Understanding human disease using both comparative genetics and genomics

My research group focuses on generating tools and applying them to finding disease genes and mutations of relevance for human disease. The comparative genetics aspect involves using domestic animals to find disease genes and pathways and then translating these to human patient collections through collaborative projects. The comparative genomics work includes improving the annotation of the human and vertebrate model organisms to allow us to better prioritize candidate mutations for functional analysis.

The unique breeding history of the domestic dog offers an unparalleled opportunity to map genes important in disease susceptibility, morphology, and behavior. The breed structures where certain genetic risk factors have been enriched within specific populations and where recent bottlenecks have generated long haplotypes makes the dog excellent for trait mapping. A substantially smaller number of individuals and genetic markers are needed to map traits compared to trait mapping in humans. The dog is also a unique animal to use for comparative analysis since; dogs spontaneously get diseases with the same aetiology as humans, they share largely the same environment and have roughly the same gene content. The research group has during the last years been able to map genes for both monogenic and complex traits such as white coat colour, Amyotrophic Lateral Sclerosis, Osteoimperfecta, Obsessive Compulsive Disorder and Cardiomyopathy. The identified mutations show a spectrum of variation types from point mutations and deletions within coding regions to regulatory insertions and duplications. We are currently performing genetic mapping in many key areas: cancer, inflammatory disease, cardiovascular disease and neuropsychiatric disease. A few examples include breast cancer, thyroiditis and Systemic Lupus Erythematous (SLE) like syndrome, where we have identified strong candidate loci and are in the process of performing targetted resequencing using an in-house adapted sequence capture method followed by Illumina sequencing at the genomics platform at SciLifeLab. Interestingly for each complex trait a majority of candidate genes fall within specific pathway(s). For example four of the candidate genes for the SLE like syndrome are all involved in T-cell activation through the NF-AT pathway. For more information on the ongoing projects please visit http://hunddna.slu.se.

The comparative genomics work is part of an ongoing collaboration with the Broad institute find functional elements in the human genome and that of model organisms. This includes analysis of 29 mammalian genomes to identify common constraint elements, of which two-thirds fall outside coding genes, and contain other functional signatures such as non-coding RNAs and associated RNA structures, potential enhancers and insulators. In addition, RNA-Seq analysis of many mammals and vertebrates is underway to get a more complete picture of the coding and non-coding transcriptome in these organisms. For both transcribed and regulatory elements we study the evolutionary changes seen among species, and of particular interest is when these changes can be couple to adaptation.

Kerstin Lindblad-Toh is a professor in comparative genomics, the Scientific Director of Vertebrate Genome Biology at the Broad Institute and the Director of SciLifeLab.