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Genomics In The Journals: Aug 30, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics, North American and European research groups describe how they teamed up to uncover alterations to a transporter gene called ABCD4 that can cause inborn errors in vitamin B12 metabolism.

Through exome sequencing on one individual with inherited vitamin B12 metabolism defects and microcell-mediated chromosome transfer experiments on another, the researchers unearthed nine especially suspicious genetic variants. Two of these fell in the ABCD4 gene. And the team's subsequent experiments suggest both of the newly identified mutations affect the way vitamin B12, also known as cobalamin, is released from the cell's lysosomes.

Neither of the individuals tested carried mutations to LMBRD1, a gene implicated in hereditary vitamin B12 metabolism deficiency in the past. But the researchers did find the protein encoded by ABCD4 at the same site in the cell as LMBRD1's gene product (the protein LMBD1) and at least one other lysosomal protein.

"Our results show that ABCD4, an ABC transporter, is an essential component of intracellular [cobalamin] metabolism," the study's authors explained, "and suggest that it interacts with LMBD1 in the lysosomal release of [cobalamin]."

A study in the journal Epigenetics & Chromatin suggests that tissue-specific genomic imprinting in the marsupial mammary gland is comparable in some respects to imprinting observed in the placenta of mammals.

A team from Australia, Japan, and the US scrutinized expression and transcription start site methylation patterns for the insulin-coding gene INS in the mammary glands of marsupial mothers during lactation using the recently sequenced tammar wallaby as a model organism. From the profiles they found and comparisons with other tissues, the researchers determined that the INS gene undergoes tissue-specific imprinting in the mammary gland that allows only the paternally inherited version of the gene to be expressed — a process that's suspected of contributing to the shifts in milk composition that are known to occur in marsupial mothers as their offspring develop in the pouch. The study also pointed to apparent INS imprinting in liver tissues of tammar wallaby adults and young.

"This is the first indication that genomic imprinting occurs in the marsupial mammary gland," University of Melbourne zoology researcher Marilyn Renfree, the study's senior author, said in a statement, "and suggests that genomic imprinting in the mammary gland may be as critical for regulating post-natal growth as it is for regulating pre-natal growth in the placenta in all mammals."

A Science Translational Medicine study by researchers in the US and the UK looks at the accumulation of mutations in hematopoietic stem cells and their potential role in acute myeloid leukemia relapse.

The team did exome sequencing on tumor samples from half a dozen individuals with a type of AML that involves internal tandem duplication to the FLT3 gene, a mutation linked to poor outcomes. Using targeted re-sequencing, the investigators screened residual hematopoietic stem cells from the same individuals for recurrent mutations found in the AML samples. Indeed, these blood precursor cells contained several of the same mutations, including alterations to NPM1, SMC1A, and TET2 genes.

The study authors speculated that some of these mutations, which occurred prior to the development of full-fledged AML, represent founder mutations that predispose cells to cancer. Through a series of single cell experiments, the group began to look at the order in which these genetic glitches accumulate, identifying patterns that may offer insights into the changes needed to initiate cancer as well as the clinical relevance of mutations that remain in blood stem cells following AML treatment.

"These pre-leukemic [hematopoietic stem cells] suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse," Stanford University researcher Ravindra Majeti, the study's corresponding authors, and colleagues wrote. "Such pre-leukemics [hematopoietic stem cells] may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions."

In a study published in Cell last month, a Washington University and MD Anderson Cancer Center team presented its own research on the evolution of mutations in hematopoietic stem cells. Based on its analyses, that group proposed that many or most mutations detected in AML tumors are actually age-related mutations that have happened in these blood precursor cells.

Researchers from the US and Denmark have taken a massively parallel, high-throughput functional metagenomics approach to characterizing antibiotic resistance in soil bacteria.

As they report in Science, the investigators relied on a de novo assembly pipeline dubbed "Parallel Annotation and Re-assembly of Functional Metagenomic Selections" — PARFuMS for short — to put together information from short-read metagenomic sequence information on almost 100 antibiotic resistant bacterial isolates from American soil samples. A mélange of DNA from the soil-borne bugs contained sequences capable of rendering Escherichia coli bacteria impervious to five different antibiotic classes, ranging from beta-lactams to tetracyclines. Among these resistance cassettes, the group found a handful of genes that were identical to those described in human pathogens in the past. That information, together with other findings from the study, prompted the team to conclude that there is likely an ongoing exchange of non-coding sequences and antibiotic resistance genes between bacteria in the environment and those turning up in the clinic.

"The exchange of resistance between soil and pathogens emphasizes the clinical importance of the soil resistome, regardless of whether resistance genes are moving from soil to the clinic, or vice versa," Washington University genome sciences and systems biology researchers Kevin Forsberg and Alejandro Reyes, co-first authors on the study, and their colleagues wrote.

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

The Scan

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.

Team Presents Cattle Genotype-Tissue Expression Atlas

Using RNA sequences representing thousands of cattle samples, researchers looked at relationships between cattle genotype and tissue expression in Nature Genetics.

Researchers Map Recombination in Khoe-San Population

With whole-genome sequences for dozens of individuals from the Nama population, researchers saw in Genome Biology fine-scale recombination patterns that clustered outside of other populations.

Myotonic Dystrophy Repeat Detected in Family Genome Sequencing Analysis

While sequencing individuals from a multi-generation family, researchers identified a myotonic dystrophy type 2-related short tandem repeat in the European Journal of Human Genetics.