Dan Koboldt at MassGenomics explains why exome sequencing often fails to identify causal variants, even in Mendelian disorders — "the very plausible possibility that a noncoding functional variant is responsible."

Koboldt, the analysis manager in the human genetics group at the Genome Institute at Washington University, says that researchers shouldn't overlook the importance of noncoding functional variants, which require a suite of technologies to detect, including RNA-seq, ChiP-seq, DNAse sequencing and footprinting, bisulfite sequencing, and chromosome conformation capture.

"These types of experiments generate a wealth of data about regulatory activity in genomes," he says. "While studying each of these independently is certainly informative, integrative analysis will be required to elucidate how all of these different regulatory mechanisms work together."

While this effort will require "robust statistical models, substantial computing resources, and productive collaboration among research groups, the end result "will be a far more complete understanding of how the genome works," he says.

Depending on how patent claims are interpreted, much of the human genome could be covered by them, say the University of Medicine and Dentistry of New Jersey's Jeffrey Rosenfeld and Christopher Mason from Cornell University in Genome Medicine.

Rosenfeld and Mason note that some gene patent claims, and rulings regarding those claims, focus on sequences as short as 15 nucleotides in length. Using the Consensus Coding Sequences database, they determined that 15-mer stretches from every gene in the human genome correspond to at least one other gene — they particularly note that 15-mers from the BRCA1 gene match 689 other genes. "These results demonstrated that short patent sequences are extremely non-specific and that a 15-mer patent claim from one gene will always 'cross-match' and patent a portion of another gene as well," Rosenfeld and Mason write.

They matched known genes to full-length genes included in patent filings, finding that about 41 percent of the human genome is under patent claims. When they examined 15-mer lengths of patented genes, the whole of the human genome appeared to be covered. A gene patented for improving bovine traits, they add, also corresponds to a number of human genes.

"If patent claims that use these 15-mer or other short k-mer sizes are enforced, it could potentially create a situation where a piece of every gene in the human genome is patented by a phalanx of competing patents, with potentially harmful consequences for genetic testing laboratories and research groups performing targeted sequencing on any gene, in virtually all species," they argue.

HT: Mike the Mad Biologist

In the early, online version of the Proceedings of the National Academy of Sciences, an international team led by investigators at Pennsylvania State University describes how it used genome sequencing to explore population patterns for the aye-aye — a nocturnal lemur species — in Madagascar. Using whole-genome sequence data on a dozen aye-ayes from the northern, western, or eastern parts of Madagascar, the researchers saw signs of genetic differentiation between aye-aye populations. That differentiation was particularly pronounced for aye-ayes from Madagascar's north, they report, pointing ongoing gene flow barriers between this lemur population and those found in other parts of the country.

Researchers from the University of California, Davis, and the University of British Columbia take a look at DNA methylation profiles in the human placenta for another PNAS study. The group performed MethylC-sequencing on DNA from full-term placental tissue, uncovering evidence of partially methylated domains over more than one-third of the genome. So far, such partially methylated domains have mainly been found in cancer samples or cell lines, the study authors say. But the new study suggests that these partially methylated epigenetic marks are stable in the placental genome over gestation, apparently contributing to gene regulation.

Southern European cattle introduced to the New World by Spanish settlers in the late 1400s primarily belonged to the so-called taurine lineage, but likely carried some genes from indicine cattle as well, according to a genomics-based study by researchers at the University of Texas at Austin and the University of Missouri. The team used new and existing genotyping data on almost 1,500 cattle — representing dozens of New World breeds as well as animals from Europe, Africa, and Asia — to assess ancestry patterns and selection histories of New World cattle. The analysis uncovered signs of previously unappreciated introgression from African cattle into the ancestors of Texas Longhorns and other present-day New World breeds, for example, as well as clues to the role that natural selection may have played in shaping New World cattle traits.

The US Congress passed a spending bill last week that may slightly dull the effects of the sequester cuts for science agencies. The bill, which is a continuing resolution, makes changes to the sequester cuts, though it leaves most of those affecting discretionary spending in place, ScienceInsider says.

As the Nature News blog reports, the bill gives the US National Institutes of Health an additional $67 million, though the agency lost about $1.6 billion of its $30.7 billion 2012 budget to the sequester. Similarly, the National Science Foundation would see an increase of about $90 million under this bill, but it also lost about 5.1 percent of its $7 billion 2012 budget to sequestration.

"We applaud this bipartisan gesture, but sequestration continues to cast a shadow on advancing science and innovation," Mary Woolley, Research!America's president and chief executive officer, tells Nature in a statement.

