Genetic Diversity in Indian Populations

Genetic Diversity in Indian Populations

{Feature has been uploaded by CSIR (Unit for Science Dissemination), Ministry of Science & Technology, New Delhi}

A home to more than one billion people, India is a land of matchless diversity in diverse ways. With scores of culturally diverse communities inhabiting the nation, each portraying a different language, religion, set of customs and cuisine, India is not only ethnically distinct that is much apparent but the human populations of this country are also distinct at the level of genes — the hereditary material that is passed on from one generation to the next — thanks to novel findings of a joint team of Indian and American scientists, with key players from the Centre for Cellular and Molecular Biology (CSIR), Hyderabad, India and from Harvard Medical School, the Harvard School of Public Health and the Broad Institute of Harvard and MIT.

Interestingly, if we look at our genetic material that biochemically comprises the DNA molecule, any two unrelated individuals surprisingly differ just by 0.1%, as the remaining 99.9% of DNA is completely identical. What an irony then that all the amazing human diversity, at the level of genes, is housed only in this variable, and apparently tiny, portion of our DNA! It is this region of DNA, comprising some three million base pairs, that is a storehouse of clues to a rich source of information, and has today helped scientists to reconstruct the historical origins of human populations in India. It is also the region of our genetic material, which clearly points to the many genetic variations in human beings that make select individuals at a higher risk of certain diseases as compared to others.

For this study on ascertaining genetic variability across various human populations in India, about 5.6 lakh genetic markers were analyzed across the genomes of 132 individuals who were selected from 25 diverse groups in India that represented 13 states comprising all six language families, traditionally upper and lower castes, as well as tribal groups. An important revelation of this study led by Lalji Singh and David Reich, published in 24^th September 2009 issue of Nature, is that different Indian groups carry genomic material from two distinct ancestral populations – the ‘Ancestral North Indians’ (ANI) who are related to western Eurasians, from whom the Indian populations have inherited 40-80 % of their ancestry and the rest from ‘Ancestral South Indians’ (ASI) who are not related to any group outside India. The ANI ancestry has been found to be significantly higher in Indo-European than Dravidian speakers, which suggests that populations descending from ASI may have spoken a Dravidian language before mixing with populations descending from ANI.

For analyzing the genetic markers, which are the regions of genetic variations occurring as single nucleotide polymorphisms (SNPs), the blood samples of select individuals of 25 diverse groups of India were collected. After DNA extraction from these samples, all DNA samples were genotyped on Affymetrix 6.0 arrays or DNA chips, and analyzed for genetic variations in 560,123 SNPs. Scientists then employed novel statistical approaches for studying the genetic variations in these individuals of diverse groups. Allele frequency differentiation among the groups as well as inbreeding in each group were assessed using sophisticated software. A novel toolkit has also been developed by scientists for understanding the relationships among population groups, thus tracing their history of origin.

This novel work has thus revealed, through modern genomic technology, that almost all Indian groups, including the traditional ‘tribes’ as well as ‘castes’, have descended from the mixtures of ANI and ASI ancestral populations. A significantly higher ANI ancestry has been found in traditionally upper castes than in middle/lower caste groups. According to CCMB scientists, it is impossible to distinguish castes from tribes using the data, which supports the view that castes grew directly out of tribal-like organizations during the formation of Indian society.

This study has also revealed that the Andamanese – a small population of indigenous people of the Andaman Islands – appear to be related exclusively to the Ancestral South Indian lineage and completely lack Ancestral North Indian ancestry. This surely opens a door to the history of the Ancestral South Indians who diverged from other Eurasians, probably tens of thousands of years ago. Genetic variation studies on tribal populations, who have been locked away from the modern world, is the key to unlock not only the mystery of our own origins but is also important for understanding the genetic basis of complex diseases. Many of the environmental risk factors related to modern lifestyles, such as intake of unhealthy diet and lack of physical exercise, which are at the crux for triggering many complex diseases, are usually uncommon in tribals. Therefore, with studies on primitive, isolated tribal populations, it would be possible to differentiate genetic factors from environmental risk factors for these diseases. In this direction, CCMB has undertaken a large project on studying the human genetic diversity in tribal and caste populations of India in collaboration with Anthropological Survey of India.

