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Genomics in the Journals: May 16, 2013

NEW YORK (GenomeWeb News) – De novo, non-inherited mutations may explain a subset of congenital heart disease cases, a Nature study suggests. A Yale University-led team performed exome sequencing on individuals with severe forms of congenital heart disease and their unaffected parents in an attempt to peek at the genetic factors behind the birth defect, which turns up in around eight of every 1,000 live births.

When they sifted through data for 362 parent-child trios and 264 unaffected trios, researchers found individuals with congenital heart disease had an unusually high burden of new protein-coding alterations not found in either of their unaffected parents.

Such changes often affected genes involved heart development, study authors said. Genes from pathways involved in adding, removing, or otherwise regulating specific epigenetic marks appeared particularly prone to de novo mutation, too. Among them: genes involved in the methylation of histone 3 lysine 4 and histone 3 lysine 27.

Alterations in genes regulating some of the same sorts of epigenetic marks have previously been implicated in autism, Yale University's Richard Lifton, a co-corresponding author on the study, noted in a statement, hinting that "there may be common pathways that underlie a wide range of common congenital diseases."

Researchers from the University of Illinois at Urbana-Champaign, the Chinese Academy of Sciences, the University of California, Los Angeles, and elsewhere used a combination of Illumina and Roche 454 instruments to sequence the genome of the sacred lotus plant, Nelumbo nucifera — work they described in Genome Biology.

The resulting assembly, cobbled together with sequence data generated with genomic DNA from a sacred lotus variety called China Antique, covers 804 million bases — some 86.5 percent of the estimated 929 million bases in the genome of the basal eudicot plant.

Within this assembly, the team uncovered almost 26,700 predicted protein-coding genes, including a set of 4,223 genes that appear to be shared across all vascular plants assessed so far.

Other comparisons indicated that the sacred lotus genome has a slow nucleotide substitution rate and has not been affected by an ancient genome triplication event that involved the ancestors of many other modern eudicots, consistent with the lotus lineage's basal position in the flowering plant clade. On the other hand, researchers did see signs of a 65 million-year-old genome duplication event within the lotus lineage specifically. And by delving into the types of duplicated genes that have been retained in the genome, they have already started to get new clues about the plant's biology.

A Stanford University team took coupled a method called isobaric tandem mass tagging with two-dimensional liquid chromatography tandem mass spectrometry to get a glimpse at interactions between genetic variants and protein abundance in humans.

As they report in Nature, the investigators used the TMT-tagging mass spec scheme to profile peptides in lymphoblastoid cell lines generated for 95 individuals of European, African, or Asian descent from the HapMap project. Analyses of proteins encoded by just shy of 6,000 genes in these samples revealed variations in protein abundance varied — not only from one individual to the next, but also between individuals of different genders and from different populations.

When they folded in available gene expression data, investigators uncovered examples of protein quantitative trait loci. But they found other indications that protein abundance has a heritable molecular component, too, including clusters of related proteins showing jumps and dips in expression that appear to be linked with one another.

"This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation," Stanford genetics researchers Michael Snyder and Hua Tang, the study's co-corresponding authors, and their colleagues noted.

In the American Journal of Human Genetics, French researchers described an exome sequencing study that unearthed mutations in the BAP1 gene with ties to a familial form of the kidney cancer renal cell carcinoma.

The group began its search for RCC culprits by focusing on a two-generational RCC-affected family that included four first-degree relatives with the condition. Exome sequencing of two affected family members — coupled with genome-wide SNP assessments of tumors from affected individuals in that family — revealed an inactivating germline mutation in BAP1 that segregated with RCC risk.

When investigators searched for similar alterations in 60 cancer-prone families that had already tested negative for mutations in an RCC-associated gene called VHL, they found 11 families with BAP1 mutations. Individuals in six of those families had been diagnosed with RCC. Nevertheless, they noted, BAP1 glitches didn't turn up in families affected exclusively by RCC, suggesting mutations in the gene might contribute to a rare syndrome that increases individuals' risk of RCC and certain other cancer types.

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