College of Veterinary Medicine - Cornell University

Research

 

The Sutter Genetics Laboratory

We are a small research laboratory (PI, post-doc and undergraduates) interested in the genetics of domestic mammals. We’re primarily focused on the dog and horse but are also interested in the evolution of size variation in the domestic rabbit, a species that arose via a much more recent domestication event than did dogs or horses.

If you are an owner or breeder of purebred dogs, horses or rabbits and think you may be willing to contribute DNA samples from some of your animals, we would love to talk with you:

Feel free to download our donation forms for dogs, horses, or rabbits so you can see what we ask for. If you have donated samples in the past we thank you very much! You make our work possible.

 

Evolution in the context of domestication

The central question we are addressing in all of our research is, “How do domestic mammals evolve?” Domestication is a rare ‘special case’ that is true for just ~1% of the world’s 4000 mammalian species. The evolutionarily recent creation of these species by drastic human intervention represents one of the largest-scale genetic enterprises in human history, perhaps second in significance only to our domestication of many plant species. We have two broad goals in our research. First, we aim to better elucidate the molecular evolution of domestication by characterizing, at genome-scale, a highly polymorphic short interspersed element (SINE) retrotransposon ‘pest’ that infests the dog genome. Second, we aim to understand the genetic architecture of complex traits in the context of domestication. To this end we have quantified size variation in three domestic mammals (dogs, horses and rabbits), mapped size genes in dogs, mapped quantitative trait loci in horses, and recently completed whole genome sequencing of two horses.

We have been greatly aided in these research goals by interactions with outstanding collaborators such as Dr. Samantha Brooks, with whom we collaborate on the horse genetics projects.

 

Aim 1 – Describe the genomic consequences of polymorphic SINE retrotransposons in the dog genome

Post-doctoral fellow Sara Kalla is studying polymorphic short interspersed elements (SINEs) in the dog genome. Genomes are full of SINEs, which can ‘copy and paste’ to new sites in the genome via retrotransposition. In the human genome most of this activity happened so long ago that all of us carry identical copies of the pasted SINEs. The dog genome, however, is very different. In 2005 Wang and Kirkness identified a set of just over 10,000 SINE retrotransposons in the dog genome that are polymorphic for insertion. That is, some dog chromosomes carry the SINE insertion at the locus, but other chromosomes do not. These SINEs therefore increase sequence diversity in a population, and Wang and Kirkness hypothesized that some of these elements are likely to disrupt the splicing and expression patterns for genes. Furthermore, there are now a number of clear examples in the dog genetics literature in which polymorphic SINEs disrupt genes and thereby cause disease or another trait (e.g. Doberman Pinscher narcolepsy, Lin et al 1999; Labrador Retriever centronuclear myopathy, Pele et al 2005; herding breeds merle coat, Clark et al 2006; Norwegian Elkhound early retinal degeneration, Goldstein et al 2010).

Sara is extending the work of Wang and Kirkness by discovering many thousands of new polymorphic SINEs in the dog genome. Our group has developed a custom wet-lab method for creating libraries of DNA molecules that are greatly enriched for sequences flanking SINEs. These libraries are sequenced on Illumina Hi-Seq sequencers and the sequences flanking each SINE are aligned to the dog reference genome in order to identify each SINE’s locus (position in the genome).

Undergraduate researcher Julian Homburger has identified phylogenetic relationships among dog breeds using patterns of insertion among a subset of our polymorphic SINEs. Although phylogenies based on microsatellites and dense SNPs scans have previously been inferred for dog breeds, this is the first time polymorphic SINEs have been used.

 

 

Aim 2 – Understand the genetics of domestic mammal size variation

Unlike naturally reproducing mammals, many domestic mammal species have sub-populations (“breeds”) in which extreme forms of size differentiation exist. In fact, differentiation for body size is nearly a hallmark of domestication in mammals. For example, the purebred Yorkshire Terrier, Chihuahua and Maltese breeds are all tiny dogs while Irish Wolfhounds and Great Danes are enormous. What are the genetic changes that make this difference possible within a single species? Did the functional genetic variation that enabled this differentiation arise within the dog species itself or were functional variants from the common ancestor with the gray wolf used instead?

Which particular genes control size in domestic mammals? Are the same genes playing this role in each species? Many genes controlling size variation in man have now been identified; are these genes also responsible for size variation in domestic mammals?

 

Morphometric patterns are conserved among dogs, horses and rabbits

To study the genetic basis of body size, we recognized that we first needed to describe and quantify the trait. Starting with dogs, and moving later to horses and then rabbits, we developed a simple protocol for measuring a set of distances between bony landmarks all over each animal’s body. Others have previously measured dogs, horses or rabbits of one or a few breeds. For example, Chase and Lark have quantified size and shape within Portuguese Water Dogs using principal component analysis of radiograph-based measurements. However, our work provides for the first time a set of quantitative morphometric phenotypes for a broad panel of breeds in three separate species—the dog, horse and rabbit (see publications for the dog and horse morphometrics). This offers a more comprehensive look at morphologic variation under domestication and enables comparison between species as well. Furthermore, we have put these phenotypes to use by mapping size quantitative trait loci (QTL) in the horse (see below).


                                        Animals stand for body measurement data collection.

Horse size variation is mostly controlled by just a few loci

In collaboration with Dr. Samantha Brooks and Dr. Jason Mezey (both at Cornell University) and Dr. Rebecca Bellone (The University of Tampa), we used our size-phenotyped horses to conduct a pair of genome-wide association scans (GWAS). In the first scan we focused on a single breed, and selected a set of 24 small and 24 large Thoroughbreds from among the 219 we measured. For the second scan we used a multi-breed design and selected three horses from each of eight small breeds and eight large breeds. Each of these 96 horses was genotyped with the Illumina 56,000 SNP array. We recently reported this work in PLoS ONE.

Undergraduate researcher Lindsay Theodore is presently fine-mapping at these loci to identify the causal variant(s) at each that contribute to size variation.

                                       An example of horse size differentiation between breeds.

 

The IGF1R gene helps control size in small dogs

In collaboration with Dr. Barbara Hoopes (Colgate University) and Dr. Elaine Ostrander (NIH/NHGRI) we identified a putative causal mutation for tiny size in dogs in the insulin-like growth factor-1 receptor gene. This study compared genotypes in hundreds of purebred dogs from dozens of breeds, a study design that has proven effective for a wide array of selected traits in the dog and other domestic species.

 

The genetics of rabbit body size variation

To further generalize our morphometric findings, we next turned to measurement of the domestic rabbit. This project has been led by two research undergraduates (at present by Molly Fisher) who have extensive rabbit breeding experience. We have solicited measurements of 439 rabbits from 47 breeds to address the extent to which morphometric patterns are conserved among domestic mammals. We find that size variation between rabbit breeds can be quantified from body measurements, just as we found for dogs and horses, and further, that principal components analysis identifies and quantifies size and thickness as the primary axes of rabbit variation. This is the first characterization of rabbit morphology across a broad set of breeds.

In collaboration with Dr. Monte Thies (Sam Houston State University) and his graduate student Katy Estill (now at the University of Arkansas), we are investigating heritable differences in hair shaft  morphology.  We are leveraging our extensive collection of hairs from purebred rabbits for this project.

             This is an example of the Satin rabbit breed, one of the larger commercial breeds.