It has also come to light that the ancestry of many groups in modern India could be traced back to a small number of founding individuals, which explains why these groups have remained genetically isolated from other groups for thousands of years, with limited gene flow due to endogamy or marriages within the group. Such ‘founder events’, as they are popularly called, are the root cause of the exceptionally high incidence of some genetic diseases among only Indians. According to Lalji Singh, former director of CCMB and a Bhatnagar Fellow whose pioneering efforts in this field are commendable, India is genetically not a single large population, but comprises many smaller isolated populations that have descended from several founder events.

Just as founder events are known to increase the incidence of recessive genetic diseases in other human populations like Finns and Ashkenazi Jews, the same could most likely be the case for many groups in India, where inter-caste marriages are a taboo. According to researchers, the founder effects are responsible for an even higher burden of recessive diseases in India than consanguinity. According to researchers, this can be confirmed by carrying out a systematic survey of Indian groups for identifying the communities that have descended from the strongest founder events. This would help in pinning down the culprit genes responsible for causing many devastating genetic diseases, thus opening the door to finding effective therapies and providing appropriate clinical care to the affected individuals and those at risk.

The history of population structure in India, therefore, has its root in two ancestral populations — ANI and ASI — and it is the rampant mixture of these populations that is the hallmark of all the amazing genetic variations in many Indian groups. The concepts of ancestral genomic content, their mixture throughout India and importance of founder events have assumed significance, for these have serious implications on the health of the Indian populations. The scope of further research in this field would be to estimate a date when the mixture of these populations might have occurred. For this, a detailed study of the length of genetic stretches of ANI ancestry in Indian samples assumes importance. Another area of scientific interest is exploring the history of ANI and ASI populations before they began to be mixed.

India, the world's second most populous nation is uniquely distinct for its varied diversity. Be it geographic or climatic diversity, be it the diversity in languages, religions and cultures of its people, or be it the genetic diversity as evident today, after all it is our very diversity that imparts strength to our oneness.

Box 1

India Cracks the Human Genome (2009)

In a ground breaking work, CSIR scientists at the Institute of Genomics and Integrative Biology (IGIB), New Delhi, completed the first human genome sequencing in India in December 2009, setting the stage for India’s entry into individual genomics that opened up new possibilities in disease diagnostics and treatment. The sequenced genome was that of an anonymous healthy individual from Jharkhand. While the first human genome sequencing took over a decade, and a whopping 3 billion US dollars to complete the task, CSIR bagged the unique credit for accomplishing the same in only 45 days, spending Rs. 15 lakhs (US$ 30,000).

The IGIB scientists triumphantly generated over 51 gigabases of data, using the most sophisticated sequencing technology that enables massive parallel sequencing of millions of fragments of the genetic material, as small as comprising only 76 base pairs. These small DNA fragment once sequenced, are then mapped back to the reference genome. This herculean task of finding the sequence of the entire human genetic material, comprising three billion base pairs, was possible due to the CSIR supercomputing facility at IGIB. With this achievement, India became the sixth country after US, China, Korea, Canada and UK, to demonstrate the capability of sequencing and assembling a complete human genome.

Understandably, sequencing of the human genome requires high computational capability and technological know-how in handling sophisticated machines and analyzing huge volume of data. The first human genome sequencing initiative was conceived as early as 1984. In addition to the United States, the ‘International Human Genome Project Consortium’ comprised geneticists from United Kingdom, France, Germany, Japan and China. The International Human Genome Project formally started in 1990 and was completed in 2003, sequencing the genomes of Craig Venter, James Watson and an anonymous Chinese individual. CSIR could achieve this by adapting to new technologies and effectively integrating complex information technology tools with analytical capabilities.

