Northwestern Events Calendar

Aug
16
2016

The Contributions of Rare Variants to the Heritability of Complex Traits

When: Tuesday, August 16, 2016
12:00 PM - 1:00 PM CT

Where: Robert H Lurie Medical Research Center, Searle Seminar Room, 303 E. Superior, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students

Contact: Michelle Mohney   (312) 503-5600

Group: Center for Genetic Medicine

Category: Lectures & Meetings

Description:

Ryan Hernandez, PhD
Associate Professor, Department of Bioengineering and Therapeutic Sciences
School of Pharmacy, University of California, San Francisco

Human evolutionary history has increased the role of rare variants in complex phenotypes

Understanding the genetic architecture of complex traits is a central challenge in human genetics. There currently exists a large disparity between heritability estimates from family-based studies and large-scale genome-wide association studies (GWAS), which has been sensationalized as the “missing heritability problem”. Among the possible explanations for this disparity are rare variants of large effect that are neither tagged by existing genotyping platforms, nor well imputed from existing reference panels. However, recent population genetic models suggest that the conditions under which rare variants are expected to substantially contribute to heritability may be fairly limited. We have extended existing models of complex traits to incorporate a wider range of plausible evolutionary features, and provide further insights into the role that rare variants play in shaping complex traits. We use these models to investigate the genetic architecture of gene expression levels across European and African individuals using RNA and whole genome sequencing data from the GEUVADIS and 1000 Genomes Projects. In particular, we investigate whether rare variants are likely to be a source of missing heritability in expression across genes. We pioneered a technique for partitioning heritability estimates across allele frequencies using Haseman-Elston (HE) regression. We find that rare variants (MAF ≤ 1%) contribute significantly more heritability than common variants (MAF > 5%) across most genes. This observation suggests that rare variants play a substantial role in the heritability of gene expression patterns, which is inconsistent with neutral evolutionary forces operating on the cis regulatory architecture of most genes. We develop an Approximate Bayesian Computation (ABC) algorithm to infer the evolutionary parameters that can explain these observations, and find a striking relationship between the evolutionary forces that have shaped human genomes and the phenotypic variation we observe.

Ryan Hernandez is an Associate Professor in the Department of Bioengineering and Therapeutic Sciences, and the Associate Director of the Biological and Medical Informatics (BMI) graduate program at UCSF. Before starting his lab at UCSF in 2010, Ryan obtained his PhD in Biometry from Cornell University and postdoctoral training at the University of Chicago. Ryan’s lab uses tools from statistical genomics, computation biology, and population genetics to gain insights into complex biological systems. His research spans theoretical and applied population genetics modeling, complex disease genetics, and host-pathogen interactions.


Seminar host:

Aaron Hamvas, MD
Raymond and Hazel Speck Barry Professor of Neonatology
Head, Division of Neonatology
Ann and Robert H. Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine

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