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Genomics in the Journals: Nov 14, 2013

NEW YORK (GenomeWeb News) – A New England Journal of Medicine study suggests high-risk variants in the apolipoprotein L1 gene APOL1 can contribute to more rapid kidney disease progression in individuals of African American ancestry.

Using genotyping data for thousands of African American or Caucasian individuals enrolled in two large kidney disease studies, researchers from Johns Hopkins University, the University of Maryland, and elsewhere assessed APOL1 variants previously suspected of contributing to elevated risk of chronic kidney disease and other conditions in African Americans.

For 693 African American individuals with hypertension-related chronic kidney disease without diabetes evaluated as part of the African American Study of Kidney Disease and Hypertension, for instance, the team found disease progression differences depending on the number of high-risk APOL1 variants in an individual's genome. Nearly 60 percent of individuals with two copies of the high-risk APOL1 variants progressed to end-stage renal disease. In contrast, less than 37 percent of individuals with one or no copies of the SNPs reached that disease stage.

Similar patterns emerged for high-risk APOL1 variant carriers in a group of almost 3,000 African American or Caucasian individuals evaluated as part of the Chronic Renal Insufficiency Cohort. In that cohort, the team determined that African Americans progressed to severe kidney disease more often than Caucasians, who also appear to be less frequent carriers of high-risk APOL1 alleles. But the decline in kidney function was further hastened by the presence of risky versions of APOL1.

"What we found is pretty remarkable — that variations in a single gene account for much of the racial disparity in kidney disease progression and risk for end-stage kidney disease," co-lead author Afshin Parsa, with the University of Maryland School of Medicine, said in a statement.

In Nature Genetics, researchers from the UK, Spain, and the US folded in epigenetic information as a means of interpreting whole-genome sequence data — an approach that helped them unearth recessive, non-protein coding mutations contributing to a condition called pancreatic agenesis.

The team did linkage assessments on individuals from three families affected by pancreatic agenesis, a condition characterized by the absence of a pancreas at birth and related complications throughout life such as diabetes and digestion problems.

Samples from two affected individuals were also subjected to whole-genome sequencing. Using this data, together with epigenomic profiles generated for pancreatic progenitor cells produced from human embryonic stem cells, investigators narrowed in on half a dozen recessive mutations that appear capable of causing pancreatic agenesis.

All six alterations clustered in a region downstream of a gene called PTF1A, they noted, a gene known to code for a pancreas-specific transcription factor. And follow-up experiments suggested that the newly detected pancreatic agenesis-associated mutations fall in an area acting as a developmental enhancer for the gene.

"This finding gives a deeper understanding to families affected by this disorder, and it also tells us more about how the pancreas develops," co-corresponding author Andrew Hattersley, a biomedical and clinical science researcher with the University of Exeter Medical School, said in a statement. "In the longer term, this insight could have implications for regenerative stem cell treatments for type 1 diabetes."

Microbial communities found in the guts of healthy children in the US are home to antibiotic resistance genes, according to a PLOS One paper. For that study, a Washington University-led team produced metagenomic sequence libraries from microbial DNA found in fecal samples from nearly two-dozen children between the ages of one month and 19 years old.

To track down antibiotic resistance genes in the children's gut microbial communities, researchers placed the metagenomic libraries into Escherichia coli, looking for recombination events that would alter the host bug's susceptibility or resistance to 18 different antibiotics.

While sequencing, assembling, and annotating gut microbial genes with apparent functional effects, the group unearthed 2,489 antibiotic resistance genes suspected of contributing to the resistance detected against 14 of the 18 antibiotics. Three of the new resistance genes were subsequently characterized in more detail.

"Frequent exposure to antibiotics accelerates the spread of antibiotic resistance," Washington University pathology and immunology researcher Gautam Dantas, the study's senior author, said in a statement. "Our research highlights how important it is to only use these drugs when they are truly needed."

University of California at Los Angeles ecology and evolutionary biology researcher Robert Wayne and collaborators from the US and other centers around the world profiled mitochondrial DNA from ancient dog fossils and from contemporary dogs and wolves in Eurasia and the New World as part of their analysis of dog domestication — work they described in Science.

The team used targeted capture sequencing to assess mitochondrial genomes from 18 ancient dog samples and 20 modern-day wolf samples from Eurasia and the Americas.

Through comparisons with nearly 150 more mitochondrial genomes from various domestic dog breeds or wild dog types, they determined that dogs in many parts of the world — including canids living in the New World before Columbus' arrival — share mitochondrial ties to Europe.

Based on the phylogeny, diversity, and other patterns detected in the canid clades defined in the study, the group estimated that dog domestication occurred in Europe sometime over the last 18,800 to 32,100 years.

"[O]ur results support the hypothesis that dog domestication preceded the emergence of agriculture and occurred in the context of European hunter-gatherer cultures," Wayne and his co-authors wrote, though they noted that "a more complete and nuanced picture of dog domestication will likely emerge with the addition of ancient canine mtDNA data from the Middle East and Asia."