David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Winter Quarter 2016

Mondays, 11am - 12pm, Gonda Building First Floor Conference Room, 1357

Mon, Dec 14
Unbiased handling of uncertainty in association studies: from imputation to estimated effects
Itsik Pe'er, PhD, Associate Professor, Department of Computer Science, School of Engineering and Applied Sciences, Columbia University and Department of Systems Biology, Columbia University Medical Center
Contact & Intro: Catharine Krebs; catharinekrebs@ucla.edu
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ABSTRACT: Naively defined association studies report the effect sizes of genotype on phenotype, with both inputs and output being a specific quantity. In practice, uncertainty is an integral part of practical such studies, in terms of both input and output, as most genetic variants tested are probabilistically imputed, rather than observed, phenotypes are noisily measured, and implied effects are distributed around their point estimate. We present Multiple Imputation, a Monte Carlo based analysis of probabilistic GWAS input data that is accurate and unbiased, yet orthogonal to downstream analysis thereby accommodating mixed models, covariates, and meta analysis. On the output end, we observe, quantify, and remove the winner's curse, which is bias induced by ascertainment of SNPs for replication attempts, that had been suggested as the cause of many such attempts failing.

Thu, Dec 17
LOCATION: Neuroscience Research Building (NRB) Auditorium, Room 132 (Address: 635 Charles Young Drive South)
From Genomics to Public Health: Integrating Multidimensional Data
Hugues Aschard, PhD, Research Scientist, Department of Epidemiology, Harvard School of Public Health
Contact & Intro: Paivi Pajukanta, x 72011
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ABSTRACT: Variability in complex human phenotypes is associated with many factors, including exposures, biomarkers and genetic variants. As cohorts move toward large-scale genomic and phenotypic collections, developing multivariate analysis framework for the combined analysis of multiple predictors and/or multiple outcomes becomes a key component to move the field forward. Here I present new statistical methods and analytical strategies to integrate multi-dimensional data to improve association mapping and advance our understanding of the genetic architecture of human traits and diseases.

Mon, Jan 25
Genome instability: A conserved mechanism of aging?
Jan Vijg, PhD, Professor and Chair, Department of Genetics, Albert Einstein College of Medicine
Contact & Intro: Steve Horvath, x 59299
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ABSTRACT: Genome instability has since long been implicated in aging and age-related diseases. I will discuss the various ways the somatic genome can be destabilized and give rise to various types of molecular and cellular end points, with a focus on how our lab is trying to characterize the landscape of genome somatic mosaicism during aging.

Mon, Feb 01
LOCATION: Neuroscience Research Building (NRB) Auditorium, Room 132 (Address: 635 Charles Young Drive South)
From genetics to biology of human body size and other polygenic traits
Joel Hirschhorn, MD, PhD, Concordia Professor of Pediatrics and Professor of Genetics, Harvard Medical School; Director, Center for Basic and Translational Obesity Research; Institute Member and co-Director of Metabolism Program, Broad Institute ;
Contact & Intro: Jennifer Zieba
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ABSTRACT: Human genetics offers an opportunity to identify the underlying basis of human disease and biology. Genome wide association studies have identified thousands of associated loci for human polygenic traits and diseases, with the signals often attributable to noncoding variation; current efforts are expanding into rarer coding and noncoding variation. The successes and challenges are nicely illustrated by studies of human height and obesity. Computational approaches that utilize multiple different types of data, including gene expression and metabolite profiling, can help identify causal biology.

Mon, Feb 08
LOCATION: Neuroscience Research Building (NRB) Auditorium, Room 132 (Address: 635 Charles Young Drive South)
Adaptations to high altitude in human populations
Anna Di Rienzo, PhD, Professor, Department of Human Genetics, University of Chicago
Contact & Intro: Nelson Freimer, x 46427
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ABSTRACT: Low barometric pressure and consequent physiological hypoxia constitute a strong selective pressure, which is unavoidable and invariant across individuals at a given altitude because it cannot be influenced by behavioral or cultural practices. Several indigenous human populations have independently adapted to high altitude environments thus providing an ideal study system for elucidating the genetic architecture of adaptive traits. This presentation will focus on comparative analyses of adaptation signals and genotype-phenotype association studies across these populations to highlight similarities and contrasts in the genetic architecture of high altitude adaptations. A particular focus will be on the interplay between the genetic history of these populations and their adaptive processes.

Mon, Mar 07
LOCATION: Neuroscience Research Building (NRB) Auditorium, Room 132 (Address: 635 Charles Young Drive South)
Highly parallel measurement of the impact of mutations in proteins
Douglas Fowler, PhD, Assistant Professor, Department of Genome Sciences, University of Washington
Contact & Intro: Nelson Freimer, x 49571
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ABSTRACT: Hundreds of thousands of genomes or exomes are sequenced each year. In order for them to be useful, we must understand the consequences of the variants we find, a step that remains a major challenge. Deep mutational scanning is a method that marries selection for protein function amongst a large library of protein variants with high-throughput DNA sequencing to measure the activity of hundreds of thousands of variants simultaneously. The result is a sequence-function map that describes the impact of all possible single and many double mutants on protein function. We have shown that sequence-function maps can guide the interpretation of coding variants in genomes and can be used to train computational predictors of variant effect. Sequence function maps can also teach us about protein properties like structure, aggregation, stability and enzyme mechanism and enable us to better understand protein evolution. Thus, they represent an important new tool for dealing with the deluge of variants we're experiencing.

Tue, Mar 08
ROOM LOCATION: Center for Health Sciences (CHS) Room 13-105
Functional variation in the human genome: lessons from the transcriptome
Tuuli Lappalainen , PhD, Assistant Professor, Department of Systems Biology, Columbia University Junior Investigator; Assistant Investigator and Core Member, New York Genome Center
Contact & Intro: Paivi Pajukanta, x 72011
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ABSTRACT: Detailed characterization of cellular effects of genetic variants is essential for understanding biological processes that underlie genetic associations to disease, as well as basic genome function. Integrating genome and transcriptome data has allowed us to characterize genetic effects on the transcriptome across multiple human tissues, as well as shed light on diverse biological phenomena such as imprinting and nonsense-mediated decay.

Mon, Mar 21
Genetic analysis of molecular phenotypes reveals disease aetiology
Emmanouil (Manolis) Dermitzakis, PhD, Professor, University of Geneva Medical School and Swiss Institute of Bioinformatics
Contact & Intro: Nelson Freimer, x 46427
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ABSTRACT: Molecular phenotypes inform us about genetic and environmental effects on cellular and tissue state. The elucidation of the genetic basis of gene expression and other cellular phenotypes is highly informative for the impact of genetic variants in the cell and the subsequent consequences in the organism. In this talk I will discuss recent advances in key areas of the analysis of the genomics of gene expression and cellular phenotypes in human populations and multiple tissues and how this assists in the interpretation of regulatory networks and human disease variants. I will also present some perspectives on how these developments are bringing us closer to the promise of precision medicine.

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