Harmit Malik, PhD

Fred Hutchinson Cancer Research Center, Seattle, WA

2012 Genetics

Harmit Malik, PhDGenetic conflicts between TREX1 and endogenous retroelements

The Study and What it Means for Patients

Could a lost evolutionary arms race cause lupus autoimmunity? We’re exploring if autoimmunity results from the evolutionary escape of ancient parasitic genes from defense mechanisms that control them, which could provide a new model for understanding what causes lupus.”

Summary:
More than 50% of the human genome is made up of endogenous retroelements — parasitic ‘jumping genes’ that can replicate and re-insert themselves into our DNA. Over millions of years of evolution, most retroelements have lost their ability to jump, but a tiny fraction is still capable of becoming active. Our cells protect us from this threat using a highly efficient system for recognizing and degrading endogenous retroelements when they become active. Recently, mutations in a component of this defense system (the TREX1 gene) have been found in some people with lupus, leading our team to propose that autoimmunity arises when our cells can no longer recognize activated retroelements — either because of a mutation in our recognition pathway or in the retroelement. The LRI grant will allow us to test this theory for the first time by analyzing genetic variation in the TREX1 gene and active retroelements, looking for evidence that each has influenced the evolution of the other.

Scientific abstract:
Primate genomes devote considerable effort to curb the activity of endogenous retroelements that constitute a significant fraction of the human genome. Recent research into a particular type of lupus, Aicardi-Goutières Syndrome (AGS), suggests that mutations in genes implicated in the control of endogenous retroelements (including TREX1) result in the autoimmune phenotype of this disease. TREX1 functions to degrade retroelement DNA, thus blocking both the activation of cytosolic DNA sensors as well as the subsequent interferon response. We find evolutionary signatures of positive selection in TREX1 that lead to a novel hypothesis that TREX1 is directly engaged in an evolutionary conflict with retrotransposons. We posit that autoimmune diseases like AGS and lupus result from a breakdown of this retroelement restriction wherein autoimmune disease may arise either from mutations of genes like TREX1 that alter retroelement restriction, or from mutations in retroelements that allow them to escape host restriction. To test this, we will assay how variation in TREX1 genes correlates with ability to restrict retroelements and whether 'young, hyperactive' human retrotransposons can overcome this restriction. Our novel experimental approach could lead to a general model for autoimmune disorders and provide general resolution to the mysterious genetics of systemic lupus erythematosus.