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Genomics In The Journals: May 19, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – An international group headed by investigators at King's College London reported in the American Journal of Psychiatry that it has tracked down a linkage peak on chromosome 3 that's associated with heightened risk of severe, recurrent depression. The team found the region through a genome-wide linkage analysis involving 839 families enrolled through the Depression Network Study. Among the participants were 971 sibling pairs diagnosed with severe, recurrent major depression.

In a second American Journal of Psychiatry paper, an independent team led by researchers at Washington University identified the same chromosome 3 region when they did their own linkage analyses on individuals from 91 Australian families and 25 families in Finland. The families had been classified as heavy smokers, a group that tends to be at elevated depression risk.

"What's remarkable is that both groups found exactly the same region in two separate studies," Washington University psychiatry researcher Pamela Madden, who was senior author on the US-led study, said in a statement.

The region contains at least one gene, GRM7, which has been loosely linked to depression in the past. But more research is needed to determine whether GRM7 accounts for the newly detected association, since the chromosome 3 locus contains dozens of genes. Moreover, researchers say there may be other depression risk loci elsewhere in the genome.

"The findings are groundbreaking," King's College London's Medical Research Council Social, Genetic and Developmental Psychiatry Centre Director Peter McGuffin, who was senior author on the British-led study, said in a statement. "However, they still only account for a small proportion of the genetic risk for depression. More and larger studies will be required to find the other parts of the genome involved."

Researchers from the University of California at San Diego and the Massachusetts-based bioinformatics company Digomics used chromatin immunoprecipitation and global run-on sequencing with the Illumina GAII to look at the gene expression consequences of dialing back levels of the prostate cell lineage-specific transcription enhancer FoxA1 — a situation seen in advanced prostate cancers with particularly poor outcomes. The findings, published in Nature, indicate that shifts in FoxA1 levels correspond to widespread changes in gene expression and androgen receptor binding patterns. Those involved in the study argue that subsequent changes in hormone response may explain, in part, how prostate cancers dodge hormone-based therapies.

"Together, these findings provide a conceptual framework to understand complex gene-expression switching events, as occurs during disease progression and development," co-corresponding author Xiang-Dong Fu, a cellular and molecular medicine researcher at UCSD, and co-authors wrote.

In Nature, Indiana University biologist Michael Lynch and co-author Ariel Fernández, a computer science and bioengineering researcher affiliated with the University of Chicago and Rice University, argue that changes in protein structure resulting from haphazard, mildly damaging mutations — and not just adaptive genetic mutations — can drive evolutionary change. The pair used mathematical models that take effective population size into account to show that protein sub-unit stability in water goes down with increasing random genetic drift. Based on patterns for 106 orthologous protein groups from 36 prokaryotic and eukaryotic species with a range of effective population sizes, they argue that larger organisms with smaller population sizes tend to have more protein foibles, leading to stickier proteins that are more likely to interact with other proteins, spurring complexity and evolutionary change.

"[O]ur results do raise questions about the necessity of invoking an intrinsic advantage to organismal complexity, and provide a strong rationale for expanding comparative studies in molecular evolution beyond linear sequence analysis to evaluations of molecular structure," the authors said.

A study in Science by researchers in the US, Italy, and France explores processes by which animals with similar diets evolve gut microbial communities with shared functional features. The Washington University-led team used a combination of shotgun pyrosequencing and 16S ribosomal RNA sequencing of fecal DNA to look at species compositions and functional capabilities for gut microbiomes within and between mammalian species. Based on their findings for 18 humans with well-documented dietary histories, and representatives from 33 other mammalian species with diverse diets and digestive strategies, the team found similar, diet-related gut microbial adaptations cropping up in various animal lineages.

"[O]ur findings emphasize the need to sample humans across the globe with a variety of extreme diets and lifestyles, including relatively ancestral hunter-gatherer lifestyles," senior author Jeffrey Gordon, a researcher at Washington University's Center for Genome Sciences, and co-authors wrote, "in order to provide new insights into the limits of variation within a host species and the possibility that microbes, in co-evolving with our bodies and our cultures, have helped shape our physiological differences and environmental adaptations."

Gordon also led a second team of researchers who used germ-free mouse models to look at how gut microbiomes adapt to dietary change. The team transplanted 13 germ-free mice with a gut microbial community consisting of 10 characterized human gut bacterial species. They then fed the mice food that contained with specific fat, protein, simple sugar, and complex sugar content, changing up each animal's diet every two weeks. As they reported in Science, shotgun sequencing and RNA sequencing of microbial DNA and RNA in mouse feces allowed them to model how each diet affected species abundance and gene expression in mouse gut microbiomes.

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

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