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Genomics in the Journals: Feb 13, 2014

NEW YORK (GenomeWeb News) – In Nature Genetics, members of several large consortia came together to perform a meta-analysis of prior genome-wide association studies focused on type 2 diabetes.

Based on data for 26,488 European, East Asian, South Asian, Mexican, or Mexican American individuals with type 2 diabetes and nearly 84,000 unaffected controls from the same populations, the researchers determined that the directionality of diabetes risk SNPs was largely consistent across the ancestry groups considered.

In addition to fine-mapping of known type 2 diabetes risk loci, the team also performed follow-up analysis of suspicious SNPs in another 21,491 type 2 diabetes cases and 55,647 controls, all of European ancestry — a search that led to seven risk loci not previously implicated in the disease.

"The overlap in signals between populations of European, Asian, and Hispanic origin argues that the risk regions we have found to date do not explain the clear differences in the patterns of diabetes between those groups," the University of Oxford's Mark McCarthy, a co-corresponding author on the study, said in a statement.


Tibetan highlanders appear to have ancestry that can be traced back to both Nepalese Sherpa and Han Chinese-related populations, according to a Nature Communications study. The research suggests such historical admixture events helped shape adaptive variation in key altitude-related genes in present-day Tibetans.

Researchers from the US and Nepal brought together new SNP profiles for 69 Sherpa individuals from the Himalayas with existing genotyping data on almost 100 Tibetans as well as HapMap3 data on individuals from populations in India, Central Asia, and Siberia.

Together, findings from the team's analyses suggested that the ancestors of present-day Sherpa and Han Chinese populations mixed around tens of thousands of years ago, eventually leading to existing Tibetan populations.

In the time since members of the Tibetan population made their way to the Tibetan plateau an estimated 30,000 years ago, selective enrichment appears to have acted on genes such as EGLN1 and EPAS1, researchers reported, leading to high elevation adaptations in high-altitude Tibetan populations that are shared with Sherpas.

On the other hand, the study authors reported, Tibetans living at low altitude do not carry such adaptations and are more similar to Han Chinese-related ancestors across such regions of the genome.

"The Tibetan genome appears to arise from a mixture of two ancestral gene pools," University of Chicago genetics researcher Anna Di Rienzo, the study's corresponding author, said in a statement.

"One migrated early to high altitude and adapted to this environment," Di Rienzo explained. "The other, which migrated more recently from low altitudes, acquired the advantageous alleles from the resident high-altitude population by interbreeding and forming what we refer to today as Tibetans."


Meanwhile, a Molecular Biology and Evolution study explored the genetics of altitude adaptation in the Tibetan Mastiff, a dog breed believed to have originated in China that has become adept at surviving high elevations of the Tibetan plateau.

Using Affymetrix canine arrays, researchers from China, the US, and Canada genotyped 32 Tibetan Mastiffs. Their comparison of the SNP profiles in these animals with those in 20 native Chinese dogs and 14 grey wolves unearthed signs of positive selection affecting 16 Tibetan Mastiff genes.

Of those, a dozen genes appear to play a particular role in high-altitude adaptations, including genes involved in energy metabolism and blood vessel formation and the canine version of EPAS1 — a hypoxia-associated gene linked to high-altitude adaptation in humans living in Tibet's highlands.

The latter finding suggests some convergent evolution may have occurred in humans and dogs living in the region, explained the study's co-corresponding author Dong-Dong Wu, based at the Chinese Academy of Sciences. In a statement, he noted that such findings show that "independently, genes can be adaptively evolved to yield similar phenotypic adaptive responses."


Researchers from Japan and Argentina used targeted gene sequencing to look for variants in the complement protein-coding gene C5 that influence individuals' response to the drug eculizumab — work they reported in the New England Journal of Medicine.

The humanized monoclonal antibody-based treatment is used to slow red blood cell recycling in paroxysmal nocturnal hemoglobinuria, study authors explained, a condition characterized by premature breakdown of the cells. But past studies have shown that a subset of individuals from the Japanese population respond poorly to the treatment, which acts by targeting complement protein-related hemolysis.

In an effort to understand the genetic basis of diminished eculizumab response, the team started by sequencing the C5 complement protein gene in 345 Japanese individuals treated with the drug, including 11 who showed poor response to it.

The search led to a heterozygous point mutation in C5 that coincided with reduced eculizumab response, the researchers reported, noting that this version of the gene is found in more than 3 percent of the Japanese population.

The team also saw a distinct point mutation in C5 affecting the same amino acid residue (arginine 885, or Arg885) in an Argentinean patient of Asian descent who had poor eculizumab response. Follow-up experiments indicated that the drug-resistant forms of C5 are less apt to bind to and be inhibited by eculizumab, though they can still spur on early red blood cell breakdown.

"The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations," the study's authors wrote.

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.