Category Archives: Nature Genetics Anniversary

Nature Genetics Anniversary

Mutation rates of Mycobacterium tuberculosis: From the archives (2013)

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Mycobacterium tuberculosis- credit: NIH-NIAID (CC-BY)

Mycobacterium tuberculosis- credit: NIH-NIAID (CC-BY)

Continuing with our month-long celebration of Nature Genetics 25th anniversary, I have chosen to highlight a study by Sarah Fortune and colleagues estimating mutation rate differences between different lineages of Mycobacterium tuberculosis published in June 2013.

Multidrug resistance in M. tuberculosis is a global problem, and understanding the origins and dynamics of the emergence of resistance is an important scientific and public health endeavor.

Building on their previous work that used whole genome sequencing to estimate mutation rates of M. tuberculosis during latent infection, the authors then went on to study the rate at which different strains acquire drug resistance mutations. Using classical fluctuation tests and measuring rifampicin resistance in both clinical and laboratory isolates, they determined the mutation rates for strains from lineage 2 and lineage 4, observing an order of magnitude difference between them, with lineage 2 having the higher rate. These lineage 2 strains also acquired resistance to other antibiotics (ethambutol, isoniazid) at a higher rate than lineage 4 strains.

The authors then sought to relate the in vitro data to the in vivo infection environment. They analyzed whole-genome sequences from a lineage 4 outbreak and determined the base substitution rate; the in vivo data were in concordance with the in vitro per-day mutation rate.

Finally, the authors took these data and developed a simulation model of the evolution of drug resistance during infection in a human host. They simulate the emergence of multidrug resistance and show that in the model, individuals infected with lineage 2 strains had a substantially higher risk of acquiring multidrug resistance mutations.

Using a combination of in vitro, clinical and simulated data, Ford et al. contributed to our understanding of the emergence of multidrug resistance, highlighting the differences between strains and underscoring the importance of timely and sufficient treatment.

Woolly mammoth hemoglobin brought to life: From the archives (2010)

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Combarelles-mammouth

{credit}Cave painting: Mammouth gravé de la grotte des Combarelles (Dordogne, France){/credit}

As part of the ongoing celebration of the last 25 years of Nature Genetics, the editors are each choosing a few papers from our archives that we want to highlight. My first pick a paper from Kevin Campbell, Alan Cooper and colleagues on their structure-function analysis of woolly mammoth hemoglobin, published in May 2010.

I’ve picked this one to highlight because, well, who doesn’t love woolly mammoths?

The authors compared the gene sequences of the adult-expressed α- and β-like globin genes from extant elephant species (African and Asian elephants) and from a 43,000 year-old Siberian mammoth specimen reported first in Science. They found that the mammoth β-like genes (designated HBB/HBD by the authors) had 3 amino acid-altering substitutions compared to the extant species.

To test the effects of these protein-coding differences, the authors then “resurrected” the mammoth hemoglobin protein by expressing the mammoth sequence in E. coli and testing its O2 affinity at different ambient temperatures. They found that the O2 affinity of the recreated mammoth hemoglobin is less affected by temperature than that of modern-day elephants. The detailed structure-function analysis reported by Campbell et al. offered us a rare glimpse into the evolutionary process that shaped an extinct organism.