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Genomics In The Journals: Oct 13, 2011

NEW YORK (GenomeWeb News) – In PLoS Genetics, members of the Cohorts for Heart and Aging Research in Genomic Epidemiology, or CHARGE, consortium report on genetic loci linked to testosterone levels in men.

The researchers did a genome-wide association study meta-analysis using data for more than 8,900 Caucasian men assessed through seven studies to look for sites in the genome coinciding with serum testosterone concentrations. When they followed up on the most promising candidate loci in two replication groups comprised of 4,620 individuals and an in silico dataset representing 871 individuals, they found a pair of variants at a locus near the chromosome 17 gene SHBG that were significantly associated with low testosterone levels, as well as a testosterone-associated SNP near FAM9B on the X chromosome.

"Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk," corresponding author Claes Ohlsson, a researcher at the University of Gothenburg in Sweden, and co-authors wrote. "The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone."

By resequencing genes affected by common variants in past GWAS of Crohn's disease, an international research team has found new, rare, or low-frequency variants that contribute to inflammatory bowel disease risk. The researchers did pooled, deep sequencing of 56 genes near Crohn's disease-associated loci in 350 individuals with and 350 individuals without the disease. They then genotyped nearly 17,600 healthy controls and tens of thousands of individuals with Crohn's disease or ulcerative colitis at 70 non-synonymous variants identified in the first phase of the study, identifying several rare variants that seem to have functional roles in IBD. The team reported their findings in Nature Genetics.

A Broad-led research team used comparisons between the genomes of 29 mammalian species to track down evolutionarily constrained elements making up more than four percent of the human genome. As they report in Nature, these elements included millions of new regulatory sites, new RNA secondary structure families, and thousands of exons not found before. The researchers also identified elements that appear to have undergone rapid evolutionary change specifically within the primate lineage.

"This new map reveals almost 3 million previously undetectable elements in non-coding regions that have been carefully preserved across all mammals, and whose disruptions appear to be associated with human disease," co-corresponding author Manolis Kellis, a researcher affiliated with the Broad Institute and MIT's computer science and artificial intelligence laboratory, said in a statement. "We can use this treasure trove of new elements to revisit disease association studies, focusing on those that disrupt conserved elements and trying to discern their likely functions."

Also in Nature, researchers from Germany, Canada, and the US describe the approach that they used to sequence a draft version of the Yersinia pestis genome from Black Death plague victims.

Using Agilent array-based sequence capture, the team enriched for Y. pestis sequences from DNA found in teeth collected at a London burial ground used for plague victims at the end of 1348 and beginning of 1349. They then sequenced the pandemic pathogen's genome to an average depth of 30 times with the Illumina GAII. Their phylogenetic analyses and comparisons to modern day bacterial strains hint that the ancient Black Death strain is ancestral to versions of Y. pestis causing infections in humans today. And, they say, the mass casualties caused by the plague may not have stemmed from an exceptionally virulent version of Y. pestis, but might have been a consequence of interactions between the pathogen and other contributors.

"[W]e posit that molecular changes in pathogens are but one component of a constellation of factors contributing to changing infectious disease prevalence and severity," co-corresponding authors Johannes Krause of the University of Tübingen and Hendrik Poinar of McMaster University Ancient DNA Centre, and their colleagues concluded, "where genetics of the host population, climate, vector dynamics, social conditions, and synergistic interactions with concurrent diseases should be foremost in discussions of population susceptibility to infectious disease and host-pathogen relationships with reference to Y. pestis infections."

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

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