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Genomics In The Journals: Oct 10, 2013

NEW YORK (GenomeWeb News) – A pair of papers appearing in Nature Genetics this week detailed loci linked to the autoimmune disease Sjögren's syndrome.

In the first, researchers from the Oklahoma Medical Research Foundation and the Oklahoma Health Sciences Center in Oklahoma City and elsewhere reported six loci associated with risk of developing the syndrome. By combining a genome-wide association study and large-scale replications, together consisting of nearly 16,800 people of European descent, the researchers confirmed an association between HLA and the syndrome and determined that IRF5-TNPO3, IL12A, STAT4, FAM167A-BLK, DDX6-CXCR5, and TNIP1 are also risk loci.

IRF5, IL12A, and STAT4, the researchers noted, are part of the type I interferon pathway signaling while CXCR5 and BLK are involved in the adaptive immune response. The function of TNIP1 remains unclear.

"Together these results highlight the importance of the innate and adaptive immune systems in the etiology of Sjögren's syndrome," the Oklahoma-led team writes. "Future work will be needed to replicate these additional candidate associations and characterize the causal variant(s) for the regions established in this study."

The second paper from a team based in China reported that they uncovered a susceptibility locus for Sjögren's syndrome in Han Chinese at 7q11.23

Through a three-stage genome-wide association study of some 1,850 cases and 3,780 controls, the team confirmed susceptibility loci, including STAT4, that had been uncovered in European populations and found an additional locus at GTF2IRD1-GTF2I. GTF2I, the team added, encodes a transcription factor that is involved in both transcription and signal transduction, and it has previously been linked to the neurocognitive defects of Williams-Beuren syndrome.

"Further resequencing of the GTF2IRD1-GTF2I risk haplotype and association mapping of newly identified variants, as well as functional studies of GTF2IRD1 and GTF2I, are expected to help clarify how they are involved in autoimmunity and primary Sjögren's syndrome," the group reported.

In a set of papers published in Science today researchers examined the paths that ancient people traced across Europe. In one, researchers from the Genographic Consortium and elsewhere reported that they created mitochondrial DNA profiles for more than 360 people from 25 archaeological sites in Germany spanning some 4,000 years and nine archaeological cultures.

"Focusing on this small but highly important geographic region meant we could generate a gapless record, and directly observe genetic changes in 'real-time' from 7,500 to 3,500 years ago, from the earliest farmers to the early Bronze Age," co-lead author Wolfgang Haak from the Australian Centre for Ancient DNA said in a statement.

Haak and his colleagues found that there was a period of relative genetic continuity for the first 2,500 years after the introduction of farming in Central Europe. But, a series of four shifts in genetic composition occurred in the later Neolithic. Those changes, the researchers noted, coincided with waves of migration from Scandinavia and then from the east and the west.

In a related paper, Johannes Gutenberg University's Joachim Burger and his colleagues reported that European hunter-gatherers and farmers coexisted for some 2,000 years in Central Europe.

Burger and his team studied ancient DNA from 29 people whose remains were found in a burial cave containing both Mesolithic hunter-gatherers and Neolithic individuals. The DNA samples suggested that the Neolithic samples were farmers with a high degree of Mesolithic ancestry. However, the researchers added that their dietary isotope analysis indicated an unusual diet.

Combining these data, they concluded that there were likely two Neolithic populations whose remains were in the cave: one group that ate farmed food and one that ate foraged foods and freshwater fish. That second group, they added, had mtDNA sequences similar to Mesolithic hunter-gatherers.

"It is commonly assumed that the European hunter-gatherers disappeared soon after the arrival of farmers," Ruth Bollongino, lead author of the study, said in a statement. "But our study shows that the descendants of the first European humans maintained their hunter-gatherer way of life, and lived in parallel with the immigrant farmers, for at least 2,000 years."

In PLOS One, Theodore Friedmann at the University of California, San Diego and his colleagues reported that a mutation in the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase behind the neurological disorder Lesch-Nyhan may play a role in other neurological diseases.

Using RNA-seq and microarray approaches, Friedmann and his colleagues studied transcriptional changes in HPRT-knockdown mouse embryonic stem cells during neuronal differentiation. While the HPRT-deficient mice developed dopaminergic neuronal cells at the same rate as wild-type mice, the deficient cells did exhibit changes in the expression of certain neurogenesis genes. Further, deficient cells had perturbations to their cell cycle and proliferation, RNA metabolism, and DNA replication and repair, among other processes.

"We believe that the neural aberrations of HPRT deficiency are the consequence of these combined, multi-system metabolic errors," Friedmann said in a statement. "And since some of these aberrations are also found in other neurological disorders, we think they almost certainly play some role in causing the neurological abnormalities in diseases like Alzheimer's, Parkinson's, Huntington's, and possibly others. That makes them potential therapeutic targets for conditions that currently have limited or no treatments, let alone cures."

Researchers led by Lawrence Shapiro from the US National Human Genome Research Institute and Columbia University reported in the Proceedings of the National Academy of Sciences this week that they have identified an antibody that neutralizes HIV-1 by sequencing an antibody repertoire.

To identify VRC01 class antibodies, which have previously been found to target the CD4-binding site, the investigators sequenced and performed a phylogenetic analysis of transcripts from the donor's B cells. From this, they identified a number of VRC01 class heavy chains, though they had little sequence homology with known VRC01 heavy chains.

Parsing through a million or so light chain sequences, Shapiro and his team focused on 13 candidate VRC01 class members. Pairing those light chains with C38 heavy chains, they found that the antibodies could neutralize HIV-1.

"Our bioinformatics methods identified heavy and light chains from a new donor that could form functional antibodies and neutralize HIV-1 effectively," Shapiro and his colleagues wrote. "Identification of HIV-1 neutralizing antibodies of the VRC01 class can thus occur solely on the basis of bioinformatics analysis of a sequenced antibody repertoire."

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