Integrating gene annotation with orthology inference at scale
Authors: Kirilenko Bogdan M. , Munegowda Chetan , Osipova Ekaterina , Jebb David , Sharma Virag , Blumer Moritz , Morales Ariadna E. , Ahmed Alexis-Walid , Kontopoulos Dimitrios-Georgios , Hilgers Leon , Lindblad-Toh Kerstin , Karlsson Elinor K. ,   Zoonomia Consortium‡, Hiller Michael , Andrews Gregory , Armstrong Joel C. , Bianchi Matteo , Birren Bruce W. , Bredemeyer Kevin R. , Breit Ana M. , Christmas Matthew J. , Clawson Hiram , Damas Joana , Di Palma Federica , Diekhans Mark , Dong Michael X. , Eizirik Eduardo , Fan Kaili , Fanter Cornelia , Foley Nicole M. , Forsberg-Nilsson Karin , Garcia Carlos J. , Gatesy John , Gazal Steven , Genereux Diane P. , Goodman Linda , Grimshaw Jenna , Halsey Michaela K. , Harris Andrew J. , Hickey Glenn , Hiller Michael , Hindle Allyson G. , Hubley Robert M. , Hughes Graham M. , Johnson Jeremy , Juan David , Kaplow Irene M. , Karlsson Elinor K. , Keough Kathleen C. , Kirilenko Bogdan , Koepfli Klaus-Peter , Korstian Jennifer M. , Kowalczyk Amanda , Kozyrev Sergey V. , Lawler Alyssa J. , Lawless Colleen , Lehmann Thomas , Levesque Danielle L. , Lewin Harris A. , Li Xue , Lind Abigail , Lindblad-Toh Kerstin , Mackay-Smith Ava , Marinescu Voichita D. , Marques-Bonet Tomas , Mason Victor C. , Meadows Jennifer R. S. , Meyer Wynn K. , Moore Jill E. , Moreira Lucas R. , Moreno-Santillan Diana D. , Morrill Kathleen M. , Muntané Gerard , Murphy William J. , Navarro Arcadi , Nweeia Martin , Ortmann Sylvia , Osmanski Austin , Paten Benedict , Paulat Nicole S. , Pfenning Andreas R. , Phan BaDoi N. , Pollard Katherine S. , Pratt Henry E. , Ray David A. , Reilly Steven K. , Rosen Jeb R. , Ruf Irina , Ryan Louise , Ryder Oliver A. , Sabeti Pardis C. , Schäffer Daniel E. , Serres Aitor , Shapiro Beth , Smit Arian F. A. , Springer Mark , Srinivasan Chaitanya , Steiner Cynthia , Storer Jessica M. , Sullivan Kevin A. M. , Sullivan Patrick F. , Sundström Elisabeth , Supple Megan A. , Swofford Ross , Talbot Joy-El , Teeling Emma , Turner-Maier Jason , Valenzuela Alejandro , Wagner Franziska , Wallerman Ola , Wang Chao , Wang Juehan , Weng Zhiping , Wilder Aryn P. , Wirthlin Morgan E. , Xue James R. , Zhang Xiaomeng 
Published: April 2023

Annotating coding genes and inferring orthologs are two classical challenges in genomics and evolutionary biology that have traditionally been approached separately, limiting scalability. We present TOGA (Tool to infer Orthologs from Genome Alignments), a method that integrates structural gene annotation and orthology inference. TOGA implements a different paradigm to infer orthologous loci, improves ortholog detection and annotation of conserved genes compared with state-of-the-art methods, and handles even highly fragmented assemblies. TOGA scales to hundreds of genomes, which we demonstrate by applying it to 488 placental mammal and 501 bird assemblies, creating the largest comparative gene resources so far. Additionally, TOGA detects gene losses, enables selection screens, and automatically provides a superior measure of mammalian genome quality. TOGA is a powerful and scalable method to annotate and compare genes in the genomic era.