Nguyen, V. P. | Search bioRxiv

bioRxiv2019

The paternal and maternal genetic history of Vietnamese populations

Vietnam exhibits great cultural and linguistic diversity, yet the genetic history of Vietnamese populations remains poorly understood. Previous studies focused mostly on the majority Kinh group, and thus the genetic diversity of the many other groups has not yet been investigated. Here we analyze complete mtDNA genome sequences and 2.34 mB sequences of the male-specific portion of the Y chromosome from the Kinh and 16 minority populations, encompassing all five language families present in Vietnam. We find highly variable levels of diversity within and between groups that do not correlate with either geography or language family. In particular, the Mang and Sila have undergone recent, independent bottlenecks, while the majority group, Kinh, exhibits low levels of differentiation with other groups. The two Austronesian-speaking groups, Giarai and Ede, show a potential impact of matrilocality on their patterns of variation. Overall, we find that isolation, coupled with some limited contact involving some groups, has been the major factor influencing the genetic structure of Vietnamese populations, and that there is substantial genetic diversity that is not represented by the Kinh.

genetics↗

bioRxiv2019

The effect of phosphatidylserine on the membrane insertion of the cancer-targeting ATRAM peptide is defined by its non-inserting end

The acidity-triggered rational membrane (ATRAM) peptide was designed to target acidic diseases such as cancer. An acidic extracellular medium, such as that found in aggressive tumors, drives the protonation of the glutamic acids in ATRAM, leading to the membrane translocation of its C-terminus and the formation of a transmembrane helix. Compared to healthy cells, cancerous cells often increase exposure of the negatively charged phosphatidylserine (PS) on the outer leaflet of the plasma membrane. Here we use a reconstituted vesicle system to explore how phosphatidylserine influences the interaction of ATRAM with membranes. To explore this, we used two new variants of ATRAM, termed K2-ATRAM and Y-ATRAM, with small modifications at the non-inserting N-terminus. We observed that the effect of PS on the membrane insertion pK and lipid partitioning hinged on the sequence of the non-inserting end. Our data additionally indicate that the effect of PS on the insertion pK does not merely depend on electrostatics, but it is multifactorial. Here we show how small sequence changes can impact the interaction of a peptide with membranes of mixed lipid composition. These data illustrate how model studies using neutral bilayers, which do not mimic the negative charge found in the plasma membrane of cancer cells, may fail to capture important aspects of the interaction of anticancer peptides with tumor cells. This information can guide the design of therapeutic peptides that target the acidic environments of different diseased tissues.\n\nStatement of SignificanceCurrent targeted therapies for cancer have limited success due to drug resistance. Resistance often arises after mutation of the receptor being targeted. A more general target is needed to prevent drug resistance. Most aggressive solid tumors have an extracellular medium. We propose that extracellular acidity is promising for improved targeted therapies. The acidity-triggered rational membrane (ATRAM) inserts in membranes only under acidic conditions. However, it is now known how the lipid changes that occur in the plasma membrane of cancer cells impact the membrane insertion of ATRAM. Here we perform biophysical experiments that show that PS, a lipid exposed in the cancer cell, can impact the membrane insertion of ATRAM. We also uncovered a region of the peptide important for insertion.

biophysics↗