Both the House of Representatives and the Senate passed this bill, and President Barack Obama is set to sign it this week, the Washington Post adds.

In PLOS One, researchers from South Africa, Germany, and Namibia describe findings from a phylogenetic study aimed at understanding how rabies is maintained within Namibia's kudu — the only kudu population known to carry the disease. Based on patterns in partial or whole-genome sequences from dozens of rabies virus isolates from kudu — a kind of antelope — or other animals, the team saw a distinct genetic cluster containing 42 of the 43 kudu-associated rabies viruses. These viruses were distinct from those found in jackals and other canids in the area, study authors note, which is consistent with the notion that rabies is transmitted and maintained in Namibian kudu in cycles that are independent of those detected in the canids. The investigators also uncovered kudu-specific mutations suspected of helping rabies virus survive and spread in kudu.

A fine-mapping study in PLOS Genetics suggests that at least some lipid-linked loci contain variants with population-specific effects. A large international team led by investigators at several centers in the US and Taiwan focused on dozens of loci linked to blood levels of triglyceride, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol previously. By fine-mapping these sites in tens of thousands of individuals from African-American, East Asian, or European populations, the researchers saw that most loci shared ties with the lipid-related traits of interest in at least one of the populations. But the analyses also unearthed examples of loci with distinct signals depending on the population considered. "[T]rans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies," they write.

Aedes albopictus mosquitoes on Réunion Island cluster genetically in ways that correspond with urban and rural mosquito populations, according to a PLOS Neglected Tropical Diseases study. French researchers embarked on an ecological and genetic study of Ae. albopictus mosquitoes, which can transmit Chikungunya, Dengue, and other disease-causing viruses. Using microsatellite DNA analyses — combined with ecological assessments that considered everything from reproduction and development to survival rates in rural and urban populations — the team got new clues to Ae. albopictus population dynamics. For instance, investigators found that though mosquito populations in rural and urban areas on Réunion Island are structured genetically, mosquitoes from natural environments can still serve as a mosquito reservoir for urban areas.

As the American College of Medical Genetics and Genomics this week issued recommendations regarding the release to doctors and patients of incidental genetic findings from clinical sequencing studies, Caroline Wright at Genomes Unzipped questions whether the term "incidental" is appropriate for describing such findings in the first place.

"One of the things that has always bothered me about the [incidental findings] debate in genomics is the idea that these findings are ‘incidental’ at all – that we just can’t help but stumble upon significant variants while reading peoples’ genomes," Wright says. "In this fantasy world, researchers and clinicians who don’t share [incidental findings] with people must be hiding them somewhere, stowed away in a drawer marked ‘Confidential’."

Wright speculates that this perception is "partly a result of the frequent comparison with medical imaging, where radiologists really can’t help but see [incidental findings]. However, the situation in genomics is less like a spot-the-different picture and more like a well-worded Google search."

As an example, she notes that analyzing someone’s genome for a genetic predisposition to breast cancer "is unlikely to incidentally throw up the fact that they also have a dominant neurodegenerative disease – the mutations are in different locations and will not both be extracted by a computational search for either one of them."

Wright argues that "simply stumbling upon" clinically actionable incidental findings in a whole genome sequence is "highly unlikely" and notes that the real question should be whether researchers have an obligation to actively look for certain types of variants when conducting whole-exome or whole-genome sequencing.

She says that throwing away the “stumble strategy” would "allow disclosure of specific classes of variants to become an evidence-based decision rather than a process of random luck."

Meanwhile, the Nature News Blog reports that there has been some criticism about the ACMG's recommendations on incidental genetic findings being "too conservative."

ACMG acknowledges in a document outlining its recommendations that it sought to reach a compromise between "genetic libertarians who feel that patients have the right to full and complete accounting of all possible risks,” and "genetic empiricists who believe that there is insufficient evidence about the penetrance of most pathogenic variants in the general population to warrant the sharing of any incidental findings."

Gholson Lyon of Cold Spring Harbor Laboratory tells the Nature News Blog that the recommendations are “biased heavily” in favor of the empiricists and could limit the ability of researchers to analyze clinical genomes for research.

On the other end of the spectrum, Nancy Spinner, chief of the division of genomic diagnostics at the Children’s Hospital of Philadelphia, tells the blog that her team actually takes "a little more of a conservative approach” than the ACMG recommends.

ACMG says that its recommendations "should, and will, evolve, as further empirical data are collected on the actual penetrance of these variants, and on the health benefits and costs that might follow from their disclosure as incidental findings."