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Genomics in the Journals: Arrays 2014.10.16

NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators at Columbia and Yale Universities unveiled previously unknown risk loci for IgA nephropathy, a kidney condition that's among the top kidney failure culprits in China.

To get a more complete look at variants contributing to IgAN, the researchers embarked on a multi-stage genome-wide association study involving tens of thousands of individuals from Europe and East Asia.

Following the discovery phase of the study — which included three cohorts comprising 2,747 individuals of European or Han Chinese ancestry with IgAN and 3,952 controls from the same populations — they tested the most suspicious SNPs in thousands more cases and controls.

By analyzing each cohort alone and in combination, the team tracked down half a dozen new variants with ties to IgAN and confirmed associations at nine more sites in the genome. Four of the signals fell in newly described loci, while two were located in and around sites implicated in IgAN in the past.

Together, these sites seemed to explain some 5 percent of IgAN's heritable risk, the study's authors noted, with population-related differences in some risk allele frequencies apparently contributing to elevated rates of the disease in certain parts of the world, including Asia.

The SNPs tended to overlap with those involved in conditions such as inflammatory bowel disease, pathogen response, and/or typical intestinal cell barrier function, they added, hinting that "follow-up studies of variants for autoimmune and inflammatory disorders, particularly in individuals with early onset of disease, will yield additional genome-wide significant associations and further clarify links to environmental risk factors."

A Nature study considered chromatin interactions behind the 3D architecture of the 13.8-million-base Saccharomyces pombe genome with the help of wild type and mutant strains of the fission yeast species. Researchers from the National Cancer Institute and elsewhere used chromatin conformation capture, or Hi-C, approaches to assess S. pombe genome organization.

Their results revealed roles for cohesin protein-dependent globules in holding together small stretches of chromatin found on the arms of fission yeast chromosomes, with cohesin carrying out functions at these sites that appear distinct from its involvement in holding sister chromatids together during cell division.

Tightly packed forms of DNA known as heterochromatin seemed to influence chromosome organization as well, the researchers reported, though it did not appear to be as crucial to the cohesin-related process of globule structure formation.

"We show that heterochromatin mediates chromatin fiber compaction at centromeres and promotes prominent inter-arm interactions within centromere-proximal regions, providing structural constraints crucial for proper genome organization," they wrote. "Loss of heterochromatin relaxes constrains on chromosomes, causing an increase in intra- and inter-chromosomal interactions."

Columbia University Center for Infection and Immunity researcher Ian Lipkin and colleagues from the US and UK detected a wide range of disease-causing viral, bacterial, and protozoan pathogens when they used molecular tools to test Norway rats (Rattus norvegicus) living in New York City — work they described in mBio.

In an effort to explore the microbial diversity present in urban rats — as well as the animals' potential role as disease reservoirs — the researchers used both targeted assays and high-throughput viral metagenomic sequencing to test urine, feces, rectal swab, oral swab, blood, and/or tissue samples from up to 133 rats collected at five housing, indoor public space, or urban park sites in midtown and lower Manhattan.

Using targeted tests such as strand-specific RT-qPCR assays, for example, the team detected known bacterial pathogens such as enteropathogenic Escherichia coli, Streptobacillus moniliformis, and Bartonella, along with the Seoul hantavirus and the protozoan Cryptosporidium parvum.

In their pooled, metagenomic sequencing study of rat blood, feces, and/or rectal swab samples, meanwhile, the investigators saw sequences from new and known viruses suspected of being capable of infecting mammals. These included viruses from more than a dozen families or genera, many of them similar to viruses known for infecting that rat species.

But there were possible human pathogens amongst the rat-borne viral suspects, too, prompting the study's authors to call for efforts to keep tabs on urban rats as possible disease carriers. "Our findings indicate that urban rats are reservoirs for a vast diversity of microbes that may affect human health," they wrote, "and indicate a need for increased surveillance and awareness of the disease risks associated with urban rodent infestation."

Mammalian gut microbes may shift in response to situations that interfere with typical circadian rhythm cycles such as jet lag or night shift work, leading to gut microbial communities that resemble those found in obese individuals, according to a paper published in Cell.

Israeli researchers used metagenomic sequencing to assess microbial genes in fecal samples from mice exposed to well-defined light and dark periods of the day. From fecal samples collected every six hours over two 24-hour light-dark cycles, they found evidence that some of the microbial genes present in mouse guts oscillated over the course of a day in concert with host feeding patterns and the time of day.

These circadian cycles were upended in mice carrying mutations that interfered with their biological clocks, the researchers reported, leading to a loss of gut microbiome rhythms, a rise in obesity-related gut bugs, and diminished glucose tolerance — patterns that appear to fit with problems described in humans with altered circadian rhythms.

"Our findings highlight a new therapeutic target that may be exploited in future studies to normalize the microbiota in those people whose lifestyle involves frequent alterations in sleep patterns, such as shift workers and very frequent fliers," senior author Eran Elinav, an immunology researcher at the Weizmann Institute of Science, said in a statement.

"Targeting the harmful changes in the microbiota in these large human populations with probiotic or antimicrobial therapies may reduce or even prevent their risk of developing obesity and its complications," he added.