A Postgenomic Perspective on Molecular Cytogenetics

Abstract

Background: The postgenomic era is featured by massive data collection and analyses from various large scale-omics studies. Despite the promising capability of systems biology and bioinformatics to handle large data sets, data interpretation, especially the translation of -omics data into clinical implications, has been challenging.Discussion: In this perspective, some important conceptual and technological limitations of current systems biology are discussed in the context of the ultimate importance of the genome beyond the collection of all genes. Following a brief summary of the contributions of molecular cytogenetics/cytogenomics in the pre- and post-genomic eras, new challenges for postgenomic research are discussed. Such discussion leads to a call to search for a new conceptual framework and holistic methodologies.Conclusion: Throughout this synthesis, the genome theory of somatic cell evolution is highlighted in contrast to gene theory, which ignores the karyotype-mediated higher level of genetic information. Since “system inheritance” is defined by the genome context (gene content and genomic topology) while “parts inheritance” is defined by genes/epigenes, molecular cytogenetics and cytogenomics (which directly study genome structure, function, alteration and evolution) will play important roles in this postgenomic era.

Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems

“…Similar patterns have been observed in metastasis and drug resistance. Therefore, system instability might be the most important aspect for the success of cancer: new systems’ emergence from normal tissue [ 69 , 70 ]. Recent single-cell sequencing of breast cancer cells supports this viewpoint.…”

ACTB and GAPDH proteins appear at multiple positions of SDS-PAGE and may not be suitable for serving as reference genes for the protein level determination in such techniques as Western blotting

“…Actually, each gene is no longer considered to encode a specific phenotype but is perceived to encode a full range of phenotypes. This newly emerging concept, dubbed by Heng et al as "fuzzy inheritance" [19][20][21], may be mechanistically attributed in part to the protein multiplicity of each gene. The mechanisms for protein multiplicity are multiple, including alternative transcriptional initiation or termination to produce different RNA transcripts with longer or shorter 5'-or 3'-ends, alternative splicing of a transcript to produce different mRNA variants with more or fewer exons, and alternative uses of translational start or stop codons in a given mRNA to produce different protein isoforms with a longer or shorter N-or C-terminus.…”

About three‐fourths of mouse proteins unexpectedly appear at a low position of SDS‐PAGE, often as additional isoforms, questioning whether all protein isoforms have been eliminated in gene‐knockout cells or organisms

“…One of the reasons is that each gene is no longer considered to encode a specific phenotype but is perceived to encode a full range of phenotypes, which is a newly emerging concept dubbed by Heng et al as "fuzzy inheritance." [9][10][11] As another reason, those genomic loci that encode non-coding RNAs are also considered by many peers as genes, whereas "non-coding RNA" itself remains to be ill-defined and is challenged by the fact that many short peptides, as short as 11 amino acids encoded by only 33 nucleotides, are known to have important biological functions. [12][13][14][15][16] With the genomic complexity gradually being better known, we have started to question some routine techniques used to explore the expression and function of genes and in turn to question the conclusions from the resultant data, inspired in part by Stepanenko and Heng.…”