Detecting and quantifying clonal selection in somatic stem cells.

As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the driver event.

Quantitative liver function imaging and whole genome sequencing - Effective modalities for a new era in personalised decision-making for operable colorectal liver metastases?

Background: The optimal strategy for patients with colorectal liver metastases (CRLM) is unclear. The Precision1 prospective, observational trial assessed whether pre-operative functional imaging and whole genome sequencing (WGS), could enhance individualized decision-making.

Methods: Patients with CRLM considered for hepatectomy were recruited.

Landscape of Genetic Alterations Underlying Hallmark Signature Changes in Cancer Reveals Aneuploidy-driven Metabolic Reprogramming.

Unlabelled: The hallmark signatures based on gene expression capture core cancer processes. Through a pan-cancer analysis, we describe the overview of hallmark signatures across tumor types/subtypes and reveal significant relationships between these signatures and genetic alterations. mutation exerts diverse changes, including increased proliferation and glycolysis, which are closely mimicked by widespread copy-number alterations.

In silico engineering a CD80 variant with increased affinity to CTLA-4 and decreased affinity to CD28 for optimized cancer immunotherapy.

CD80 or cluster of differentiation 80, also known as B7-1, is a member of the immunoglobulin super family, which binds to CTLA-4 and CD28 T cell receptors and induces inhibitory and inductive signals respectively. Although CTLA-4 and CD28 receptors belong to the same protein family, slight differences in their structures leads to CD80 having a higher binding affinity to CTLA-4 (-14.55 kcal/mol) compared with CD28(-12.

Clonal diversification and histogenesis of malignant germ cell tumours.

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood.

Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.

The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs.

Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma.

Purpose: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards.

Experimental Design: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations).

Association of MSY haplotype background with nonobstructive azoospermia is AZF-dependent: A case-control study.

Identifying causal genes of spermatogenic failure on the male-specific region of Y chromosome (MSY) has been a challenging process. Due to the nonrecombining nature of MSY, haplotype-based approaches have recently been shown to be promising in identifying associated MSY haplogroups. We conducted an MSY analysis of nonobstructive azoospermia (NOA) patients in a case-control setting (N = 278 and 105 respectively) to identify modal haplogroups strongly associated with NOA.

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages.

Group-based pharmacogenetic prediction: is it feasible and do current NHS England ethnic classifications provide appropriate data?

Inter-individual variation of drug metabolising enzymes (DMEs) leads to variable efficacy of many drugs and even adverse drug responses. Consequently, it would be desirable to test variants of many DMEs before drug treatment. Inter-ethnic differences in frequency mean that the choice of SNPs to test may vary across population groups.

Can We Assume the Gene Expression Profile as a Proxy for Signaling Network Activity?

Studying relationships among gene products by expression profile analysis is a common approach in systems biology. Many studies have generalized the outcomes to the different levels of central dogma information flow and assumed a correlation of transcript and protein expression levels. However, the relation between the various types of interaction (i.

A novel gene-wide haplotype at the macrophage migration inhibitory factor (MIF) locus is associated with endometrioma.

Objective: Endometriosis is a common complex gynecological disorder that may result in infertility. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is overexpressed in endometriosis tissues. However, hitherto, no study tested the possible relevancy at genetic level.

Identification of a missense variant in CLDN2 in obstructive azoospermia.

Obstructive azoospermia (OA), defined as an obstruction in any region of the male genital tract, accounts for 40% of all azoospermia cases. Of all OA cases, ~30% are thought to have a genetic origin, however, hitherto, the underlying genetic etiology of the majority of these cases remain unknown. To address this, we took a family-based whole-exome sequencing approach to identify causal variants of OA in a multiplex family with epidydimal obstruction.

Label-free discrimination of single nucleotide changes in DNA by reflectometric interference Fourier transform spectroscopy.

Phenotypic variation - such as disease susceptibility and differential drug response - has a strong genetic component. Substantial effort has therefore been made to identify causal genomic variants explaining such variation among humans. Point mutations (PMs), which are single nucleotide changes in the genome, have been identified to be the most abundant form of causal genomic variants, making them useful, reliable diagnostic markers.

Systems genetics of nonsyndromic orofacial clefting provides insights into its complex aetiology.

Nonsyndromic oral clefting (NSOC) is although one of the most common congenital disorders worldwide, its underlying molecular basis remains elusive. This process has been hindered by the overwhelmingly high level of heterogeneity observed. Given that hitherto multiple loci and genes have been associated with NSOC, and that complex diseases are usually polygenic and show a considerable level of missing heritability, we used a systems genetics approach to reconstruct the NSOC network by integrating human-based physical and regulatory interactome with whole-transcriptome microarray data.

Why, When and How to Adjust Your P Values?

Currently, numerous papers are published reporting analysis of biological data at different omics levels by making statistical inferences. Of note, many studies, as those published in this Journal, report association of gene(s) at the genomic and transcriptomic levels by undertaking appropriate statistical tests. For instance, genotype, allele or haplotype frequencies at the genomic level or normalized expression levels at the transcriptomic level are compared between the case and control groups using the Chi-square/Fisher's exact test or independent (i.

Optimization of Porous Silicon Conditions for DNA-based Biosensing via Reflectometric Interference Spectroscopy.

Objective: Substantial effort has been put into designing DNA-based biosensors, which are commonly used to detect presence of known sequences including the quantification of gene expression. Porous silicon (PSi), as a nanostructured base, has been commonly used in the fabrication of optimally transducing biosensors. Given that the function of any PSi-based biosensor is highly dependent on its nanomorphology, we systematically optimized a PSi biosensor based on reflectometric interference spectroscopy (RIS) detecting the high penetrance breast cancer susceptibility gene, BRCA1.