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Genomics In The Journals: Mar 15, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics, an international team headed by investigators in France report that they have found a third gene behind a form of familial arterial hypertension called hyperkalemic hypertension.

The researchers did SNP- or microsatellite-based linkage analysis, combined with whole-exome sequencing, in two affected French families. The search led to mutations in KLHL3, a gene that normally down-regulates the same ion transporter that becomes more active than usual in the presence of the WNK1 and WNK4 mutations that were previously linked to familial hyperkalemic hypertension. Researchers saw 11 more missense mutations in KLHL3 when they did targeted sequencing of the gene in 43 more individuals.

An international team used insertional mutagenesis with the Sleeping Beauty transposon system to find hundreds of potential pancreatic cancer-related genes in mice — work that is slated to appear online in the Proceedings of the National Academy of Sciences this week.

The investigators used Sleeping Beauty movement to introduce new mutations around the genome in mice that already carried alterations to KRAS, an oncogene already implicated in pancreatic and other cancers. In this system, the team tracked down mutations in 543 genes, including 75 genes already implicated in human pancreatic cancer through past studies. Some 10 percent of candidate cancer genes identified in the study contribute to chromatin remodeling, the study authors note, while publicly available human expression data suggests levels of 20 of the candidate genes may have ties to pancreatic cancer outcomes.

In another PNAS study, French and German researchers explore the contributions that a retrotransposon-containing non-coding RNA makes to Ravine encephalopathy, a severe autosomal recessive infantile encephalopathy and anorexia condition nicknamed for a region on Reunion Island.

The team did homozygosity mapping in dozens of individuals from affected families before narrowing in on a 400,000 base region on chromosome 8 that they subsequently sequenced in two patients and two unaffected individuals from the same population. In the process, they found a disease-associated point mutation in a primate-specific retrotransposon sequence that was, itself, nestled in a brain-expressed long non-coding RNA from an intron of the SLC7A2 gene. Follow-up experiments hint that the lncRNA has a regulatory role in the brain, since knocking down its levels in a neuroblasoma cell line led to a jump in apoptosis.

"[A] mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy," the team reports. Based on the finding, they argue that "RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development."

A study in the early, online edition of Science by a team from the UK, US, and Netherlands illustrates the potential of using population sequence data to do fine-scale genome mapping. The group generated genome sequence for 10 unrelated Western chimpanzees and used the data to put together a detailed recombination map of the chimp genome that could be applied in comparisons of recombination profiles in humans and chimps.

For example, the investigators found that recombination hotspots in the chimp genome are distinct from those detected in humans. And though both species share similar overall rates of recombination, there were recombination rate differences in specific parts of the genome. Results of the analysis also suggest that chimps have a good deal of variation within PRDM9, a gene whose product is believed to bind recombination hotspot sequences in the genome.

"This is an exciting difference between humans and chimpanzees," co-senior author Peter Donnelly, from the Wellcome Trust Centre for Human Genetics and the University of Oxford, said in a statement. "PRDM9 is potentially one of the fastest evolving genes since humans split from chimpanzees 6.5 million years ago. It supports studies which suggest that the gene somehow determines where recombination occurs."

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

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