Using information on genomic history to help identify therapeutic targets

PUBLISHED ON March 9, 2017 by Gaurav Chauhan

You and any other person on Earth have approximately 99.9% of your DNA identical to one another. However, no two individuals have 100% identical DNA. Even identical twins have infrequent genetic differences due to mutations occurring during development. DNA is made up of 4 building blocks denoted by letters A, T, G and C, and the total DNA that makes up the human genome is made up of approximately 3 billion such paired letters called base pairs. These base pairs are arranged in a specific sequence with only 0.1% base pairs differing from that sequence. The positions where these base pairs differ are called single nucleotide polymorphisms (SNPs). These differences in DNA arise from mutations, changes that arise randomly in DNA. Due to various environmental factors, specific mutations can be beneficial in certain parts of the world, and can increase in frequency.

Humans originated in Africa. Some groups of people stayed there, and others migrated and settled in different parts of the world. The small bunch of people populated a given area and all their progeny had their genome coming from these small group of people. This gave rise to populations with genome having same SNPs. Also, these people started to adapt to their environmental conditions and in the process acquired and maintained the same SNPs which made them better equipped to survive in those conditions. Together these processes gave rise to a population within a given geographical location who have very similar SNPs in each of the individual, but very different SNPs as compared to individuals from population in a different geographical location. People in East Asia have SNPs very similar to each other and unique to them, but different from the SNPs in people in Europe.

SNP picture photo credit:https://isogg.org/wiki/Single-nucleotide_polymorphism

Eventually, humans from these different populations began to move about the world, and to have children together. This resulted in mixing of the population specific SNPs giving rise to groups of people with SNPs that first arose in many different parts of the world. These populations, too, tend to keep the SNPs that arose in their ancestral environment and are beneficial in this new location, too. By looking for SNPs that originated in one part of the world and are now present in a population elsewhere we can predict which segment of the DNA comes from which ancestral population. By doing such kind of study on a particular population, we can determine if there are any segment of DNA that mostly comes from a particular ancestral population, suggesting that these segments contain information that is important for surviving in the given conditions.

We performed this analysis on the Bangladeshi population, which was formed about 52 generations ago by people from East Asian (17%), European (11%) and South Asian (72%) ancestral populations. We found that the segments of DNA having SNPs coming from European ancestry in the Bangladeshi population help protect people from severe cholera infection. This result is consistent with the view that cholera infection is one of several different selective pressures that have shaped genome evolution in Bangladesh. We are now combining results from many other techniques to identify the factors that play a role in resistance to cholera improving the survival fitness of the Bangladeshi individuals. These factors like host immune response genes can then be targeted to develop therapy for cholera.

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