An interview with Kerstin Lindblad-Toh, comparative genomicist…
An important means by which we try to understand the human genome is, oddly enough, by looking at the genomes of other mammals. The aim is to identify areas of evolutionary constraint, regions of the genome that we all share (both coding and non-coding) and are thus likely to be important for all of these species. These regions have not only assisted with the identification and assignment of genes on the human genome, but they also provide important information about disease associated mutation. One mammal genome, unique amongst the others, offers particular insight into our genes and inherited genetic disease, the domestic dog.
The dog genome, published in 2005, was the fourth mammalian genome to be completed (after man, mouse and rat); the dog occupies a curious position in nature as it has shared a mutually beneficial relationship with humans for at least 15,000 years, living in the same environments as us and sharing our food. Over this time humans have selectively bred dogs for companionship, hunting, shepherding and other uses, and in so doing have channeled the diverse canine genome into a variety of behaviours, shapes and sizes.
This selective breeding has resulted in dogs having a ‘simplified’ genetic architecture, but has inevitably made them a storehouse of some 400 inherited diseases, many of which are shared by humans.
I contacted Nobel Week Dialogue participantProfessor Kerstin Lindblad-Toh, whose contributions towards mammalian genome projects span the mouse, dog, horse and short-tailed opossum. I spoke to her about her ongoing work based on the dog genome, to find out more about the contribution of ‘man’s best friend’ to science and society, and the other work with which she’s involved.
Q. The domestic dog genome work seems to have benefitted from of the particular importance of dogs in society, and given that they are prone to a number of shared diseases it seems appropriate that this relationship can also benefit human health. I appreciate that all this work is the product of collaborations, but I’m curious about how the dog genome studies actually got started? Was there a particular demand from groups/societies focussed on dogs?
Kerstin: The early dog research was advocated by Jasper Rine [UC Berkeley] and Don Patterson [Rtd. University of Pennsylvania] and funding by organizations such as the American Kennel Club/Canine Health Foundation. In 2002, I was contacted by a group of researchers, led by Elaine Ostrander, interested in dog genetics and wanted the genome sequenced. We (I) then developed a plan to sequence the genome where we also surveyed the variation in the genome. This work was funded by NIH for its comparative value and was performed under my leadership at the Broad Institute.
Q. How do we actually translate disease information from these studies? Are there key findings from your comparative genomics work that are being successfully translated into human patient studies?
Kerstin: Examining the human genome and understanding the function of every gene and how they are turned on and off correctly is challenging. We try to address this in two different ways: First we compare the genomes of many mammals to find elements that are similar across all species. These must be important/functional as nature has conserved them. Secondly, we know that finding disease genes is easier in dogs than humans. Therefore we find novel disease genes in dogs and then we examine the same genes in human patients. We have very exciting results where genes found in lupus, autoimmune inflammatory diseases and lymphoma respectively is teaching us about the corresponding human diseases.
In addition we find genes that define specific pathways involved in obsessive compulsive disorder.
Q. So clearly the sequencing of the canine genome will have a significant role to play in understanding the basis of shared diseases between dogs and human, but I also see that a number of your papers reflect on an area of more fundamental pursuit, that of the evolutionary history of dogs. Is an area of academic writing that has a particular interest?
Kerstin: [these areas] can reveal exciting information about canine evolution, and perhaps its connection to human evolution, we have sequenced the genomes of many dogs and wolves and compared them. We find signatures of selection that show which types of genes have been important for dogs to adapt to living with humans.
Q. It’s tempting to speculate, nurture not withstanding, whether by selectively breeding an animal to have familiar human-interactive traits, such as a dog’s ability to recognize social stimuli, we can look at those regions that are changed compared with ancestral lineages (such as the wolf), and perhaps derive from this a tantalising glimpse of those parts of our genome that reflect those same traits in us?
Kerstin: I believe that there will we regions of the genome associated with behavior and the ability to read human social signals. In addition to comparing dogs and wolves to detect genomic regions of importance. We are also comparing working dogs that have been carefully tested for behavioral traits. We hope to find genes underlying positive behaviors such as curiosity and sociability but also for more pathological conditions such obsessive compulsive disorder. I believe that many of the genes and mechanisms underlying behavior will be shared between man and his best friend.
Q. An area of genomics that is increasingly being featured in science reporting is that of the roles of epigenetic DNA modification and 3D chromosomal architecture in regulation and function of genomes. To what extent are you also comparing animal and human ‘epigenomes’, is this a feature of current studies?
Kerstin: Epigenetic signal of course have great importance for genome regulation. While others in the field have started on these studies, we have not done so ourselves yet. While epigentics should also be studied, I believe it is the inherited mutations and the breed structure that makes dogs unique.
Q. At the Broad Institute you are responsible for the Mammalian Genome Project, which includes the 29 mammal project. How has the project chosen the 29 mammals? Why these particular mammals?
Kerstin: The 29 mammals project brings important information about the genes and regulatory elements in the human genome. The first few mammals (including mouse and dog) were chosen for their biomedical relevance. The next 24 mammals were chosen primarily to provide a broad sampling of mammals to bring as much evolutionary divergence, contributing power to the project. When two mammals contribute equal power a species with biomedical relevance would of course be chosen.
Q. The early genome sequencing projects heralded an age of ‘big data’, and in the past our ability to analyse such volumes of data has struggled to keep pace. Are the tools you now have available for looking at big data finally starting to keeping pace? Or has the process by which research is undertaken in these fields had to change?
Kerstin: The amount and complexity of data generated is amazing and is continuously growing. At SciLifeLab we have the competence and resources to design, generate and analyze innovative experiments. We strive to make use of unique human or canine patient materials and to ask questions of relevance to translational medicine. Due to the continuously changing arena both in technology and analytical methods we need to be both nimble and innovative.
Q. In terms of careers, I’m curious about your route to where you are now? Early career scientists are often interested to hear how established scientists have arrived where they are.
Kerstin: After a basic education in molecular biology at Stockholm university I received my PhD in human genetics at the Karolinska Institute. My postdoc time was spent with Tom Hudson at WI/MIT, where I had perfect combination of freedom and a supportive advisor when needed. I performed multiple genomics projects involving both disease mapping and technology development. One day I ventured into Eric [Lander]’s office with an idea, and apparently my timing was right, because he asked me to lead the mouse genome project. This project emphasized the value of interdisciplinary collaborative projects and made me realize the need for a better understanding of the human genome and the value of comparative genomics, making me determined to realize these goals.
Q. You currently have appointments both at the Broad Institute at MIT, Uppsala Universitet and SciLifeLab. Senior appointments in any one place would take a huge amount of time and effort, not least to keep on top of research projects, and writing papers/grants. How do you manage?
Kerstin: This is challenging, but with good colleagues, hard work and efficient planning it is possible. I spend roughly half a year in each place, with some travel back and forth. Either way I spend a lot of time on the phone.
Q. Finally, the nwd12 conference will bring together many faces familiar to you, as well as potentially new ones. Are there any particular messages – for your own part – that you’re aiming to communicate, and are there any discussions you’re particularly looking forward to?
Kerstin: I’m really hoping to convey the message of how important the non-coding regions of the human genome are. The regulatory portions of the genome facilitate evolution and adaptation to novel environments as well as underlie the vast majority of our common diseases.