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Can a single gene change how an animal behaves? In the early 1970s Obaid Siddiqi began to study the genetic basis of behaviour using the fruit fly, Drosophila melanogaster. He also founded two research centres in India: the Molecular Biology Unit at TIFR and the National Centre for Biological Sciences. This post explains his main findings, works through the genetics idea behind his early work, and ends with what a student can learn from how he worked.
Who was Obaid Siddiqi?
The Current Science obituary records that he was born on 7 January 1932 in Basti, Uttar Pradesh, studied at Aligarh Muslim University and earned his PhD at the University of Glasgow in 1961. The NCBS announcement of his death adds that his PhD was in microbial genetics with Guido Pontecorvo, and that he then worked with Alan Garen at Cold Spring Harbor and the University of Pennsylvania.
In 1962, at Homi Bhabha's invitation, NCBS says, he set up the Molecular Biology Unit at the Tata Institute of Fundamental Research (TIFR) in Mumbai. Thirty years later, in 1992, he became founding director of the TIFR National Centre for Biological Sciences (NCBS) in Bangalore. He was elected a Fellow of the Royal Society and a member of the US National Academy of Sciences, and received the Padma Bhushan and Padma Vibhushan. He died on 26 July 2013.
How did his early work connect to stop codons?
With Garen he worked on the bacterium E. coli; their 1962 paper, Suppression of mutations in the alkaline phosphatase structural cistron of E. coli, was about mutations in the gene for the enzyme alkaline phosphatase whose effects could be suppressed. The NCBS announcement says this postdoctoral work led to the discovery of stop codons and the mechanism of chain termination during protein synthesis.
Worked example. Stop codons (UAA, UAG, UGA) end translation; they are listed among the features of the genetic code in NCERT Class 12 Biology, Chapter 5. Take an mRNA that reads AUG UUU CAG GGA, coding for Met, Phe, Gln, Gly.
A single change, C to U, at the first position of the third codon turns CAG into UAG.
UAG is a stop codon, so the ribosome stops after Phe. The protein is cut short after two amino acids.
This is a nonsense mutation: a codon for an amino acid has become a stop codon. Studying mutations of this kind, and suppressor mutations that partly undo their effect, is the line of work NCBS links to the discovery of stop codons.
A common mistake is to call any single-base change a frameshift. A substitution keeps the reading frame. The same NCERT chapter explains that inserting or deleting one or two bases shifts the frame, while inserting or deleting three bases (or a multiple of three) leaves the frame unaltered from that point on. Our guide to the genetic code and translation has more practice.
What were the temperature-sensitive paralytic mutants?
From the mid-1970s Siddiqi made the first of three visiting professorships to Seymour Benzer's laboratory at Caltech. The Current Science memorial by Mani Ramaswami and K. S. Krishnan describes the flies he focused on: they looked normal at room temperature, became paralysed when shifted to a higher temperature, and recovered when shifted back.
In Siddiqi and Benzer's 1976 PNAS paper, they described a new mutant, comatose, and compared it with two known ones, para and shibire. The three differed in how quickly they were paralysed at high temperature and how they recovered, comatose was unusually sensitive to paralysis by cooling, and neurophysiological experiments pointed to a different mechanism of paralysis in each. The memorial notes that his method of recording from single muscle fibres could be used to identify the likely molecular targets of such mutations, and that it gave impetus to studies of fly neural excitability mutants by Benzer's postdocs Chun-Fang Wu and Barry Ganetzky, who went on to give the first glimpse of important classes of ion channel genes. In 2014 they wrote a tribute titled Remembering Obaid Siddiqi, a pioneer in the study of temperature-sensitive paralytic mutants in Drosophila.
How did he study taste and smell?
Back in India, Siddiqi suggested a similar genetic approach to his PhD student Veronica Rodrigues. Using behavioural tests they designed, the two isolated and characterised the first collection of Drosophila mutants with defects in smell or taste, according to the Current Science memorial. One example is their 1981 paper on a gustatory mutant of Drosophila defective in pyranose receptors, which, as its title says, concerns a fly mutant defective in receptors for pyranose sugars. NCBS says this work on taste and smell paved the way for the modern understanding of how such senses are detected and encoded in the brain, and that he kept an active laboratory at NCBS as an emeritus professor until the end of his life.
What can a student take from how he worked?
Pick a simple system for a big question. He asked how genes shape behaviour, and answered it with single mutant fruit flies whose defects could be seen and measured.
Design the test. His taste and smell work rested on behavioural assays he and Rodrigues built. When you study, design your own small tests instead of only reading.
Move between fields. He went from bacterial genetics to nerves to the senses. Ideas from one chapter often explain another; our guide to the molecular basis of inheritance is the base for linking a gene to the protein it makes.
Share credit. The memorial records that when he received the Birla Award for the taste and smell work, he gave a cheque for half the prize to his student.
If you get stuck linking a gene to a protein to a behaviour, the Fermi Concept Library covers every concept in biology with its own lesson, so you can fill one gap at a time.
Try it now: write an mRNA codon for tryptophan (UGG) and find the two single-base changes that turn it into a stop codon.
