The Impact of Identity by Descent on Fitness and Disease in Dogs
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The impact of identity by descent on fitness and disease in dogs Jazlyn A. Mooneya,b, Abigail Yohannesc, and Kirk E. Lohmuellera,d,1 aDepartment of Human Genetics, University of California, Los Angeles, CA 90095; bDepartment of Biology, Stanford University, Stanford, CA 94305; cDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; and dDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095 Edited by Elaine A. Ostrander, National Human Genome Research Institute, Bethesda, MD, and approved March 11, 2021 (received for review September 17, 2020) Domestic dogs have experienced population bottlenecks, recent unclear. For example, several studies have associated an increase inbreeding, and strong artificial selection. These processes have in ROH with complex traits in humans (18–23), though some simplified the genetic architecture of complex traits, allowed dele- associations remain controversial (24–28). Determining how ROH terious variation to persist, and increased both identity-by-descent and IBD influence complex traits and fitness could provide a (IBD) segments and runs of homozygosity (ROH). As such, dogs pro- mechanism for differences in complex-trait architecture across vide an excellent model for examining how these evolutionary pro- populations that vary in their burden of IBD and ROH. cesses influence disease. We assembled a dataset containing 4,414 Here, we use IBD segments and ROH from 4,741 breed dogs breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 and village dogs, and 380 wolves to determine the recent de- markers and data for clinical and morphological phenotypes. Breed mographic history of dogs and wolves and establish a connection dogs have an enrichment of IBD and ROH, relative to both vil- between recent inbreeding and deleterious variation associated lage dogs and wolves, and we use these patterns to show that with both disease and inbreeding depression. This comprehen- breed dogs have experienced differing severities of bottlenecks in sive dataset contains genotype data from 172 breeds of dog, village their recent past. We then found that ROH burden is associated with dogs from 30 countries, and gray wolves from British Colombia, phenotypes in breed dogs, such as lymphoma. We next test the North America, and Europe. We test for an association with the prediction that breeds with greater ROH have more disease alleles burden of ROH and case-control status for a variety of complex reported in the Online Mendelian Inheritance in Animals (OMIA). traits. Remarkably, we also find that the number of disease- EVOLUTION Surprisingly, the number of causal variants identified correlates associated causal variants identified in a breed is positively cor- with the popularity of that breed rather than the ROH or IBD bur- related with breed popularity rather than burden of IBD or ROH den, suggesting an ascertainment bias in OMIA. Lastly, we use the in the genome, suggesting ascertainment biases also exist in da- distribution of ROH across the genome to identify genes with de- tabases of dog disease mutations and that many breeds of dog are pletions of ROH as potential hotspots for inbreeding depression and understudied. Lastly, we identify multiple loci that may be asso- find multiple exons where ROH are never observed. Our results ciated with inbreeding depression by examining localized deple- suggest that inbreeding has played a large role in shaping genetic tions of ROH across dog genomes. and phenotypic variation in dogs and that future work on under- studied breeds may reveal new disease-causing variation. Results and Discussion Global Patterns of Genetic Diversity across Dogs and Wolves. Dog inbreeding depression | fitness | deleterious mutations | complex traits breeds were initially formed through domestication of one or he unique demographic and selective history of dogs has Significance Tenabled the persistence of deleterious variation, simplified genetic architecture of complex traits, and caused an increase in Dogs and humans have coexisted together for thousands of both runs of homozygosity (ROH) and identity-by-descent (IBD) years, but it was not until the Victorian Era that humans segments within breeds (1–6). Specifically, the average FROH was practiced selective breeding to produce the modern standards ∼0.3 in dogs (7), compared to 0.005 in humans, computed from we see today. Strong artificial selection during the breed for- the 1000 Genomes populations (8). The large amount of the mation period has simplified the genetic architecture of com- genome in ROH in dogs, combined with a wealth of genetic plex traits and caused an enrichment of identity-by-descent variation and phenotypic data (2, 5, 7, 9–11), allow us to test how (IBD) segments in the dog genome. This study demonstrates ROH and IBD influence complex traits and fitness (Fig. 1). the value of IBD segments and utilizes them to infer