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Genomics In The Journals: May 17, 2012

NEW YORK (GenomeWeb News) – In Nature Biotechnology, two teams describe efforts to sequence and characterize the genome of foxtail millet, Setaria italica, a crop plant in the grass family that's been proposed as a model organism owing to its relationship to the bioenergy candidate plant switchgrass, Panicum virgatum.

"We're not thinking of Setaria as a biofuel crop per se but as a very informative model since its genome is so structurally close to switchgrass," University of Georgia BioEnergy Science Center researcher Jeff Bennetzen, co-first author on one of the studies, said in a statement.

Bennetzen and colleagues from the University of Georgia, the HudsonAlpha Institute, the Department of Energy's Joint Genome Institute, and elsewhere used Sanger sequencing complemented by high-throughput sequencing methods to generate a high-quality, 400 million base reference genome for foxtail millet. They also did expression studies on the plant's developing leaf tissues. Along with their assembly, annotation, and analyses of the reference sequence — which covers an estimated 80 percent of the overall genome and more than 95 percent of gene-coding sequences — the team sequenced foxtail millet's wild ancestor S. viridis, comparing patterns within the two genomes.

Meanwhile, a BGI-Shenzhen-led group used a whole-genome, next-generation shotgun approach to sequence a 423 million base draft sequence for foxtail millet using DNA from a northern Chinese foxtail millet strain called Zhang gu. That sequence covers roughly 86 percent of the plant's genome. By re-sequencing another hybrid millet strain, the researchers tracked down markers for putting together a high-density genetic linkage map for foxtail millet. Among the other analyses included in that study were quantitative trait locus mapping for herbicide resistance and RNA-sequencing on root, leaf, spica, and stem tissue.

Using data on 100 breast cancer tumors, researchers from around the world tracked down nine new risk genes and characterized some of the mutation combinations that contribute to the disease — work that they describe in Nature. From protein- and microRNA-coding sequence data on 100 primary breast cancers, the team found driver mutations in at least 40 different genes and uncovered more than 70 mutated gene combinations in the cancers. The number and nature of mutations varied between individuals, though factors such as age at diagnosis and tumor grade appeared to correspond to the presence of more mutations overall.

"These results highlight the substantial genetic diversity underlying this common disease," corresponding author Michael Stratton, director of the Wellcome Trust Sanger Institute, and colleagues wrote.

In conjunction with the International Cancer Genome Consortium, members of the same group came up with bioinformatic methods to retrace the genetic events involved in the clonal expansion and evolution of 21 breast cancers. As they report in a pair of papers in Cell, their analyses provide new information on breast cancer life histories, as well as the mutational processes at play in the disease and their relationship to transcriptional patterns. For instance, the group found that mutational processes vary from one breast cancer to the next, in part, depending on the stage of the disease, though all of the tumors tested appeared to have undergone expansions involving a dominant subclone.

A deep exome sequencing study involving thousands of individuals of European or African ancestry is underscoring the prevalence of rare variants in the human genome.

Researchers involved with the National Heart, Lung, and Blood Institute Exome Sequencing Project sequenced 15,585 protein-coding genes in 1,351 individuals of European descent and 1,088 individuals of African descent at a depth of more than 110 times. Analyses of the sequences uncovered almost 13,600 single nucleotide variants in each individual's exome, on average. And nearly 96 percent of variants predicted to affect protein function were rare, the researchers report in the early, online version of Science, hinting that such rare alterations are apt to affect biological processes.

"[T]he vast majority of protein-coding variation is evolutionarily recent, rare, and enriched for deleterious alleles," co-corresponding authors Joshua Akey and Michael Bamshad, both at the University of Washington, and colleagues wrote. "Thus, rare variation likely makes an important contribution to human phenotypic variation and disease susceptibility."

A second Science paper supports the notion that rare genetic variants are abundant in human protein-coding sequences. For that study, an international team led by investigators at GlaxoSmithKline and the University of California at Los Angeles sequenced 202 drug target-coding genes in more than 14,000 individuals from different human populations, including participants of European, African American, and South Asian ancestry. That group saw rare variants cropping up once every 17 bases or so, on average, and found that rare variant patterns tended to cluster in populations in ways that corresponded to geographic distance.

"[T]he results show that there is an abundance of rare variation in human populations, and that surveys of common variants are only observing a small fraction of the genetic diversity in any gene," the study's authors wrote. "Because the genes studied are related to drug discovery, development, or repositioning efforts this work has potential to help investigate target biology and drug response."

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

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