Kerstin Lindblad-Toh research group

Comparative Genetics and Genomics

The overall research focus is to generate tools and apply them to identification of genes and mutations of relevance for canine and human disease. Two strategies are utilized together to accomplish this; all the functional elements in the human and mammalian genomes need to be identified and domestic animals allow us to find disease mutations, genes and pathways and then translate these to human medicine.

The comparative genomics work is part of an ongoing collaboration with my group and other colleagues at the Broad Institute to find functional elements in the human genome and that of model organisms. This includes a previous 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. This project has now been expanded to 200 mammals, which should allow the detection of the evolutionary history of every base in the mammalian genome. 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/selection.

The unique breeding history of the domestic dog offers an unparalleled opportunity to map genes important in disease susceptibility, morphology, and behaviour. 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. 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 been able to map genes for both monogenic and complex traits including white coat colour, Amyotrophic Lateral Sclerosis, Obsessive Compulsive Disorder, several cancers and Systemic Lupus Erythematous (SLE) like syndrome. The identified mutations show a spectrum of variation types from point mutations and deletions within coding regions to regulatory insertions and duplications. For several diseases we have identified strong candidate loci and are in the process of performing targeted resequencing using an in-house adapted sequence capture method followed by next generation sequencing in human patients.

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