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Indian Journal of Medical Microbiology, Vol. 28, No. 3, July-September, 2010, pp. 193-195 Special Article The incredible journey of mankind: Helicobacter pylori as the narrator P Desikan Department of Microbiology, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, Karond, Bhopal 462 036, Madhya Pradesh, India Keywords: Genome, H. pylori, journey, mankind Introduction As we move forward at a dizzying speed in our quest for knowledge and new worlds, it may be worthwhile to pause, retrospect, and examine our journey through time and space. Where did we originate? Who were our ancestors? We know that we are descendants of a few small groups of Africans, who united in the face of adversity, not only to the point of survival, but also to the development of a worldwide social structure. However, if Africa was our cradle, how, and why, did we migrate from the site of our origins? Was it an inhospitable nursery that drove us out? When did that happen? What were our routes out of Africa, and through the world? These are questions that address our fundamental need to know where we come from; in order to understand where we are headed. Unfortunately, only recent events in human history have been actively documented by us. Older events have not been recorded and have been the subject of much conjecture. Nevertheless, microbes, diminutive witnesses to the events in our distant past, may be able to provide answers to some of our most basic questions. Over the past decade, sequence differences between microbes from different geographical areas have been studied with the intent to interpret population movements of their hosts. An organism that is a reliable storehouse of such data, by virtue of its long association with its human host, is Helicobacter pylori. Functional and comparative analyses of its genome have provided fascinating insights into human behaviour in the ancient past. Yet - why analyse microbial genomes, instead of the human genome, for information about our own past? After all, the draft human genome sequence, announced with much fanfare in 2000, promised great insights into human biology and evolution. [1] The answer, perhaps, lies in the fact that, for all the intellectual ferment of the past decade, the complexity of post-genome biology has left us with limited success in deciphering our genome. We have a mismatch between the rapidly increasing ease of gathering human genomic data and the continuing difficulty of establishing what the genetic elements actually do. On the other hand, in the 15 years after the publication of the genome sequence of Haemophilus influenzae - the first free living micro-organism to be sequenced, a concomitant revolution in bioinformatics and functional genomics have enabled us to elucidate functions of microbial genomes with greater rapidity than that of the human genome. [2] H. pylori As the Narrator The global sample of H. pylori DNA, when compared with human DNA, provides evidence for a long-standing relationship between humans and H. pylori on an evolutionary time scale. With its comfortable niche in the human stomach, high DNA sequence diversity and predominant intrafamilial transmission routes, it has a unique edge as a marker for human population movements. [3],[4] Pairwise FST , a measure of genetic differentiation between populations, has been used to compare the population structure between H. pylori and its human host. Pairwise FST obtained from human microsatellite data has been found to strongly correlate (R2 = 0.73) with Pairwise FST H. pylori housekeeping gene sequences from the same human populations. [5],[6] This confirms a directly comparable population structure between the bacterium and the host, and indicates a similarity in evolutionary trajectories, making H. pylori an ideal surrogate marker to study human population movements. Six defined major bacterial populations have been identified from a global collection of 769 H. pylori isolates using model-based cluster and assignment analyses. [5],[6] They are named after the geographic location where they are found most frequently, and include hpEurope, hpAsia2, hpNEAfrica, hpAfrica2, hpAfrica1 and hpEastAsia. Partitioning of H. pylori sequences in this manner has enabled a tracking of prehistoric as well as more recent human population movements. The Journey Out of Africa The migratory herds and nomadic pastoral tribes of Africa continually move from the dry and withered, to the wet and green areas, in search of sustenance. This is testimony to the continuous balancing act of weighing one survival strategy against another. It is reasonable to presume that our ancestors may have had to choose a survival strategy that eventually took them out of Africa. The question now, is, when did it happen? In humans, genetic diversity has been found to decrease with distance from Africa, possibly due to serial founder effects, where only a proportion of an original population migrates further with each thrust of migration, and then forms a new population. [7],[8] When diversity for each population of H. pylori is plotted against distance from Africa, a similar trend is observed, confirming an African origin for both, the bacterium and its human host. [6] Computer simulations of the H. pylori DNA data, using a stepping stone model of migration, indicate that these strains migrated out of Africa around 58,000 years ago. [6] This would imply that our forefathers (and mothers) carried this pathogen in their stomachs during their migrations out of Africa approximately 58,000 years ago. Given the land mass structures at that period in time, it would be reasonable to assume that the movement out of Africa was