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Genomics In The Journals: Jan 26, 2012

NEW YORK (GenomeWeb News) – By sequencing the exomes of 11 individuals with a rare form of hypertension, an international group led by researchers at Yale University tracked down mutations in two genes that appear to contribute to high blood pressure and altered electrolyte patterns — work they outline in Nature.

The researchers focused on individuals from 41 families with a form of hypertension called pseudohypoaldosteronism type II that is characterized by amped up blood potassium levels and excess acidity. Using exome sequencing, SNP genotyping, and linkage analyses, they homed in on the most promising candidate mutations, identifying two ubiquitination-related genes — KLHL3 and CUL3 — that were mutated in individuals PHAII.

"These genes were not previously suspected to play a role in blood pressure regulation, but if they are lost, the kidney can't put the brakes on salt reabsorption, resulting in hypertension," Richard Lifton, chair of the Yale Department of Genetics and the study's senior author, said in a statement.

Another Nature study looks at how a combination of RNA interference and sequencing can be used to explore the biological mechanisms behind drug response or resistance in a human parasite.

UK researchers used a method called RNA interference target sequencing, or RIT-sequencing, to find sites across the genome that influence drug response in Trypanosoma brucei, a parasite that causes a form of sleeping sickness known as human African trypanosomiasis. By using RIT-sequencing to screen for mutations that shift the parasite's response to five drugs used to treat HAT, the team tracked down 50 new genes that seem to influence T. brucei susceptibility to the drugs, along with genes already known to participate in drug transport.

"We now know a lot more about how these drugs work," London School of Hygiene and Tropical Medicine researcher David Horn, the study's corresponding author, said in a statement. "This new understanding of how these medications kill parasites, or fail to kill parasites, could lead to the development of tests that guide the intervention strategy as well as more active and safer intervention options."

A Clinical Chemistry study by a team in the Netherlands illustrates the potential of doing non-invasive, sequencing-based testing for trisomy 21 using Helicos' Heliscope single-molecule sequencing instrument, which does not rely on PCR amplification prior to sequencing.

Study authors sequenced cell-free DNA in blood samples collected from 20 pregnant women at nine weeks gestation or more and from four adult male controls using the Heliscope as well as Illumina's GAII instrument. One sample, taken from a woman carrying a fetus that did not have trisomy 21, did not contain enough quality DNA to generate informative sequence on either platform.

Using sequence tag density data for samples taken from the other 19 women, researchers detected all 11 authentic trisomy 21 cases and correctly ruled out trisomy 21 for eight more fetuses on both of the sequencing platforms. Still, they say, the Helicos platform offered somewhat clearer distinctions between trisomy 21 cases and unaffected fetuses, owing to a lack of amplification-related bias toward certain sequences — particularly those rich in guanine and cytosine residues.

"This study shows for the first time that single molecule sequencing is an attractive and easy to use alternative for reliable non-invasive fetal aneuploidy detection in diagnostics," senior author Elles Boon, a researcher with Leiden University's Center for Human and Clinical Genetics, and colleagues wrote. "With this approach, previously described experimental noise associated with PCR amplification, such as GC bias can be overcome."

In Science Translational Medicine, an American and Australian-led research group reports on the use of high-throughput sequencing for diagnosing mitochondria-related disease in infants.

The researchers used an approach dubbed MitoExome sequencing — targeted capture sequencing of mitochondrial DNA and coding regions for more than 1,000 nuclear genes believed to influence mitochondrial function — to test samples from 42 infants suspected of having an oxidative phosphorylation (OXPHOS) disease. They also did MitoExome sequencing on 371 unaffected control individuals.

MitoExome sequencing helped to uncover variants in genes suspected of causing recessive mitochondrial disease in more than half of the cases. Of these, 10 children were conclusively diagnosed with mutations linked to OXPHOS disease. Moreover, the study pointed to potentially pathogenic mutations in genes not previously linked to the OXPHOS conditions.

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

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