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Q+A: Studying the Past Through Genetics

Priya Moorjani



In the academic community, there are many ways to study a population and its history. Priya Moorjani, Assistant Professor of Genetics, Genomics and Development, University of California, Berkeley, is working to develop a more extensive view of the South Asian population identifying mutations and diseases in ancient DNA.

Before her participation in the upcoming panel “Are South Asians a Single Population? Insights from Culture, Genetics, and Disease,” The Mittal Institute asked Priya Moorjani about her research, which uses statistical and computational approaches to study questions in human genetics and evolutionary biology.

The panel discussion will take place on Monday, April 23rd at 4pm in CGIS South SO10. Priya will be joined by David ReichProfessor, Harvard Medical School; Richard Meadow, Director, Zooarchaeology Laboratory, Peabody Museum of Harvard University; Michael WitzelWales Professor of Sanskrit, Harvard University; and seminar chair Venkatesh MurthyProfessor and Chair of Molecular and Cellular Biology.


When studying a population’s history, what does the genetic lens put into focus? 

Genetic data carries a wealth of information about our ancestors. By studying the similarities and differences in genetic variants across individuals or groups, we can learn about how people relate to each other, what are some of the migration and gene flow events that have occurred in their past, and what genes that have helped them adapt to diverse climates or caused harmful diseases. Moreover, the breakthroughs in ancient DNA sequencing have made it possible to directly study patterns of genetic variation that existed in the past. This is very powerful, as it allows one to track the changes through space and time and build a more comprehensive view of human history and evolution.


Which recent adaptations have had the most impact on human and primate evolution? 

In humans, the main signals of recent adaptation are related to immunity, diet, and pigmentation. For instance, a mutation in the lactase gene enables Europeans to digest milk in adulthood, which is likely an adaptation to animal domestication and milk consumption. There is also evidence for adaptations related to immunity or resistance to diseases; Africans living in malaria endemic zones have a mutation that confers resistance to this disease. Recent studies have also documented many variants that cumulatively explain changes in skin color and height across populations. More anciently, there is evidence for selection at a gene called FOXP2 that is associated with speech and language. In primates, there have been multiple instances of balancing selection related to pathogen response and defense.  


What is introgression and what do introgressions tell us about early humans?  

Introgression refers to gene flow (or mixing) between two divergent groups or populations. Studies of early humans tell us that ancestors of all non-Africans and Neanderthals mixed with each other, conferring approximately 1-2% Neanderthal ancestry in non-Africans today. Moreover, ancestors of Oceanians and Asians mixed with another archaic population Denisova that lived ~50,000 years ago. This means that these early humans were not very different from us and likely had similar culture, language, and traits. More generally, these studies also tell us that mixtures between groups are very commonplace throughout human history and population relationships are best modeled as graphs with many interconnections among groups versus trees with population splits and separations.    


How can introgression be identified in genetic data?

Introgression can be identified by comparison of genomic sequences from the source, test, and an outgroup. The signal we are looking for is one where the source and test share significantly more genomic variants compared to the outgroup. We also want to see that these shared genomic variants are clustered together in “blocks” and not just randomly distributed throughout the genome — as this can allow us to differentiate between just shared ancestry and recent mixing. Block length can further tell us about the timing of the events, larger blocks imply recent events, and smaller blocks are due to older events. 


 When studying the South Asian population, are there specific diseases or mutations that you are focusing on?

In our recent study, we identified ~80 groups in India that have a history of founder events that are more extreme than those seen in Ashkenazi Jews and Finns, both of which have high rates of recessive diseases. There is no good survey of rare disease prevalence by groups in India, so instead of restricting ourselves to a few known rare diseases, we are taking a broader approach. We are collecting data from individuals in these 80 founder groups to identify recessive diseases that occur at higher rates in these communities and performing exome sequencing to map associated disease mutations. This approach will allow us to build a catalog of variants related to rare recessive diseases in India that can be used for future screening and testing efforts to reduce disease burden in the subcontinent.


What is disease mapping and what makes India such an interesting region for disease mapping?

Disease mapping refers to the comparison of cases (individuals with the disease) and controls (individuals without the disease) to identify genetic variants that cause the disease. South Asians have a unique history of population mixture between divergent groups, followed by a shift to endogamy leading to severe founder events in many groups. This history predicts that many groups may have a high burden of recessive diseases stemming from one or two mutations specific to individual groups, that are segregating at high frequencies in these groups. By tracing the signature of founder events in these groups, we can identify the variants associated with these diseases. Such an approach has been extremely powerful in founder populations of European descent like Amish, Ashkenazi Jews, and Finns. In India, there are many founder groups providing even greater opportunity for disease mapping. Moreover, extending studies to more diverse ethnic populations in South Asia provides an opportunity to discover rare, population-specific disease variants, as well as replicate findings in Europeans to minimize false positives.


How do you hope your lab’s research will help both the scientific and South Asian communities?

I am deeply interested in understanding population history and human evolution. To this end, my lab is focusing on developing methods for characterizing population relationships and identifying genetic variants that are associated with human adaptation and disease. A particular focus in the lab is to apply these methods to South Asian populations, which have been majorly underserved by genetic studies thus far. In this regard, there are two main projects that we are working on:

  • Studying how the population history of South Asia has changed over the past 5,000 years — a period of major mixture and profound change in the subcontinent.
  • Performing disease mapping in South Asians that leverages the history of founder events, uncovering disease genes in many endogamous groups.

These studies will not only provide insights about South Asian history and disease but also help refine our understanding of the biological function of various genes and pathways and offer potential new therapeutic targets.