NEW YORK (GenomeWeb) – A PLOS Genetics study suggests genetic variants introduced into the mitochondrial genome relatively recently may moderate individuals' risk of developing late-onset diseases.
Researchers from Newcastle University's Institute of Genetic Medicine brought together mitochondrial DNA data for more than 38,600 individuals from the Wellcome Trust Case Control Consortium who are affected by 11 different diseases — ranging from ulcerative colitis and multiple sclerosis to type 2 diabetes and coronary artery disease.
After imputing additional mitochondrial DNA SNPs with information from thousands more mitochondrial genomes, they compared mtDNA variants in individuals affected by various medical conditions to those in almost 17,500 healthy control individuals.
Indeed, the analysis unveiled instances in which mtDNA variants acted to curb or enhance risk for various diseases, including variants with ties to more than one condition. Because alleles that bumped up disease risk tended to be more common than mitochondrial variants that modified disease risk in a protective manner, the study authors reasoned that "recent [mtDNA] mutations interact with nuclear loci to modify the risk of developing multiple common diseases."
"Our study confirms the important role that mitochondrial DNA variation plays on complex traits," they wrote, "and additionally supports the utility of a GWAS-based approach for analyzing mitochondrial genetics."
Two independent research teams reporting in Nature presented findings from large-scale studies of the human proteome.
Members of an international team led by investigators in the US and India profiled protein and peptide patterns in dozens of human tissue samples. Their high-resolution mass spectrometry-based analysis of adult tissues, fetal tissues, and primary hematopoietic stem cell samples detected protein products for almost 17,300 human genes. That set included proteins present in some tissues and not others, as well as those expressed during fetal development that seem to vanish from adult tissues.
By considering these proteins in a proteogenomic context, the team also narrowed in on new protein-coding parts of the genome, including sequences in and around non-coding RNAs and pseudogenes.
For another proteomic study, German researchers took a mass spec-based look at the human proteome, pulling together their resulting data to produce a publicly available database known as ProteomicsDB.
In addition to defining proteins and peptides present in various human tissue types, cell lines, and body fluid samples, that team also considered protein interactions in relation to messenger RNA expression, long intergenic non-coding RNA regulation, and previously reported drug sensitivity or resistance patterns.
For more on the research groups' efforts and additional commentary please see this article published yesterday in ProteoMonitor.
Researchers from the US and Germany did exome sequencing on samples from half a dozen chronic lymphocytic leukemia (CLL) individuals with acquired resistance to the Bruton's tyrosine kinase (BTK) inhibiting drug ibrutinib to look for mutations that help tumors dodge the anti-cancer treatment — work they reported in the New England Journal of Medicine.
By comparing the patients' exome sequences at the start of the ibrutinib treatment to those in tumors after treatment resistance appeared, the team unearthed a shared BTK gene mutation in treatment-resistant samples from five of the patients that seems to meddle with ibrutinib's proper binding to the resulting kinase protein.
In two more patients, the ibrutinib resistance seemed to stem from gain-of-function glitches in a gene downstream of BTK called PLC-gamma-2 that appeared to prompt excess B-cell receptor activity.
In contrast, researchers did not see the same sorts of resistance-related mutations when they performed follow-up sequencing experiments on samples from nine individuals with persistent lymphocytosis, a condition characterized by higher-than-usual lymphocyte white blood cell counts.
A related correspondence paper in NEJM by the University of Chicago's Lynn Wang and colleagues outlined findings from a study of ibrutinib resistance in a 61-year-old woman who had been diagnosed with CLL when she was 49 years old.
The investigators did sequential RNA sequencing on blood samples from the patient before, during, and after treatment resistance — an approach that unearthed the same BTK mutation described by the American and German team.
Based on information obtained from the relapse sample, along with findings from follow-up experiments, authors of that study also concluded that the BTK mutation interferes with the efficiency of ibrutinib binding to the BTK protein, ultimately leading to treatment resistance.
In the American Journal of Human Genetics, researchers from France, Korea, Turkey, and the US offered evidence suggesting mutations in the CEP83 gene can contribute to a hereditary ciliopathy condition marked by intellectual disability and a form of kidney disease called nephronophthisis in infants.
With the help of targeted sequencing on the exons of more than 1,200 genes in 1,255 individuals with ciliopathies involving nephronophthisis, the team found CEP83 mutations in eight individuals from seven affected families.
The gene codes for a so-called distal appendage of centrioles, or DAPs, the study authors explained, a group of proteins known for securing the cell's centrioles to cell membranes during cilia formation — a process that can go awry in ciliopathies.
Indeed, they noted that in the presence of the newly detected CEP38 mutations, fibroblasts and renal cells in the kidney appeared to contain both cilia flaws and unusual DAP assemblies. Half of the individuals carrying biallelic CEP38 mutations also had central nervous system symptoms and/or learning difficulties.