into modern day Asia, and Europe. Migration into Asia, and Beyond At about the time our ancestors migrated out of Africa, during the last ice age, a Pleistocene landmass, known as Sundaland, existed (i.e., the Malay Peninsula, Sumatra, Java, Borneo and Bali). Sundaland was joined to the Asian mainland as a result of low sea levels. Low sea levels also allowed Australia, New Guinea and Tasmania to be connected in a continent called Sahul, separated from Sundaland by a few narrow, deep-sea channels. Human migration across these landmasses about 31,000-37,000 years ago has been corroborated by the detection of strains of H. pylori, belonging to the hpSahul population, in these areas. [9] The hpSahul population split from the Asian population of H. pylori strains at around the same period in time, indicating a major migration during that period. The hpSahul populations in New Guinea and Australia have diverged sufficiently to indicate that they have remained isolated for the past 23,000-32,000 years. [9] This would probably mean that there was no further human migration from those regions. H. pylori strains across eastern Asia, the Koreas and Japan belong almost uniformly to the hpEastAsia population. It is possible to link this up with the expansion of the empires of the Chinese Western and Eastern Zhou dynasties between 1066 and 221 BC. This confirms the Korean ancestry of modern Japanese, indicating that there was a migration across the Korean peninsula into Japan, leading to the introduction of rice cultivation into the Japanese islands. [6] However, H. pylori isolates among the Thai population are predominantly assigned to hpAsia2, indicating that something stopped the spread of the Chinese Zhou dynasty empire in that area. There is also evidence of an eastward wave of human migration about 5000 years ago, leading to a further spread of the hpEastAsia strain from mainland Taiwan to the Philippines, and eventually to New Zealand indicating the movement of seafaring migrants to these geographic areas. Moving from island to island appears to have accelerated the genetic drift, leading to the formation of distinct subpopulations of H. pylori in New Zealand - the hspMaori. [5],[6],[9] Until recently, mixing within H. pylori strains occurred mainly within populations. Therefore, signals for ancient events that occurred between populations still persist. Using a nucleotide linkage model, five ancestral populations have been identified - ancestral Europe 1 (AE1), ancestral Europe 2 (AE2), ancestral East Asia, ancestral Africa 1 and ancestral Africa 2. [10] An analysis of H. pylori housekeeping gene sequences using the linkage model shows that isolates from Muslims in the Ladakh region in India have a uniform AE1 ancestry. This suggests that Islam was probably introduced by a few persons into the area, contrary to the concept that an extensive invasion introduced the religion in that area. In contrast, H. pylori isolates from Buddhists in the same area show a cline of introgression from pure ancestral East Asia to almost pure AE1, which could be indicative of introduction of migration of Buddhist preachers (and hpEastAsia H. pylori) into a pre-existing native Ladakhi population. [11] Interestingly, the high frequency of hpEurope H. pylori strains among isolates from India indicates a link to an ancient migration of Aryans into the subcontinent, rather than the relatively recent British colonisation of India. [12] Into America Recent studies have identified East Asian strains of H. pylori among Native Americans in North and South America. This suggests that the Americas were initially populated by people of Asian origin when land connected Asia and North America nearly 18,000 years ago, across what is now the Bering strait. [13],[14],[15] Perhaps it is not so wrong to call native Americans, Indians, after all! Migration in Europe Determination of human migrations in Europe has necessitated fairly complex deductions due to the detection of various recombinants of H. pylori in Europe. It has been designated a hybrid zone. In order to understand human population movements in Europe, the ancestral data have been partitioned into its varying layers of complexity using a multivariate technique called Principal Component Analysis (PCA). [16] Each layer, known as a Principal Component (PC) describes a portion of the data. The first PC describes a movement from Southeast to Northwest Europe. This movement correlates with archaeological data on the westward spread of agriculture by Neolithic farmers. This was found to also correlate with H. pylori ancestry derived from Northeast Africa. Hence, one route taken by Neolithic races out of Africa was probably through Northeast Africa, to the adjoining Southeastern region of Europe. The second PC describes human migrations from north to south and, finally, third PC describes a movement along the plains between the Volga and Don rivers, which could be interpreted as the spread of pastoral nomads after the domestication of the horse. [17] Conclusion The emerging discipline of microbial phylogeography is a powerful means of monitoring not only the spread of microbes, but also the movements of their human hosts. The major drawback in using microbial sequences as markers for human migrations is the potential for frequent horizontal transmission between unrelated hosts. However, some organisms, like H. pylori, have a strong phylogeographic structure that help unravel fiercely debated topics in human history with unprecedented detail. This only reiterates the fact that we have much to learn, even about ourselves, from microbes. It is time to give microbes their due. References
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