Periannan Senapathy

Periannan Senapathy is a molecular biologist, geneticist, author and entrepreneur. He is the founder and president of Genome International Corporation, a biotechnology firm based in Madison, Wisconsin, which develops clinical decision support systems for analyzing patient genome data to aid in diagnosis and treatment of diseases.

Senapathy is known for his contributions in genetics, genomics and clinical genomics, especially in the biology of RNA splicing and the split structure of eukaryotic genes. He developed the Shapiro & Senapathy algorithm (S&S) for predicting the splice sites in eukaryotic genes, which has become a primary methodology for discovering disease-causing splice site mutations. The S&S algorithm has been implemented in many gene-finding and mutation detection tools that are used in clinical and research institutions for uncovering mutations in patients with numerous diseases, including cancers and inherited disorders. It is increasingly used in the Next Generation Sequencing era, as it is widely realized that over 60% of all diseases and adverse drug reactions occur within the splicing regions of genes. The S&S algorithm has been cited in ~6,000 publications that analyze splicing mutations in cancer and inherited disorders.

Senapathy proposed the "split gene theory," which suggests that the split structure of eukaryotic genes originated from random DNA sequences, and provided tangible evidence from the genome sequences of several organisms.

Noted molecular biologist and biophysicist Colin Blake from the Laboratory of Molecular Biophysics and Oxford Centre for Molecular Sciences, University of Oxford, commented on Senapathy's theory that: "Recent work by Senapathy, when applied to RNA, comprehensively explains the origin of the segregated form of RNA into coding and non-coding regions. It also suggests why a splicing mechanism was developed at the start of primordial evolution. The presence of random sequence was therefore sufficient to create in the primordial ancestor the segregated form of RNA observed in the eukaryotic gene structure."

Origin of RNA splice junction signals from stop codons of ORFs Senapathy's research also elucidates the origin of the splice junctions of eukaryotic genes, again the major questions of why and how the splice junction signals originated. Senapathy predicted that, if the split gene theory was true, the ends of these ORFs that had a stop codon would have become the ends of exons that would occur within introns, and that would define the splice junctions. Senapathy found that almost all splice junctions in eukaryotic genes contained stop codons exactly at the ends of introns, bordering the exons as predicted. In fact, these stop codons were found to form the "canonical" AG:GT splicing sequence, with the three stop codons occurring as part of the strong consensus signals. Senapathy had observed that mutations in these stop codon bases within splice junctions were the cause of the majority of diseases caused by splicing mutations, emphasizing the importance of stop codons in the splice junctions. Thus, the basic split gene theory led to the hypothesis that the splice junctions originated from the stop codons.

Why exons are short and introns are long Research based on the split gene theory sheds lights on other basic questions of exons and introns. The exons of eukaryotes are generally short (human exons average ~120 bases, and can be as short as 10 bases) and introns are usually very long (average of ~3,000 bases, and can be several hundred thousands bases long), for example genes RBFOX1, CNTNAP2, PTPRD and DLG2. Senapathy has provided an answer for why exons are short and introns are long. Based on the split gene theory, exons of eukaryotic genes, if they originated from random DNA sequences, have to match the lengths of ORFs from random sequence, and possibly should be around 100 bases (close to the median length of ORFs in random sequence). The genome sequences of living organisms, for example the human, exhibits exactly the same average lengths of 120 bases for exons, and the longest exons of 600 bases (with few exceptions), which is the same length as that of the longest random ORFs. In addition, the introns can be very long, based on the split gene theory, which is found to be true in eukaryotic organisms.

Why genomes are large This work also explains why the genomes are very large, for example, the human genome with three billion bases, and why only a very small fraction of the human genome (~2%) codes for the proteins and other regulatory elements. If split genes originated from random primordial DNA sequences, it would contain a significant amount of DNA that would be represented by introns. Furthermore, a genome assembled from random DNA containing split genes would also include intergenic random DNA. Thus, the nascent genomes that originated from random DNA sequences had to be large, regardless of the complexity of the organism. Furthermore, the findings that the genomes of several organisms are smaller, although they contain essentially the same number of genes as that of the human, such as those of the C. elegans (genome size ~100 million bases, ~19,000 genes) and Arabidopsis (genome size ~125 million bases, ~25,000 genes), adds support to this theory. The split gene theory predicts that the introns in the split genes in these genomes could be the "reduced" (or deleted) form compared to the larger genes with long introns, thus leading to reduced genomes.

Origin of the spliceosomal machinery and the eukaryotic cell nucleus Senapathy's research also addresses the origin of the spliceosomal machinery that edits out the introns from the RNA transcripts of genes. If the split genes had originated from random DNA, then the introns would have become an unnecessary but integral part of the eukaryotic genes along with the splice junctions at their ends. The spliceosomal machinery would be required to remove them and to enable the short exons to be linearly spliced together as a contiguously coding mRNA that can be translated into a complete protein. Thus, the split gene theory shows that the whole spliceosomal machinery originated due to the origin of split genes from random DNA sequences, and to remove the unnecessary introns. exactly as predicted by Senapathy's theory.

The spliceosome is a highly complex machinery within the eukaryotic cell, containing ~200 proteins and several SnRNPs. In their paper