the recent Furthermore, many of the deleterious alleles within dogs likely demography of canids, predict case-control status for complex arose relatively recently within a breed, and dogs tend to share traits, locate regions of the genome potentially linked to in- similar disease pathways and genes with humans (4, 12, 13), in- breeding depression, and to identify understudied breeds creasing their relevance for complex traits in humans. where there is potential to discover new disease-associated Despite IBD segments and ROH being ubiquitous in ge- variants. nomes, the extent to which they affect the architecture of com- Author contributions: J.A.M. and K.E.L. designed research; J.A.M. and A.Y. performed plex traits as well as reproductive fitness has remained elusive. research; J.A.M. and K.E.L. contributed new reagents/analytic tools; J.A.M. and A.Y. ana- Given that ROH are formed by inheritance of the same ancestral lyzed data; and J.A.M. and K.E.L. wrote the paper. chromosome from both parents, there is a much higher proba- The authors declare no competing interest. bility of the individual to become homozygous for a deleterious This article is a PNAS Direct Submission. recessive variant (8, 14), leading to a reduction in fitness. This This open access article is distributed under Creative Commons Attribution-NonCommercial- prediction was verified in recent work in nonhuman mammals NoDerivatives License 4.0 (CC BY-NC-ND). that has shown that populations suffering from inbreeding de- 1To whom correspondence may be addressed. Email: [email protected]. pression tend to have an increase in ROH (15, 16). ROH in hu- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ man populations are enriched for deleterious variants (8, 14, 17). doi:10.1073/pnas.2019116118/-/DCSupplemental. However, the extent to which ROH impact phenotypes remains Published April 14, 2021. PNAS 2021 Vol. 118 No. 16 e2019116118 https://doi.org/10.1073/pnas.2019116118 | 1of7 Downloaded by guest on October 2, 2021 Fig. 1. Potential mechanisms for associations between ROH and phenotypes that depend on recessive mutations. If a recessive deleterious mutation is nonlethal (blue), it may lead to ROH correlating with disease, while lethal (red) recessive mutations will cause a depletion of ROH. more ancestral wild populations, in a process involving pop- no trait associations (6 observed associations versus 1.45 associa- ulation bottlenecks. Then, over the last 200 y or so, modern dog tions expected under the null, P = 0.0027, binomial test; Fig. 2). breeds were formed (1, 3, 5, 10, 29–32). To examine genetic We observed a significant association between the burden of diversity in dogs and wolves, we merged three previously pub- ROH and case-control status for five traits: portosystemic vas- lished genotype array-based datasets (9–11). As an initial quality cular anomalies (PSVA) in Yorkshire Terriers (β = −0.394 and check, we used principal component analysis (PCA) to examine P < 0.027), lymphoma within both Labrador (β = −0.604 and P < the relationship between domesticated dogs, village dogs, and 0.0340) and Golden Retrievers (β = 0.913 and P < 0.001), cranial SI Appendix wolves ( , Fig. S1). We observed a split between dogs cruciate ligament disease (CCLD) in Labrador Retrievers and wolves on the first PC. The dogs that fall closest to wolves (β = −0.403 and P < 0.003), elbow dysplasia across all breeds SI Appendix trace their origins back to Australasia ( , Fig. S1), (β = 0.238 and P < 0.047), and mast cell tumors across all breeds which has been previously shown to be the origin of some of the (β = 0.286 and P < 0.027). For lymphoma in Golden Retrievers, more ancient dog breeds (5, 29). When we performed a PCA case status is positively associated with the amount of the ge- with only breed dogs, they clustered by clade (SI Appendix, Fig. nome within an ROH [odds-ratio (OR) = 2.491, SI Appendix, S2). Clades are composed of multiple breeds and were defined in Table S1], and on average cases carried more ROH than controls previous work (7, 30). We also observed separation based on the SI Appendix geographic location of wolf populations. Wolves showed clear ( , Fig. S6). Conversely, ROH appeared to show a clustering by the location of where samples originated from, which includes the United States, Mexico, or Europe (SI Ap- pendix, Fig. S3). Lastly, we inferred the recent demographic PSVA Yorkshire Terrier PSVA Tibetan Spaniel history of 10 standard breeds of dog, village dogs, and gray PSVA Norfolk Terrier wolves from the United States and Europe (SI Appendix, Fig. S4) PSVA Miniature Schnauzer PSVA Maltese using patterns of IBD sharing between individuals (33). This PSVA Havanese PSVA Cairn Terrier analysis shows that all breed dogs experienced a domestication PSVA bottleneck followed by another severe bottleneck ∼200 y ago, MVD Cocker Spaniel MVD corresponding with modern breed formation during the Victo- MCT Vizsla SI Appendix MCT Labrador Retriever rian Era (1800s) ( , Fig.