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A Chromosome Level Genome of Astyanax Mexicanus Surface Fish for Comparing Population

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A Chromosome Level Genome of Astyanax Mexicanus Surface Fish for Comparing Population bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.189654; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Title 2 A chromosome level genome of Astyanax mexicanus surface fish for comparing population- 3 specific genetic differences contributing to trait evolution. 4 5 Authors 6 Wesley C. Warren1, Tyler E. Boggs2, Richard Borowsky3, Brian M. Carlson4, Estephany 7 Ferrufino5, Joshua B. Gross2, LaDeana Hillier6, Zhilian Hu7, Alex C. Keene8, Alexander Kenzior9, 8 Johanna E. Kowalko5, Chad Tomlinson10, Milinn Kremitzki10, Madeleine E. Lemieux11, Tina 9 Graves-Lindsay10, Suzanne E. McGaugh12, Jeff T. Miller12, Mathilda Mommersteeg7, Rachel L. 10 Moran12, Robert Peuß9, Edward Rice1, Misty R. Riddle13, Itzel Sifuentes-Romero5, Bethany A. 11 Stanhope5,8, Clifford J. Tabin13, Sunishka Thakur5, Yamamoto Yoshiyuki14, Nicolas Rohner9,15 12 13 Authors for correspondence: Wesley C. Warren ([email protected]), Nicolas Rohner 14 ([email protected]) 15 16 Affiliation 17 1Department of Animal Sciences, Department of Surgery, Institute for Data Science and 18 Informatics, University of Missouri, Bond Life Sciences Center, Columbia, MO 19 2 Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 20 3 Department of Biology, New York University, New York, NY 21 4 Department of Biology, The College of Wooster, Wooster, OH 22 5 Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter FL 23 6 Department of Genome Sciences, University of Washington, Seattle, WA 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.189654; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 24 25 7 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United 26 Kingdom 27 8 Department of Biological Sciences, Florida Atlantic University, Jupiter FL 28 9 Stowers Institute for Medical Research, Kansas City, MO 29 10 McDonnell Genome Institute, Washington University, St Louis, MO 30 11 Bioinfo, Plantagenet, ON K0B 1L0, Canada 31 12 Department of Ecology, Evolution, and Behavior, University of Minnesota, Saint Paul, MN 32 13 Genetics Department, Blavatnik Institute, Harvard Medical School, Boston, MA 33 14 Department of Cell and Developmental Biology, University College London, London, United 34 Kingdom 35 15 Department of Molecular & Integrative Physiology, KU Medical Center, Kansas City, KS 36 37 Abstract 38 Identifying the genetic factors that underlie complex traits is central to understanding the 39 mechanistic underpinnings of evolution. In nature, adaptation to severe environmental change, 40 such as encountered following colonization of caves, has dramatically altered genomes of species 41 over varied time spans. Genomic sequencing approaches have identified mutations associated with 42 troglomorphic trait evolution, but the functional impacts of these mutations remain poorly 43 understood. The Mexican Tetra, Astyanax mexicanus, is abundant in the surface waters of 44 northeastern Mexico, and also inhabits at least 30 different caves in the region. Cave-dwelling A. 45 mexicanus morphs are well adapted to subterranean life and many populations appear to have 46 evolved troglomorphic traits independently, while the surface-dwelling populations can be used as 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.189654; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 47 a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish 48 genome, enabling the first genome-wide comparison between surface fish and cavefish 49 populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses 50 for pigmentation and eye size and found new candidate genes for eye loss such as dusp26. We 51 used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye 52 size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion 53 variability that includes an analysis of the impact on protein-coding genes across cavefish 54 populations to gain insight into this potential source of cave adaptation. The new surface fish 55 genome reference now provides a more complete resource for comparative, functional, 56 developmental and genetic studies of drastic trait differences within a species. 57 58 Main Text 59 Establishing the relationship between natural environmental factors and the genetic basis of trait 60 evolution has been challenging. The ecological shift from surface to cave environments provides 61 a tractable system to address this, as in this instance the polarity of evolutionary change is known. 62 Across the globe, subterranean animals, including fish, salamanders, rodents, and myriads of 63 invertebrate species have converged on reductions in metabolic rate, eye size, and pigmentation1- 64 3. The robust phenotypic differences from surface relatives provide the opportunity to investigate 65 the mechanistic underpinnings of evolution and to determine whether genotype-phenotype 66 interactions are deeply conserved. 67 The Mexican cavefish, Astyanax mexicanus, has emerged as a powerful model to 68 investigate complex trait evolution4. A. mexicanus comprises at least 30 cave-dwelling populations 69 in the Sierra de El Abra, Sierra de Colmena and Sierra de Guatemala regions of northeastern 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.189654; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 70 Mexico, and surface-dwelling fish of the same species inhabit rivers and lakes throughout Mexico 71 and southern Texas5. The ecology of surface and cave environments differ dramatically, allowing 72 for functional and genomic comparisons between populations that have evolved in distinct 73 environments. Dozens of evolved trait differences have been identified in cavefish including 74 changes in morphology, physiology, and behavior4,6 . It is also worth noting that comparing 75 cavefish to surface fish reveals substantial differences in many traits of possible relevance to 76 human disease, including sleep duration, circadian rhythmicity, anxiety, aggression, heart 77 regeneration, eye and retina development, craniofacial structure, insulin resistance, appetite, and 78 obesity7-17. Further, generation of fertile surface-cave hybrids in a laboratory setting has allowed 79 for genetic mapping in these fish10,18-25. Clear phenotypic differences, combined with availability 80 of genetic tools, positions A. mexicanus as a natural model system for identifying the genetic basis 81 of ecologically and evolutionary relevant phenotypes17,26,27. 82 Recently, the genome of an individual from the Pachón cave population was sequenced28. 83 While this work uncovered genomic intervals and candidate genes linked to cave traits, an 84 important computational limitation was sequence fragmentation due to the use of short-read 85 sequencing. In addition, lack of a surface fish genome prevents direct comparisons between surface 86 and cavefish populations at the genomic level. Here, we address these two obstacles by presenting 87 the first de novo genome assembly of the surface fish morph using long-read sequencing 88 technology. This approach yielded a much more comprehensive genome that allows for direct 89 genome-wide comparisons between surface fish and Pachón cavefish. As a proof-of-principle, we 90 first confirmed known genetic mutations associated with pigmentation and eye loss, then 91 discovered novel quantitative trait loci (QTL), and identified coding and deletion mutations that 92 highlight putative contributions to cave trait biology. 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.189654; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 93 94 Results 95 De novo assembly and curation of the surface fish genome. We set out to generate a robust 96 reference genome for the surface morph of A. mexicanus from a single lab-reared female, 97 descended from wild caught individuals from known Mexico localities (Fig. 1a, Supplementary 98 Figure 1). We sequenced and assembled the genome using Pacific Biosciences single molecule 99 real time (SMRT) sequencing (~73x genome coverage) and the wtdbg2 assembler29 to an 100 ungapped size of 1.29 Gb. Initial scaffolding of assembled contigs was accomplished with the aid 101 of an A. mexicanus surface fish physical map (BioNano) followed by manual assignment of 70% 102 of the assembly scaffolds to 25 total chromosomes using the existing A. mexicanus genetic linkage 103 map markers30. The final genome assembly, Astyanax mexicanus 2.0, comprises a total of 2,415 104 scaffolds (including single contig scaffolds) with N50 contig and scaffold lengths of 1.7 Mb and 105 35 Mb, respectively, which is comparable to other similarly sequenced and assembled teleost 106 fishes (Supplementary Table 1). The assembled regions (394 Mb) that we were
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