochondrial haplotype, and is also significantly correlated with disease severity. We conclude that mitochondrial function impacts ALS progression but not risk; our findings have therapeutic implications.

genetics↗

bioRxiv2021

Whole Genome and Exome Sequencing Reference Datasets from A Multi-center and Cross-platform Benchmark Study

With the rapid advancement of sequencing technologies in the past decade, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from errors or artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically benchmarking sequencing platforms, library protocols, bioinformatics pipelines and for measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples, a human triple-negative breast cancer cell line and a matched normal cell line derived from B lymphocytes. We generated whole-genome (WGS) and whole-exome sequencing (WES) data using 16 NGS library preparation protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the paired reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.

bioinformatics↗

bioRxiv2019

Establishing reference samples for detection of somatic mutations and germline variants with NGS technologies

We characterized two reference samples for NGS technologies: a human triple-negative breast cancer cell line and a matched normal cell line. Leveraging several whole-genome sequencing (WGS) platforms, multiple sequencing replicates, and orthogonal mutation detection bioinformatics pipelines, we minimized the potential biases from sequencing technologies, assays, and informatics. Thus, our \"truth sets\" were defined using evidence from 21 repeats of WGS runs with coverages ranging from 50X to 100X (a total of 140 billion reads). These \"truth sets\" present many relevant variants/mutations including 193 COSMIC mutations and 9,016 germline variants from the ClinVar database, nonsense mutations in BRCA1/2 and missense mutations in TP53 and FGFR1. Independent validation in three orthogonal experiments demonstrated a successful stress test of the truth set. We expect these reference materials and \"truth sets\" to facilitate assay development, qualification, validation, and proficiency testing. In addition, our methods can be extended to establish new fully characterized reference samples for the community.

bioinformatics↗

bioRxiv2018

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

Mitochondrial dysfunction has been implicated in the aetiology of monogenic Parkinsons disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here we comprehensively assessed the role of mitochondrial function associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. First, we identified that a proportion of the \"missing heritability\" of the PD can be explained by common variation within genes implicated in mitochondrial disease (primary gene list) and mitochondrial function (secondary gene list). Next we calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. Most significantly we further report that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomisation, which showed that 14 of these mitochondrial function associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

genetics↗

bioRxiv2018

The genetic legacy of continental scale admixture in Indian Austroasiatic speakers

Surrounded by speakers of Indo-European, Dravidian and Tibeto-Burman languages, around 11 million Munda (a branch of Austroasiatic language family) speakers live in the densely populated and genetically diverse South Asia. Their genetic makeup holds components characteristic of South Asians as well as Southeast Asians. The admixture time between these components has been previously estimated on the basis of archaeology, linguistics and uniparental markers. Using genome-wide genotype data of 102 Munda speakers and contextual data from South and Southeast Asia, we retrieved admixture dates between 2000 - 3800 years ago for different populations of Munda. The best modern proxies for the source populations for the admixture with proportions 0.78/0.22 are Lao people from Laos and Dravidian speakers from Kerala in India, while the South Asian population(s), with whom the incoming Southeast Asians intermixed, had a smaller proportion of West Eurasian component than contemporary proxies. Somewhat surprisingly Malaysian Peninsular tribes rather than the geographically closer Austroasiatic languages speakers like Vietnamese and Cambodians show highest sharing of IBD segments with the Munda. In addition, we affirmed that the grouping of the Munda speakers into North and South Munda based on linguistics is in concordance with genome-wide data.

genetics↗