SciLifeLab The Svedberg seminar series 2014-02-10


Attention – double seminar: Melissa A. Gymrek (15.15-15.45) Alon Goren (15.50-16.20)

 

Melissa A. Gymrek 
Whitehead Institute, Cambridge, MA USA, Broad Institute of MIT and Harvard, Cambridge, MA USA

Melissa A. Gymrek is a PhD Student in Bioinformatics and Integrative Genomics at the Harvard-MIT Division of Health Sciences and Technology where she develops front line methods for deep seqencing data
analysis.

“Short tandem repeats create an abundant source of expression variability in humans”

A central goal in biology is to understand the genetic architecture of complex traits. Studies that link genotypes to phenotypes have focused primarily on single nucleotide polymorphisms. However, multiple lines of evidence from dozens of single gene studies in humans and model organisms have shown that Short Tandem Repeat (STR) length variations may significantly affect gene expression. Despite strong evidence that they may participate in genomic regulation, STRs and their association with gene expression have not been characterized in humans on a large scale. I recently led the development of lobSTR, an algorithm that addresses these difficulties and rapidly profiles hundreds of thousands of previously inaccessible STRs from sequencing datasets. Here I will first present the lobSTR algorithm and the results of genome-wide STR genotyping on thousands of individuals. Next, I will demonstrate the accuracy of lobSTR genotypes by showing how we can use Y chromosome STR calls from samples from the 1000 Genomes Project to infer their surnames, and will discuss the important privacy implications of this result. Finally, I will present the first genome-wide association study between STR variations and expression profiles, which discovered more than 1,500 STRs associated with gene expression in cis (eSTRs). These loci provide a novel set of regulatory variants that may explain a significant fraction of variance in expression levels between individuals.

 

Alon Goren
Broad Institute of MIT and Harvard, Cambridge, MA USA, MGH Pathology, Harvard Medical School, Boston, MA USA

Alon Goren is researcher at the Broad Institute with interests focused on epigenetic and epigenomic mechanisms. In these areas he merges basic biology, technological innovations and computational analyses. A central topic in his research is  chromatin regulatory networks of early mouse development.

“Chromatin regulatory circuits in mammalian in vivo and in vitro early development”

Prominent changes mark the first stages of mammalian development, as differentiation transforms the totipotent zygotic cell into the more committed blastocyst, which is comprised of several distinct cell types. This process is orchestrated by several regulatory mechanisms, one of which is the organization of chromatin, known to play an important role in developmental transitions. The shaping and stabilization of chromatin is carried out by specialized enzymes called chromatin regulators (CRs).

We established an original approach for screening antibodies and conditions, and generated ChIP-seq CR maps in Human cells. I will present how using this approach, we observed that CRs work in distinct modules made up of different combinations of regulators, an important insight on the road to understanding their mechanism of action. I will discuss the relevance of our observations to pluripotency and embryogenesis.

To study the genomic organization of chromatin in early embryogenesis, we have developed techniques to generate ChIP-seq and RNA-seq maps from minimal numbers of cells, which enable us to examine chromatin structure and transcription in in vivo samples from early embryogenesis for the first time. From these maps, we identify differentially expressed genes, including key transcription factors (TFs) and chromatin regulators. Importantly, the enhancer patterning is markedly different between in vivo and in vitro models, and correlates with differential expression of TFs whose motifs are enriched in (and thus predicted to bind) differentially-regulated enhancer sets. These maps enable comparison of epigenetic states between ES cells cultured in vitro and early embryos, including in vivo pluripotent model of mICM (mouse inner cell mass).

Host: Johan Elf