Researcher | Research Overview
Our laboratory focuses on the development of computational methods for the design and analysis of genetic studies in humans and model organisms. In addition to developing widely applicable methods, we work closely with other groups at Boston Children's Hospital on study design and bioinformatics tools suitable for their ongoing research studies.
Mapping and identification of genetic changes associated with disease
We use both traditional, family-based linkage approaches and more recent methods like copy number variation (CNV) analysis, next-generation transcriptome and exome sequencing to identify genetic changes when only limited family history or just population samples are available. Typically our lab is responsible for informatics and study design; we work closely with other labs responsible for patient data collection and functional studies of putative causative mutations.
Most complex diseases have proven refractory to genetic analysis. Even for simple single-gene disorders, the mechanism of action is often not understood. The emergence of whole-transcriptome sequencing allows us to investigate transcriptome levels, alternative splicing and mutation changes simultaneously throughout the genome with unprecedented precision.
In collaboration with pathologist Mark Fleming, MD, DPhil, we used high-density Affymetrix 6.0 chips to map a new locus associated with sideroblastic anemia (a rare group of blood disorders in which the bone marrow cannot make red blood cells) in a large multiplex pedigree. We used the same Affymetrix 6.0 chips to identify another locus through haplotype sharing among unrelated affected individuals. We are now pursuing CNV analysis and whole-exosome sequencing to identify the causative genetic changes.
In collaboration with Christopher Walsh, MD, PhD, we are using homozygosity mapping to identify autism susceptibility genes in Middle Eastern pedigrees with shared ancestry. We have identified a number of genetic changes associated with the disease, including disruption of three genes implicated in synaptic development (c3orf58, NHE9, and PCDH10). These findings contribute to our growing understanding that autism results from miswiring or missing connections in the brain.
The malarial parasite Plasmodium falciparum is rapidly evolving resistance to existing antimalarial drugs. We are hoping to facilitate the design of new strategies by uncovering the underlying genetics behind natural mosquito resistance to the malarial parasite. We have traced the resistance in African mosquito field populations to a single region of the genome. We are now conducting a follow-up association study to pinpoint the specific variants responsible for resistance or susceptibility.
Facioscapulohumeral muscular dystrophy (FSHD)
In collaboration with Louis Kunkel,PhD, we are developing expertise and analytic tools for transcriptome sequencing of tissue samples from patients with FSHD, an inherited disease that is linked to a contraction of transcriptional repeats, and whose clinical manifestations vary widely. By characterizing the widespread changes in transcriptional regulation, we hope to uncover the mechanism of action and further understand what lies behind the variability of the disease.
We are creating an analysis pipeline to routinely employ for the analysis of disease-associated CNVs. In collaboration with Christopher Walsh, MD, PhD, we are working to identify copy number changes associated with sporadic cases of intellectual disability. We are also analyzing samples collected by Patricia Donahoe, MD, at Massachusetts General Hospital and Cynthia Morton, MD, at Brigham and Womenâ€™s Hospital, to identify CNVs associated with hearing loss and congenital diaphragmatic hernia. In the future, we plan to use the same pipeline to identify CNVs associated with sideroblastic anemia and Sudden Infant Death Syndrome.
Researcher | Research Background
Kyriacos Markianos received his PhD in physics from the University of Massachusetts. He studied statistical genetics and computational biology at the Kruglyak laboratory at the Fred Hutchinson Cancer Research Center in Seattle.