Genetic Variations and Precision Medicine.
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ABSTRACT:
SUBMITTER: Alzu'bi AA
PROVIDER: S-EPMC6462879 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Genetic Variations and Precision Medicine.
Alzu'bi Amal Adel AA Zhou Leming L Watzlaf Valerie J M VJM
Perspectives in health information management 20190401 Spring
The time and costs associated with the sequencing of a human genome have decreased significantly in recent years. Many people have chosen to have their genomes sequenced to receive genomics-based personalized healthcare services. To reach the goal of genomics-based precision medicine, health information management (HIM) professionals need to manage and analyze patients' genomic data. Two important pieces of information from the genome sequence are the risk of genetic diseases and the specific me ...[more]
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The FFPE samples were further processed including macrodissection, protein extraction, protein precipitation, protein digestion, and peptide clean up according to a previously published and modified protocol (Buczak et al., 2020). For further details, please refer to the Materials and Methods section of the manuscript.
In depth proteomic characterization of the samples a label free high-resolution LC-MS/MS approach using an Orbitrap Tribrid Fusion mass spectrometer was chosen (operated in DIA mode). Tryptic peptides were loaded onto a µPAC Trapping Column with a pillar diameter of 5 µm, inter-pillar distance of 2.5 µm, pillar length/bed depth of 18 µm, external porosity of 9%, bed channel width of 2 mm and length of 10 mm; pillars are superficially porous with a porous shell thickness of 300 nm and pore sizes in the order of 100 to 200 Å at a flow rate of 10 µl per min in 0.1% trifluoroacetic acid in HPLC-grade water. Peptides were eluted and separated on the PharmaFluidics µPAC nano-LC column: 50 cm µPAC C18 with a pillar diameter of 5 µm, inter-pillar distance of 2.5 µm, pillar length/bed depth of 18 µm, external porosity of 59%, bed channel width of 315 µm and bed length of 50 cm; pillars are superficially porous with a porous shell thickness of 300 nm and pore sizes in the order of 100 to 200 Å by a linear gradient from 2% to 30 % of buffer B (80% acetonitrile and 0.08% formic acid in HPLC-grade water) in buffer A (2% acetonitrile and 0.1% formic acid in HPLC-grade water) at a flow rate of 300 nl per min. The remaining peptides were eluted by a short gradient of 10 minutes from 30% to 95% buffer B; followed by 25 minutes at 2% of buffer B, the total gradient run was 120 min.
Spectra were acquired in DIA mode using 50 variable-width windows over the mass range 350-1500 m/z. The Orbitrap was used for MS1 and MS2 detection, with an AGC target for MS1 set to 20x104 and a maximum injection time to 100 ms. MS2 scan range was set between 200 and 2000 m/z, with a minimum of 6 points across the peak. Orbitrap resolution for MS2 was set to 30K, isolation window set to 1.6, AGC target to 50x104 and maximum injection time to 54 ms. MS1 and MS2 data were acquired in centroid mode.
In order to check for retention time (RT) stability, iRT standards (Biognosys) were spiked in each sample according to the manufacturer recommendations, the 11 iRT peptide sequences were manually added to the database and used during DIA-NN search to generate the precursor ion library used for MS data analysis. To reduce the possibility of carry over and cross contamination between the samples, two BSA washes were used between samples, and a trap column wash followed by 2 BSA washes was used every 10 samples sequence.
The above-mentioned workflow is schematically displayed in Fig. 1B.
LC-MS/MS was performed at the Proteome Center Tuebingen (PCT). Here, 250 ng of peptides were loaded onto an Easy-nLC 1200 system coupled to a quadrupole Orbitrap Exploris 480 mass spectrometer (all Thermo Fisher Scientific, Waltham, MA, USA) as previously described (Krauss et al, 2023).
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