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Genomics In The Journals: Jul 12, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics, researchers involved in the National Heart, Lung, and Blood Institute's GO Exome Sequencing Project report on the extreme phenotype-based strategy that they used to find genetic variants mediating Pseudomonas aeruginosa infection risk in individuals with cystic fibrosis.

The team, led by investigators at the University of Washington, did exome sequencing on 91 individuals with cystic fibrosis who had been enrolled in the Early Pseudomonas Infection Control study or in the Genetic Modifiers Study of cystic fibrosis. By comparing the exomes of 43 individuals who had developed chronic P. aeruginosa infections at early ages to the exomes of 48 of the oldest, chronic infection-free individuals, the team traced infection risk modification back to a dynactin-coding gene called DCTN4 on chromosome 5. The team verified these findings through tests of more individuals with cystic fibrosis, showing that variants in DCTN4 are associated with ages of initial P. aeruginosa infection, chronic infection, and progression to a more advanced mucoid infection state.

Researcher from China, the US, Korea and Saudi Arabia offer a look at some genetic features contributing to salt tolerance in plants in the Proceedings of the National Academy of Sciences. The team sequenced the genome of a salt tolerant Arabidopsis relative previously known as Thellungiella halophila and now called T. salsuginea to delve into the roots of salt, cold, drought, and oxidative stress resistance. Analyses of the resulting draft sequence — an almost 234 million base draft assembly that covers roughly 90 percent of the plant's genome sequence to a depth of around 134 times — revealed some 28,457 predicted protein-coding genes and a preponderance of transposable element sequences. The investigators' comparisons between the T. salsuginea genome and those of other plants, including A. thaliana, hint that stress tolerance in T. salsuginea could stem from contributions made by genes involved in everything from ion transport to the maintenance of a waxy outer coating that helps the plant hold in water.

"This genome provides resources and evidence about the nature of defense mechanisms constituting the genetic basis underlying plant abiotic stress tolerance," the study's authors wrote.

Also in PNAS, a paper provides insights into the inheritance of DNA methylation patterns in rice as well as the interplay between rice methylome and transcriptome patterns.

An American team used bisulfite sequencing, RNA sequencing, and small interfering RNA sequencing to test two inbred rice sub-species — a Oryza sativa spp japonica variety known as Nipponbare, or NPB, and a O. sativa spp indica cultivar called 93-11 — along with two hybrid rice plants produced by crossing NPB and 93-11. Together, this data made it possible to track down SNPs between the plants, along with parts of the genome that were differentially methylated and/or expressed in each of them — information that researchers used to assess methylation changes across generations and their causes and consequences. For instance, results from the study suggest that DNA methylation is quite variable from one rice generation to the next, especially within parts of the genome where parental strains produce different siRNAs.

Those involved in the study say the results "reinforce the notion of epigenetic plasticity and suggest that it may play important roles in both environmental adaptation and hybrid vigor."

An international team led by investigators at Decode Genetics characterized a coding substitution in the amyloid beta precursor protein-coding gene APP that protects against Alzheimer's disease and cognitive decline — work that is described in Nature.

The researchers pinpointed the change, which swaps out the amino acid alanine for threonine at position 673 in the resulting protein, by scouring APP sequences in a collection of genomes representing almost 1,800 Icelanders and doing imputation in tens of thousands more individuals from the same populations who were tested using arrays.

After verifying the association in other cohorts, collaborators from the San Francisco-based pharmaceutical company Genentech went on to show that cells harboring this mutant version of APP churn out lower-than-usual levels of amyloid beta peptide — a cleavage product produced from the APP protein that's been implicated in Alzheimer's disease. Because the substitution falls near a site targeted by the APP chopping enzyme encoded by BACE1, the team reasoned that the same protective effects might be possible by targeting BACE1 directly.

"Our results suggest that late-onset Alzheimer's disease may represent the extreme of more general age-related decline in cognitive function," University of Iceland researcher and Decode CEO Kari Stefansson, the study's senior author said in a statement.

"Our findings and the in vitro work done by Genentech also provide a proof of principle for the idea that blocking BACE1 cleavage of APP may protect against Alzheimer's," Stefansson added, "offering greater confidence to pharmaceutical companies with active BACE1 inhibitor drug development programs."

Existing methods for finding and interpreting variation in the human genome appear to be ill equipped to deal with the extent and complexity of the variation that's actually present in human populations, a PLoS ONE study finds.

Researchers from PerkinElmer, the University of Medicine & Dentistry of New Jersey, and Weill Cornell Medical College tapped HapMap data, along with genome sequences generated for the 1000 Genomes Project and by Complete Genomics, to explore the accuracy of tools and techniques based on the human reference genome — from the microarray probes used to genotype samples in genome-wide association studies to computational methods for calling variants.

Based on the changeable variant and linkage disequilibrium patterns they found in the samples, including altered variant profiles for shared genomes tested in different analyses, the team argued that comparisons between individual genomes and a human reference sequence in the clinical arena may not be as straightforward as previously believed.

"Resources such as microarrays and bioinformatics programs, as well as guiding assumptions used in genetic studies need to be revised," PerkinElmer researcher Todd Smith, the study's senior author, said in a statement.

"For example," he explained, "regions of linkage disequilibrium and runs of homozygosity, used to tag and predict disease alleles, are much shorter than previously estimated and we found that many GWAS studies contain potentially complicating unprobed variants."

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

The Scan

Self-Reported Hearing Loss in Older Adults Begins Very Early in Life, Study Says

A JAMA Otolaryngology — Head & Neck Surgery study says polygenic risk scores associated with hearing loss in older adults is also associated with hearing decline in younger groups.

Genome-Wide Analysis Sheds Light on Genetics of ADHD

A genome-wide association study meta-analysis of attention-deficit hyperactivity disorder appearing in Nature Genetics links 76 genes to risk of having the disorder.

MicroRNA Cotargeting Linked to Lupus

A mouse-based study appearing in BMC Biology implicates two microRNAs with overlapping target sites in lupus.

Enzyme Involved in Lipid Metabolism Linked to Mutational Signatures

In Nature Genetics, a Wellcome Sanger Institute-led team found that APOBEC1 may contribute to the development of the SBS2 and SBS13 mutational signatures in the small intestine.