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The highly pathogenic avian influenza (HPAI) type H5N1 has become a menace in the recent years, causing huge economic losses to the poultry industry. However, a proper understanding of the factors governing its transmission cycle and possible outbreaks in space and time is lacking. The ecological niche modelling tool, Genetic Algorithm for Rule-Set Prediction (GARP) has been used to model the 'black box' of H5N1 transmission in the Indian subcontinent. Ninety outbreak records for veterinary cases of H5N1 in West Bengal and Bangladesh, and 18 environmental parameters with a pixel resolution of ≈4 km were used in the modelling. The final optimized rules generated by GARP were projected on a broad geographical scale covering India, Bangladesh, Nepal and many parts of Pakistan to anticipate the potential areas for the presence of H5N1. The niche model predicted vast areas in the Indo-Bangladesh region for the presence of H5N1. The areas having high level of model agreements are in the Gangetic Plains, Assam, Tripura, West Bengal and some parts of Andhra Pradesh, Maharashtra and Gujarat. The model also predicted large areas in northern Pakistan and some parts of Nepal to be suitable for H5N1 transmission. The modelled ecological niche of H5N1 in the present study is characterized by a mean annual temperature range of 21-26°C, lower slope angle, areas with a tendency to pool water, a significant monthly variation in the degree of greenness and human population density of more than 100 persons/km2. The resultant niche model validated 49 cases of HPAI outbreak out of the total 52 past as well as the latest outbreaks in India, Bangladesh, Pakistan and Nepal. [ABSTRACT FROM AUTHOR]