The sequencing of the human genome would help us to understand the variations at genetic level that make two individuals different. More importantly, since there is an association between the genetic variants and predisposition to diseases, human genome sequencing would be enormously important in diagnosis and management of various diseases including cancer. Interestingly, the sequencing of the Indian genome has revealed a large number of hitherto unknown variations that include single nucleotide polymorphisms (SNPs) as well as many insertion/deletions in our genetic material. Understanding the functional role of these variations would, for sure, throw light on identifying the markers linked to specific diseases, which could be specifically hunted for predicting diseases before they spell disaster. 

Earlier, CSIR scientists also completed the genome sequencing of zebrafish – an organism popularly used to model human diseases – that has half the size of the human genome. With this feat, India became the first country to sequence the wild type strain of zebrafish.

Box 2

Another Door Opened –

 Genetic Diversity Mapped in Asia

Housing 60% of the human inhabitants of planet Earth, Asia – the world's largest continent – is a huge melting pot of genetic diversity. The contributors of this exceedingly rich human resource are the scores of unknown ancestors who migrated from different parts of the world and settled down in this region over thousands of years.

Ancestral human populations are believed to have originally spread out from Africa, from where they slowly began to adapt different parts of the globe due to the pressures of climate, food and health conditions. The present genetic human diversity of the Asian populations is all due to these best adapting individuals, who proved most fit to survive in a given place. It is the tracking down of the ancestry of the human populations, through certain tell-tale signs written in every person’s genes, that has empowered scientists to remarkably establish a link between two geographically separated groups of people. To understand the genetic history of the people living in Asia, over 90 scientists from the Human Genome Organization’s (HUGO’s) Pan-Asian SNP Consortium undertook the human genetic mapping of Southeast Asian (SEA) and East Asian (EA) populations, the findings of which have been published in the December 2009 issue of Science. The hallmark of this human ingenuity is nothing but the tracing of certain ‘marker’ genes that for example, may bestow the individual an advantage of better survival in a particular environment, or a disease-gene marker which could be tracked back in time to discover the human population from where that altered/mutated gene may have originated.

In this unique attempt 1,928 unrelated individuals representing 73 populations from 10 countries and 10 linguistic lineages from mainland China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan and Thailand were studied. For establishing genetic differences between two unrelated individuals, scientists basically look at more than three million differences in their genes. Variations at the level of single nucleotides, are commonly referred to as single nucleotide polymorphism (SNP). Therefore, it is the tracking of genetic variations through human migrations that provide clues to evolution of diseases and genetic diversity. Genotyping of more than 50,000 SNPs was done at eight different centres while the filtering of collected data was centralized to maximize the standardization of results. This genetic mapping of people inhabiting different parts of Asia has opened the door to understand the migratory patterns in human history as well as the genetic basis of many diseases afflicting human populations of this region.

This study has revealed that populations from the same linguistic group tend to cluster together, which means that there is considerable relatedness within ethnic/linguistic groups. It has also revealed that there was a south-to-north migration of East Asians, which means that the majority of East Asian gene pool has been derived from Southeast Asia. According to the study, the most recent common ancestors of Asians arrived first in India. Later, some of them migrated to Thailand, and also South to Malaysia, Indonesia, and the Philippines. The first group of settlers must have gone very far south before they settled successfully. These included the Malay Negritos, Philippine Negritos, the East Indonesians, and the early settlers of the Pacific Islands. Later, one or several groups of people migrated North, mixed with previous settlers there resulting in various populations now known as Austronesian, Austro-Asiatic, Tai-Kadai, Hmong-Mien, and Altaic etc. Interestingly, most of the Indian population showed evidence of shared ancestry with European population.

Signifying the implications of this study, nothing can better echo the sentiments of scientists than the words of Professor Samir Brahmachari, former Director General, CSIR: “We have breached political and ideological boundaries to show that the people of Asia are linked by a unifying genetic thread.”