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Genomics In The Journals: Aug 2, 2012

NEW YORK (GenomeWeb News) – Studies in Nature Genetics by four independent research groups are pointing to the same candidate gene, NMNAT1, in a form of inherited blindness that develops shortly after birth or during an infant's first year of life.

Researchers from each team tracked down mutations in the enzyme-coding gene through exome sequencing experiments on individuals or families affected by a condition called Leber congenital amaurosis, or LCA. Alterations in NMNAT1 also turned up in a subset of LCA-affected individuals who were screened in each group's follow-up analyses.

The reason for the relationship between NMNAT1 mutation and retinal degeneration is still a matter of debate. Some point to the gene's potential role in protecting against neurodegeneration as a possible explanation. Others report that at least one of the LCA-associated mutations in NMNAT1 can reduce the enzymatic activity of the resulting protein, leading to lower levels of a coenzyme important to many metabolic pathways.


A Yale University-led team used exome sequencing to track new recurrent mutations in melanoma — work it describes in another Nature Genetics article. The researchers sequenced protein-coding regions from 147 primary or metastatic melanoma samples, comparing patterns in these sequences to those found in matched normal exomes. As expected, the number of mutations per melanoma exome varied depending on whether the tumor originated from a sun-exposed or sun-shielded site on the body: sun-exposed samples contained more mutations overall and tended to contain the kinds of DNA damage that have been attributed to ultraviolet.

Along with mutations affecting genes previously linked to melanoma, the group tracked down new genes with recurrent mutations. For instance, some of the sun-exposed tumors that harbored BRAF or NRAS mutations also had alterations affecting the active site of the enzyme-coding gene PPP6C, and more than 9 percent of sun-exposed melanomas that were tested contained activating mutations in a gene called RAC1. Subsequent experiments indicate that these RAC1 changes bump up the activity of a pathway that encourages melanocyte skin cells to proliferate and migrate, prompting study authors to speculate that "pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit."


The complex patterns of genetic variation found in the protozoan parasite Toxoplasma gondii stem from both recombination and admixture between strains, according to an analysis by a Massachusetts Institute of Technology and University of Pennsylvania research team. As they reported in the Proceedings of the National Academy of Sciences, the investigators put together a Toxoplasma haplotype map from RNA sequence data for more than two-dozen strains from around the world, using SNPs found in seven newly sequenced Toxoplasma genomes and three existing reference genomes to define haplotype blocks. Based on the patterns in these strains, the group started teasing apart genetic relationships between them, taking into account the parasite's ability to reproduce sexually in cat species and asexually in other warm-blooded animals.

"[M]ost current isolates are recent recombinants and cannot be easily grouped into a limited number of haplogroups," MIT biologist Jeroen Saeij, the study's senior author, and his colleagues reported. "A complex picture emerges in which some genomic regions have not been recently exchanged between any strains, and others recently spread from one strain to many others."

The analysis also offered hints about Toxoplasma's evolution and spread, suggesting that the relative lack of genetic diversity detected in North American Toxoplasma strains may relate to an extinction event around 11,500 years ago that wiped out several cat species on the continent that may have once carried Toxoplasma, such as the American lion and saber-toothed cats.


In the journal Blood, a team from the US and Turkey takes a look at the genetics behind a type of non-Hodgkin's lymphoma called peripheral T-cell lymphoma.

Using mate-pair sequence data generated for samples from 16 individuals with peripheral T-cell lymphoma and six cell lines, the researchers used a bioinformatics method to look for large rearrangements across the tumor genomes. In the process, they detected a known peripheral T-cell lymphoma-associated rearrangement involving the ALK gene. But they also uncovered a dozen other recurrent rearrangements.

One of these involved the well-known cancer risk gene TP53, which codes for the tumor suppressor protein p53, and four affected genes that influence p53 function: TP63, CDKN2A, WWOX, or ANKRD11. The TP53 rearrangement — found in nearly 6 percent of the peripheral T-cell lymphoma cases that the team tested and just over 1 percent of the diffuse large B-cell lymphomas — appeared to correspond with poorer peripheral T-cell lymphoma survival.


The human gut microbiome undergoes an extensive overhaul over the course of pregnancy, taking on patterns that are reminiscent of those seen in some individuals with metabolic disease, according to a study in Cell.

Researchers in the US, Finland, and Sweden used 16S ribosomal RNA sequencing to characterize gut microbial communities in 91 Finnish women during and after pregnancy, assessing fecal samples collected in the first and third trimesters of pregnancy and in the month after delivery. Samples from a handful of the pregnant women were also tested by metagenome sequencing, a method for identifying the complete collection of genes present in a microbial community.

When they compared samples from the first and last few months of pregnancy, investigators saw gut microbiome changes that seemed to be independent of each woman's diet. In general, gut microbial communities became more variable from one individual to the next. But within each woman's gut, the species diversity decreased and microbial communities became enriched for representatives from the Actinobacteria and Proteobacteria phyla later in pregnancy, coinciding with a rise in markers for inflammation. Such changes can herald metabolic problems in individuals who aren't pregnant, the team noted, and subsequent experiments illustrated that the introduction of third trimester gut microbes to mouse models led to weight gain and insulin resistance in the animals. On the other hand, researchers say, the gut microbiome shifts seem to be a boon during pregnancy, augmenting maternal metabolic capabilities.

"The findings suggest that our bodies have coevolved with the microbiota and may actually be using them as a tool — to help alter the mother's metabolism to support the growth of the fetus," Cornell University molecular biology and genetics researcher Ruth Ley, the study's senior author, said in a statement.

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In Science this week: a number of editorials and policy reports discuss advances in human genomic research, and more.