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Genomics In The Journals: Dec 13, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics this week, an international team led by Italian investigators has reported on recurrent mutations to a gene called SETBP1, found in a subset of the heterogenous myelodysplastic/myeloproliferative disorders grouped under the umbrella of atypical chronic myeloid leukemia, or aCML.

The first SETBP1 mutations linked to aCML fell out of researchers' exome sequencing analyses on matched tumor and normal samples from eight individuals with the condition. Targeted sequencing on samples from another 70 individuals with aCML uncovered SETBP1 mutations in almost one-quarter of the cases, including many cases that were characterized by particularly poor outcomes. When the group tested hundreds of cancer cell lines and blood cancer/myelodysplasia samples, meanwhile, they found a handful of additional samples harboring SETBP1 mutations — primarily from individuals with aCML-related conditions, such as chronic myelomonocytic leukemia.

"Our results increase the knowledge of the mechanisms by which malignancy arises," the study authors wrote, "and will have important consequences for the diagnosis, prognosis, and treatment of aCML and diseases associated with SETBP1 alterations."

A PLOS Biology paper this week offered a look at genetic mechanisms acting on duplicated genes over the course of evolution. Using information for several yeast species, researchers based in Belgium and the US relied on algorithms to reconstruct the ancestral form of genes within a family of fungal glucosidase enzymes, which influence the types of sugars that yeast can use. By scrutinizing the sequence and predicted enzymatic ability of the pre-duplicated form of the enzyme that gave rise to this large gene family — and comparing it with the glucosidase enzymes found in the fungal lineage today — the team was able to get a peek at the gene duplication and/or diversification mechanisms that shaped these genes over the past 100 million years or more.

"By reconstructing a piece of prehistoric DNA that was copied several times during evolution, we were able to investigate in detail which changes occur in each of the copies and gradually lead to new functions," co-corresponding author Kevin Verstrepen, a genetics and genomics researcher with the University of Leuven and the VIB Laboratory for Systems Biology, said in a statement. "As such, our results provide a unique and detailed view into the molecular details of Darwinian evolution."

Researchers reporting in Nature have described a set of messenger RNAs whose protein expression appears to be controlled by the fragile X mental retardation protein, encoded by the FMR1 gene.

The Rockefeller University, Duke University, and Albert Einstein College of Medicine-based team used bioinformatics, coupled with immunoprecipitation, microarray, and other experiments in human cells and mouse models, to track down RNA recognition elements in mRNA that are recognized by the fragile X mental retardation protein's RNA binding domains. The work revealed a set of predicted mRNA targets for the fragile X protein — a list that included transcripts for proteins found at lower-than-usual levels in specific tissues when FMR1 was not expressed. In addition, the study's authors noted, the collection of mRNAs apparently targeted by fragile X mental retardation protein included transcripts for 93 genes implicated in autism spectrum disorder, which often co-occurs with fragile X syndrome when FMR1 gene expression is hindered by expansions to its promoter region.

Mutations in a gene called LRIT3 can cause congenital stationary night blindness, or CSNB, according to a new American Journal of Human Genetics study.

An international team led by investigators in France performed exome sequencing on an individual with complete CSNB, a retinal condition that leads to impaired vision in low light. The woman selected for this analysis had no mutations in the four previously identified CSNB genes and appeared to have inherited an autosomal recessive form of the disease. Researchers' analyses of her exome sequence revealed a missense mutation in one copy of her LRIT3 gene on chromosome 4 and a nonsense mutation in the other copy of the gene.

Meanwhile, targeted LRIT3 sequencing in dozens more CSNB cases identified a second affected individual carrying autosomal recessive LRIT3 mutations — in that case, a nonsense LRIT3 mutation in one copy of the gene coupled with a premature stop codon-producing mutation in the other. Together with findings from the group's follow-up studies, the results hint that LRIT3 alterations may affect the function of cells in the retina known as "ON" bipolar cells.

"Further functional studies will eventually clarify the exact role of LRIT3 within the ON bipolar cell pathway," INSERM researcher Christina Zeitz, the study's corresponding author, and her colleagues wrote, "which will also improve our understanding of the overall visual signal transduction through the retina."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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