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. He also showed that the splice junctions of eukaryotic genes could have originated from the stop codon ends of the Open Reading Frames (ORFs) in random DNA sequences. Marshall Nirenberg, the Nobel Laureate who deciphered the genetic code, communicated Senapathy's article on the origin of introns to PNAS. Senapathy has published his other scientific findings in journals including Science, Nucleic Acids Research, PNAS, Journal of Biological Chemistry, and Journal of Molecular Biology, and is the author of several patents in the genomics field.
Biography Senapathy has a Ph.D. in molecular biology from the Indian Institute of Science, Bangalore, India. He spent twelve years in genome research for the National Institutes of Health's Laboratory of Molecular and Cell Biology and the Laboratory of Statistical and Mathematical Methodology in the Division of Computer Research and Technology in Bethesda, Maryland (1980–87), and the Biotechnology Center and the Department of Genetics of the University of Wisconsin, Madison (1987–91). Senapathy founded Genome International in 1992 for developing computational biology research, products and services.
Notable research contributions Senapathy has provided major contributions in RNA splicing biology, improving the understanding of the structure, function, and origin of eukaryotic split genes, and the applications of these findings in human medicine. His work has helped the diagnosis and treatment of patients with hundreds of diseases including cancers and inherited disorders. His research is an example of the application of basic molecular biology research findings to human medicine, and a variety of practical applications in animals and plants.
Origin of split genes from random DNA sequences The split gene theory answers major questions of why and how the split genes of eukaryotes originated. It states that if coding sequences for biological proteins originated from random primordial genetic sequences, the random occurrence of the 3 stop codons out of 64 codons would limit the open reading frames (ORFs) to a very short length of ~60 bases. Thus, coding sequences for biological proteins with average lengths of ~1,200 bases, and long coding sequences of 6,000 bases, can practically never occur in random sequences. Thus, genes had to occur in pieces in a split form, with short coding sequences (ORFs) that became exons, interrupted by very long random sequences that became introns. When the eukaryotic DNA was tested for ORF length distribution, it exactly matched that from random DNA, with very short ORFs that matched the lengths of exons, and very long introns as predicted, supporting the split gene theory. Thus, introns are relics left over from their random sequence origin, and thus are earmarked to be removed at the primary RNA stage, although incidentally they may have few genetic elements useful to the cell. The Nobel Laureate Marshall Nirenberg, who deciphered the codons, communicated the paper to the PNAS. New Scientist covered this publication titled "A long explanation for introns". 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. Marshall Nirenberg supported the publication of this paper in the PNAS. New Scientist covered this publication titled "Exons, Introns and Evolution".
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