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Genomics in the Journals: Oct 24, 2013

NEW YORK (GenomeWeb News) – A study in Nature Genetics suggests inherited variants in a gene called GATA3 can dial up children's risk of developing an especially aggressive form of pediatric acute lymphoblastic leukemia, or ALL.

Researchers from St. Jude Children's Research Hospital and elsewhere did a genome-wide association study focused on finding inherited risk factors in children with Philadelphia chromosome-positive pediatric ALL.

Based on genotyping profiles for 75 children with this so-called "Ph-like" ALL form, 436 children with other ALL types, and 6,661 children without ALL, the team picked up on apparent ties between a pair of chromosome 10 SNPs in GATA3and Ph-like-ALL risk.

An association for one of the variants was subsequently verified using samples from thousands more children with or without ALL and in cell line experiments. The risk allele, which appears to increase the risk of developing the Ph-like form of ALL by almost four-fold, is found at particularly high frequency in Hispanic Americans and Native Americans, the researchers reported.

The GATA3 variant had ties to treatment response and disease recurrence too, perhaps explaining the poor outcomes that have been described for children with Ph-like-ALL in the Hispanic populations.

"In this study, we discovered a genetic basis for susceptibility to Ph-like ALL, but even more importantly, the evidence that host and tumor genomes may interact with each other to influence the risk of developing and surviving ALL," senior author Jun Yang, a pharmaceutical researcher at St. Jude, said in a statement.

In another Nature Genetics paper, researchers from China's Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of the Ministry of Agriculture and elsewhere reported on results from a population sequencing study of the cucumber plant.

The team did deep re-sequencing on representatives from 115 cucumber lines grown around the world and generated an almost 205 million base de novo genome assembly for the wild cucumber plant, Cucumis sativus var. hardwickii.

Within the cucumber sequences, researchers tracked down more than 3.3 million SNPs, hundreds of thousands of small insertions and deletions, and almost 600 sequences that were present in some lines and absent in others.

Along with orthologous gene data from wild and cultivated cucumber plants, this collection of variants was subsequently used to explore everything from cucumber domestication and relationships to the genetics of specific plant nutritional traits. For instance, the group identified more than 100 selective sweeps that appear to have contributed to the process of the plant's domestication.

"This study not only generates valuable genomic resource including additional wild reference genome, genome-wide variations for further studies and breeding applications on cucumber, but also gave us a better picture about how the cucumber genome evolved during domestication," BGI's Xin Liu, co-first author on the study, said in a statement, noting that the work "is also a good example for studies on vegetable or other economic crops."

In mBio, a University of California at Berkeley team presented findings from a cultivation-free genome sequencing study of sediment bacteria from four candidate phyla. By doing deep metagenomic sequencing on sediment samples from an acetate-stimulated aquifer in Rifle, Colo., the investigators generated complete genomes for three previously unknown bacterial representatives and a partial genome for another.

The newly sequenced bugs — which fell into candidate phyla called SR1, WWE3, TM7, and OD1 — all had compact genomes characterized by streamlined biosynthetic pathways, despite containing sequences that seem to code for a slew of previously undescribed proteins.

Along with microbes' biochemical wherewithal, the group scoured the genome sequences for clues to bacterial codon use and sequences that might explain the varying prevalence of bugs from each of the candidate phyla under different environmental conditions.

"As more sequence data from the [candidate phyla] become available, conserved protein families will likely emerge," the study's authors noted, "preparing the way for further exploration at the phylogenetic, biochemical, and structural levels."

Researchers from the Lawrence Berkeley National Laboratory, the US Department of Agriculture's Joint Genome Institute, and elsewhere scrutinized epigenomic patterns and performed in vivo mouse experiments in an effort to identify distant regulatory sequences contributing to face shape — work that they described in Science.

The group focused its attention on distant enhancer sequences, first using chromatin immunoprecipitation sequencing to profile potential enhancers of a protein called p300 in facial tissue from embryonic mice. The search led to just shy of 4,400 distant enhancers with potential ties to facial morphology in the developing mice, including some at sites already suspected of contributing to human face and/or skull development.

Using enhancer reporter assays in transgenic mice, coupled with reporter imaging experiments and targeted deletion studies, the researchers went on to test a subset of the distant candidate enhancers. Indeed, their results suggest that some of the regulatory sequences do play a discernible role in craniofacial development — information that's expected to prove useful for understanding human facial development and conditions that interfere with it.

"Knowing about the existence of these enhancers … knowing their exact location in the human genome, and knowing their general activity pattern in craniofacial development should facilitate a better understanding of the connection between genetics and human craniofacial morphology," senior author Axel Visel, a researcher affiliated with LBNL and JGI, said in a statement.

"Our results also offer an opportunity for human geneticists to look for mutations specifically in enhancers that may play a role in birth defects," he added, "which in turn may help to develop better diagnostic and therapeutic approaches."