We are a group of evolutionary geneticists who are interested in addressing many interesting problems in evolutionary biology. One central topic for our team is to understand adaptive evolution in many model systems. Our research can be structured into three major directions.

Methods for detecting adaptive evolution and applications to viral evolution

How to detect adaptive evolution using patterns of sequence evolution has been a very interesting topic for the team. Using theories from the continuous time Markov Chain, we are trying to develop new methods to detect adaptive evolution on large phylogenies. Classical methods in this direction have been the codon-based models proposed by Goldman and Yang 1994, Muse and Gaut 1994. Codon based models implemented in PAML and HYPHY are very rigorous models with high computational burden (typically # of taxa cannot be very high). Using Mutational mapping, a probabilistic approach originally proposed by Rasmus Nielsen in 2002, we are extending the method and have been applying it to the evolution of seasonal Influenza viruses (H3N2).

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In seasonal Influenza virus, we are interested in one special evolutionary process known as the passage adaptation. When you isolate an Influenza strain from a patient, you will need to grow the virus into large quantities. Various culturing mediums (e.g. embryonated eggs or MDCK cell lines) have been used to culture the Influenza. During the culturing process, Influenza viruses adapt to the culture condition known as passage adaptation. In 2007, we found that passage adaptation does seem to contaminate the evolution on the tip branches of the influenza phylogenetic tree (Zhai et al 2007).  In 2016, we found that passage adaptation in embryonated eggs and mammalian cells are very dynamic.  Adaptation in embryonated eggs are getting progressively much stronger while adaptation in the mammalian cell lines are getting a lot weaker. We hypothesize that due to the constant adaptation to human populations, influenza viruses are getting progressively more adaptive to the mammalian conditions. Passaging them in embryonated eggs (an avian condition) will lead to stronger adaptation (Chen et al 2016).  Interestingly, this strong egg passage adaptation seems to be correlated with recent reduction in flu vaccine efficacy. Using a new metric defined as the adaptive distance, we found that the level of passage adaptation during vaccine production seems to be negatively correlated with vaccine efficacy (Chen et al 2019). This explains why influenza vaccines are not working so well in recent years.

Population Genetics of domesticated species during East Asian civilization

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We have been interested in applying population genetic methods to understand adaptive evolution in domesticated animals and plants. We have been particularly interested in species related to East Asia civilization:  domesticated dogs and rice. Using large scale sequencing approaches, we inferred the history of domestication for domesticated dogs (Wang* & Zhai* et al 2013 and Wang*Zhai*, Yang* and Wang* et al 2016,Yang et al 2017) as well as two cultivars of rice (He*, Zhai* and Wen* et al 2011).  In dogs, we found that the history of dog domestication is a lot more ancient than previous thought (32,000 years ago as supposed to 16,000 or 12,000 year ago, Wang* & Zhai* 2013). We think that dogs are domesticated through a self-domestication process (i.e. scavenging with humans). 

We found that genes related to neurological process, metabolism and digestion as well as sexual reproduction are strongly selected during dog domestication. Very interestingly, genes that are selected in dogs show a lot of convergence to humans. This opens chapters for new investigations on dog evolution. In 2016, using a large collection of canids across the world, we draw the out-of-Asia migration of dogs across the globe. We pinpointed several pivotal time points in ths history of dog domestication. Studies from these two studies have attracted a lot of public attention. We particularly enjoyed one report from New York Times by Carl Zimmer. Understanding the history of domestication for East Asia has been an interesting topic for the lab.

Tumor evolution and evolutionary medicine

In the past 10 years or so (2009-now), we have been exploring a new research domain in evolutionary biology known as somatic cell evolution.

Organismal development is an amazing cellular orchestra starting from a single zygote. Following morphogenesis, massive amount of cells with diverse functions are first built following large-scale construction and deconstruction of cellular structures. Subsequently, this architecture is actively maintained though homeostasis. There are many interesting population genetic and evolutionary questions in this regard. For example, what is the genealogical relationship of all cells within a multi-cellular organism? What are the roles of stem cells in the genealogy? How this genealogy might differ within and between species?

When the normal homeostatic renewal is broken, the aberrant version of the cellular dynamics can be manifested in many aspects. Many somatic disorders, for example cancer and many age-related diseases are due to the breaking down of the normal control. There are a lot of evolutionary questions in this direction. For example, what are the roles of natural selection in the evolution of cancers? What are the roles of stem cells in cancer progression and metastasis?

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In 2009, with my mentor Chung-I Wu and colleagues from the Beijing Institute of Genomics (BIG), we draw the first evolutionary story of liver cancer (Tao et al PNAS 2011). Subsequently, we have been pursuing in understanding the tissue renewal dynamics in mouse colon using population genetic modeling and single cell genomic data (Hu et al PLOS Genetics, 2013). In 2017, we drew one of the first comprehensive landscape of tumor heterogeneity for liver cancer and discovered several interesting phenomena in HCC (e.g. spatial organization of tumor heterogeneity, Zhai et al Nat Comm, 2017).

In 2018, we published a study comparing tumor heterogeneity in lung cancer across Asians and Caucasians (Nahar*, Zhai* and Zhang* et al Nat Comm 2018). Understanding tumor evolution and heterogeneity, especially the ethnic differences, has been a very active area of research for the team.

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