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PNAS Papers Look at Roots of Drug-Resistant TB, Fat Gene Regulation, More

A team from the US, South Africa, and Norway takes a look at an extensively drug-resistant Mycobacterium tuberculosis strain called LAM4/KZN that first was first found in HIV patients in South Africa's KwaZulu-Natal province in 2005. The researchers did whole-genome sequencing on more than 300 extensively drug-resistant LAM4/KZN and non-LAM4/KZN clinical isolates collected from 2011 to 2014, which were analyzed phylogenetically alongside geographical clues and other epidemiological insights. They estimate that the LAM4/KZN clade took on key resistance mutations in the early 1960s and 1980s, for example, expanding from a site in the province's northeast in concert with HIV infections for more than a decade before being detected. Based on these and other findings, the authors "propose that integrating whole-genome sequencing in routine public health surveillance can enable the early detection and local containment of [antimicrobial resistant] pathogens before they achieve widespread dispersal." 

Researchers from the University of Pennsylvania and Princeton University explore thr regulation of a potential obesity-associated gene called PM20D1. That gene appears to be found at higher-than-usual levels in mouse brown fat or cold-exposed white fat from mice, the team says. Unlike mouse fat cells, human adipocytes bump up PM20D1 expression after treatment with an antidiabetic drug that activates the PPAR-gamma pathway. That prompted investigators to use chromatin immunoprecipitation sequencing and other approaches to assess PPAR-gamma regulatory sites stemming from a primate-specific segmental duplication, including a variant upstream of PPAR-gamma that seems to coincide with higher or lower PM20D1 levels. "[T]he effect of PPAR-gamma on PM20D1 in adipocytes differs among people due to natural genetic variation in a PPAR-gamma binding site upstream of the gene," the authors conclude, suggesting the regulatory variant "functions as a 'rheostat' to change adipose PM20D1 levels in response to PPAR-gamma ligands."

A University of Washington-led team reports on findings from a primate evolution analysis that relied on short tandem repeat (STR) and variable number tandem repeat (VNTR) comparisons between human, chimpanzee, gorilla, and orangutan genomes. Starting with more than 21,400 tandem repeats identified in haplotype-resolved genome assemblies for Yoruban, Han Chinese, and Puerto Rican individuals profiled by the Human Genome Structural Variation Consortium, the researchers put together phased chimpanzee, gorilla, and orangutan genomes, uncovering nearly 1,600 STR or VNTRs that appear to be expanded in the human genomes. The set included VNTR repeats falling near sub-telomeric and other genes, repeats linked to retrotransposition that were not near genes, and VNTRs that seemed to influence transcript spicing or expression differences detected in human and chimp brains, the authors report. They also highlighted dozens of human-specific, repeat-rich regions with potential ties to disease.