Congratulations to recently graduated PhD student Mike Sively on publication of two papers describing his work on the spatial distribution of human genetic variation in protein 3D structures and models. The first, published in the American Journal of Human Genetics, describes a comprehensive analysis of more the four million genetic variants in their structural contexts. We found that pathogenic and benign variants exhibit different patterns of spatial constraint, and that these patterns can be informative about protein function:
Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures
The second paper describes an application of the analysis of the spatial distribution of pathogenic and benign variants to characterized uncharacterized variants in RTEL1 identified in patients with pulmonary fibrosis. Our new PathProx performs competitively with popular methods for pathogenicity prediction and suggests specific hypotheses for how variants influence protein function:
Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia
Congratulations to Dr. Mike Sivley on successfully defending his PhD! His dissertation is titled “Constraint on Rare Protein-Coding Variation: Pathogenicity Prediction and Phenotypic Discovery.”
Alex’s paper on how mismatches in local genetic ancestry along the genome in admixed individuals can influence associations between genetic variants and traits has just come out in the 2018 Proceedings of the Pacific Symposium on Biocomputing. In this manuscript, we develop a model that captures the effect of both single variants and local ancestry on traits of interest, and use it to identify examples where local ancestry transitions significantly interact with nearby variants to influence metabolic traits. Check it out!
Local ancestry transitions modify snp-trait associations
Laura and I gave talks at the annual ASHG meeting in Orlando earlier this month on our work to understand how interbreeding with archaic hominins has influenced modern humans and what it can tell us about these groups.
Science, Nature, and several other news outlets covered our talks:
Modern humans lost DNA when they left Africa—but mating with Neandertals brought some back
Geneticists are starting to unravel evolution’s role in mental illness
Ling and Alex’s paper about the factors that determine the evolutionary conservation of enhancer activity across species has been published in Genome Biology and Evolution! We studied maps of liver enhancers across 20 mammalian species and found that enhancers with conserved activity have higher regulatory potential, are active in more contexts, and regulate more genes than enhancers that are not conserved. This argues that pleiotropy is associated with the conservation of regulatory regions across mammalian evolution.
Gene regulatory enhancers with evolutionarily conserved-activity are more pleiotropic than those with species-specific-activity
Patrick Abbott and I just published a Insight article in eLife about a recent manuscript that demonstrated similarities between genes expression dynamics in the short-lived marsupial placenta and marsupial mammary glands with genes expressed in eutherian placentas. This illustrates that many developmental functions in marsupials and eutherian mammals are accomplished by different tissues, but similar genes. We argue that similar comparative genomics approaches will yield more insights into the evolution and molecular basis of pregnancy.
What’s a placental mammal, anyway?
Congratulations to former intern Vir Patel on the publishing of his paper about how the evolutionary histories of miRNAs are informative about their functions and potential to cause disease. Vir started this project several years ago as a summer intern and worked hard to finish it over the past year. Great job Vir!
Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs
We are delighted to welcome Abin Abraham, a new MD/PhD student, to the lab. Abin will join the Human Genetics PhD program. He is interested in understanding the genetic architecture and evolution of diseases of pregnancy. Abin graduated from the University of Michigan with a B.S.E in Biomedical Engineering.
Congratulations to Corinne for publishing her paper on how transposable elements gain enhancer activity in Molecular Biology and Evolution. Check it out:
Transposable Element Exaptation into Regulatory Regions is Rare, Influenced by Evolutionary Age, and Subject to Pleiotropic Constraints
Congratulations to Laura for publishing her first paper! If you are interested in how enhancers’ DNA sequences influence their activity take a look. Spoiler alert: patterns are different between humans and flies!
Short DNA sequence patterns accurately identify broadly active human enhancers