Harmonizing heterogeneous transcriptomics datasets for machine learning-based analysis to identify spaceflown murine liver-specific changes.

NASA has employed high-throughput molecular assays to identify sub-cellular changes impacting human physiology during spaceflight. Machine learning (ML) methods hold the promise to improve our ability to identify important signals within highly dimensional molecular data. However, the inherent limitation of study subject numbers within a spaceflight mission minimizes the utility of ML approaches.

A multi-omics longitudinal study of the murine retinal response to chronic low-dose irradiation and simulated microgravity.

The space environment includes unique hazards like radiation and microgravity which can adversely affect biological systems. We assessed a multi-omics NASA GeneLab dataset where mice were hindlimb unloaded and/or gamma irradiated for 21 days followed by retinal analysis at 7 days, 1 month or 4 months post-exposure. We compared time-matched epigenomic and transcriptomic retinal profiles resulting in a total of 4178 differentially methylated loci or regions, and 457 differentially expressed genes.

Genomic and molecular characterization of preterm birth.

Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB.

New observations on maternal age effect on germline de novo mutations.

Germline mutations are the source of evolution and contribute substantially to many health-related processes. Here we use whole-genome deep sequencing data from 693 parents-offspring trios to examine the de novo point mutations (DNMs) in the offspring. Our estimate for the mutation rate per base pair per generation is 1.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis.

Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

Background: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear.

Methods: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis.

A chromosomal region 7p11.2 transcript map: its development and application to the study of EGFR amplicons in glioblastoma.

Cumulative information available about the organization of amplified chromosomal regions in human tumors suggests that the amplification repeat units, or amplicons, can be of a simple or complex nature. For the former, amplified regions generally retain their native chromosomal configuration and involve a single amplification target sequence. For complex amplicons, amplified DNAs usually undergo substantial reorganization relative to the normal chromosomal regions from which they evolve, and the regions subject to amplification may contain multiple target sequences.

Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements.

We have developed a polymerase chain reaction (PCR)-based strategy for the synthesis and analysis of rearranged epidermal growth factor receptor (EGFR) fragments associated with the vIII mutant receptor expressed in glioblastomas with EGFR amplification. The sequencing of aberrant tumor fragments showed that intragenic deletion rearrangements consistently involve an approximately 600-bp region in intron 7 of EGFR and several rearrangement sites interspersed throughout the large (>100 kb) first intron of this gene. Examination of the intron 7 breakpoint region revealed an Alu repeat element, and all intron 7 rearrangement sites were located within or downstream of this repeat sequence.

Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms.

This study presents the annotated genomic sequence and exon-intron organization of the human and mouse epidermal growth factor receptor (EGFR) genes located on chromosomes 7p11.2 and 11, respectively. We report that the EGFR gene spans nearly 200 kb and that the full-length 170-kDa EGFR is encoded by 28 exons.

Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas.

Several types of epidermal growth factor receptor (EGFR) gene mutations have been reported in glioblastomas, and in nearly all cases the alterations have been reported in tumors with EGFR amplification. The objectives of this study were to determine the frequency and diversity of EGFR mutations in glioblastomas and to determine whether gene mutation is inevitably associated with increased EGFR gene dosage. To accomplish these aims, we sequenced cDNA products representing the entire EGFR coding region in 44 glioblastomas, half of which had EGFR amplification.

3' end structure and rearrangements of EGFR in glioblastomas.

Rearrangements of EGFR are known to occur in a significant fraction of glioblastomas, the most common and malignant form of central nervous system tumor. Although the consequences of these alterations have been described at the mRNA and protein level, little is known about human EGFR genomic sequence or organization at the rearrangement sites. To investigate one group of alterations in glioblastoma, we used long-range PCR to synthesize a segment of the gene near its 3' end, which is frequently rearranged in tumors with EGFR amplification.