title: Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs.
abstract: Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rd top hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Freedman
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Rena M
authors.initials: RM
authors.lastname: Schweizer
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Diego
authors.initials: D
authors.lastname: Ortega-Del Vecchyo
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Han
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Davis
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Ilan
authors.initials: I
authors.lastname: Gronau
authors.affiliation: CIBIO-UP, University of Porto, Vairão, Portugal.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Silva
authors.affiliation: ISPRA, Ozzano dell'Emilia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Galaverni
authors.affiliation: Key Laboratory of Bioresources and Ecoenvironment, Sichuan University, Chengdu, China.
authors.forename: Zhenxin
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Marx
authors.affiliation: ICREA at Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Lorente-Galdos
authors.affiliation: ICREA at Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Ramirez
authors.affiliation: Department of Computer Science, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Farhad
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Bilkent University, Ankara, Turkey.
authors.forename: Can
authors.initials: C
authors.lastname: Alkan
authors.affiliation: Estación Biológia de Doñana EBD-CSIC, Sevilla, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Vilà
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Squire
authors.affiliation: Department of Zoology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Geffen
authors.affiliation: Department of Biology, University of Zagreb, Zagreb, Croatia.
authors.forename: Josip
authors.initials: J
authors.lastname: Kusak
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Boyko
authors.affiliation: ICREA at Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain.
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Parker
authors.affiliation: Life Technologies, Foster City, California, United States of America.
authors.forename: Clarence
authors.initials: C
authors.lastname: Lee
authors.affiliation: Life Technologies, Foster City, California, United States of America.
authors.forename: Vasisht
authors.initials: V
authors.lastname: Tadigotla
authors.affiliation: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Siepel
authors.affiliation: Stanford School of Medicine, Stanford, California, United States of America.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Life Technologies, Foster City, California, United States of America.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Harkins
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: ICREA at Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain.|Centro Nacional de Analisis Genomico (CNAG/PCB), Baldiri Reixach 4-8, Barcelona, Spain.
authors.forename: Tomas
authors.initials: T
authors.lastname: Marques-Bonet
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Wayne
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Novembre
mesh_terms: D000818:Animals; D003710:Demography; D004285:Dogs; D005828:Genetics, Population; D016678:Genome; D023281:Genomics; D050356:Lipid Metabolism / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic