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Genomics In The Journals: Dec 8, 2011

NEW YORK (GenomeWeb News) – In Nature Genetics, a Chinese-led group describes how it used whole-exome sequencing, combined with targeted screening, to find mutations in ubiquitin-mediated proteolysis pathway genes in an aggressive type of kidney cancer called clear cell renal cell carcinoma.

The researchers sequenced matched tumor-normal samples from 10 individuals with ccRCC. For another 88 ccRCC tumors they used targeted sequencing to look for mutations in around 1,100 genes, including genes harboring suspicious changes in the ccRCC exomes and genes implicated in ccRCC or other cancers in the past. Along with mutations in known ccRCC-related genes, the investigators uncovered alterations affecting a dozen genes not previously linked to the disease. In particular, they saw an over-representation of mutations in ubiquitin-mediated proteolysis genes, hinting that the pathway may be involved in ccRCC tumorigenesis.

"The new discovery on the potential contribution of UMPP to ccRCC justifies more comprehensive investigation of this pathway, including proteomics research of the protein network to fully elucidate its role in ccRCC genesis," co-corresponding author Jun Wang, BGI's executive director, said in a statement.


Another Nature Genetics study explores the genetic underpinnings of a chronic and progressive form of inflammatory arthritis called ankylosing spondylitis in the Han Chinese population. Researchers from China and Singapore did a genome-wide association study involving 1,837 Han Chinese individuals with ankylosing spondylitis and more than 4,200 unaffected controls. They then tested the top 30 candidate SNPs from that discovery GWAS in another 2,100 cases and nearly 3,500 controls. Among the ankylosing spondylitis associated loci: a major histocompatibility locus and a chromosome 2 locus that have been associated with ankylosing spondylitis in European populations and two previously undetected loci on chromosomes 5 and 12 that contain genes related to bone formation and cartilage development.


Researchers from the US, the Netherlands, and Japan used exome sequencing to characterize mutation patterns in the coding regions of various pancreatic cyst sub-types — findings they report in the early, online edition of the Proceedings of the National Academy of Sciences.

The team sequenced the exomes of 32 pancreatic cysts, including eight samples from each of the four main neoplastic pancreatic cysts sub-types. Though the nature and number of mutations varied by sub-type, the pancreatic cysts did share certain genetic features, namely alterations related to the function of the ubiquitin ligase complex, which brands shoddy or spent proteins for destruction. The team also found a handful of candidate genes that could help in differentiating between neoplastic cyst sub-types using DNA from cyst fluid samples.

"When combined with clinical and radiological data, the molecular genetic analysis of cyst fluid could thereby lead to more accurate diagnosis," co-corresponding author Bert Vogelstein, an oncology researcher at the Johns Hopkins Kimmel Cancer Center and co-director of the Ludwig Center for cancer research, and colleagues wrote. "The examination of a large number of cyst fluid samples from patients with all four cyst types will be required to determine the added value of molecular genetic analyses for these and other diagnostic purposes."


An American Journal of Human Genetics study outlines the findings of a new population structure study of South Asia. By genotyping 142 individuals from 30 populations in India and folding in existing genome-wide data for more than 1,000 individuals from the region, the international group conducting the study was able to discern new details on ancestry components and population histories in South Asia. The team also tracked down sites in the genome that appear to be under positive selection in populations in India — including loci housing genes related to lipid metabolism and type 2 diabetes.


Researchers from Spain used the model organism Caenorhabditis elegans to explore ways in which sporadic variation affects the genetic interactions that influence penetrance in the presence of mutations. As they report in Nature, their reporter assay experiments in roundworms harboring specific genetic changes suggested that the phenotypic outcome of mutations can differ from one individual to the next due to stochastic, inter-individual variations in the processes that compensate for those mutations, including general buffering mechanisms and more specific systems related to ancestral gene duplications.

"Two cells are not completely identical and sometimes these differences have their origin in random or stochastic processes," first author Alejandro Burga, a researcher affiliated with the European Molecular Biology Laboratory-Centre for Genomic Regulation Systems Biology Research Unit, said in a statement. "The results of our study show that this type of variation can be an important influence [on] the phenotype of animals, and that its measurement can help to reliably predict the chance of developing an abnormal phenotype such as a disease."

The Scan

For Better Odds

Bloomberg reports that a child has been born following polygenic risk score screening as an embryo.

Booster Decision Expected

The New York Times reports the US Food and Drug Administration is expected to authorize a booster dose of the Pfizer-BioNTech SARS-CoV-2 vaccine this week for individuals over 65 or at high risk.

Snipping HIV Out

The Philadelphia Inquirer reports Temple University researchers are to test a gene-editing approach for treating HIV.

PLOS Papers on Cancer Risk Scores, Typhoid Fever in Colombia, Streptococcus Protection

In PLOS this week: application of cancer polygenic risk scores across ancestries, genetic diversity of typhoid fever-causing Salmonella, and more.