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Downloaded SRA Files from Which Are Associated with Pigmentation (Table 1) Samaniego Castruita et al. BMC Genomics (2020) 21:543 https://doi.org/10.1186/s12864-020-06940-0 RESEARCH ARTICLE Open Access Analyses of key genes involved in Arctic adaptation in polar bears suggest selection on both standing variation and de novo mutations played an important role Jose Alfredo Samaniego Castruita†, Michael V. Westbury*† and Eline D. Lorenzen* Abstract Background: Polar bears are uniquely adapted to an Arctic existence. Since their relatively recent divergence from their closest living relative, brown bears, less than 500,000 years ago, the species has evolved an array of novel traits suited to its Arctic lifestyle. Previous studies sought to uncover the genomic underpinnings of these unique characteristics, and disclosed the genes showing the strongest signal of positive selection in the polar bear lineage. Here, we survey a comprehensive dataset of 109 polar bear and 33 brown bear genomes to investigate the genomic variants within these top genes present in each species. Specifically, we investigate whether fixed homozygous variants in polar bears derived from selection on standing variation in the ancestral gene pool or on de novo mutation in the polar bear lineage. Results: We find that a large number of sites fixed in polar bears are biallelic in brown bears, suggesting selection on standing variation. Moreover, we uncover sites in which polar bears are fixed for a derived allele while brown bears are fixed for the ancestral allele, which we suggest may be a signal of de novo mutation in the polar bear lineage. Conclusions: Our findings suggest that, among other mechanisms, natural selection acting on changes in genes derived from a combination of variation already in the ancestral gene pool, and from de novo missense mutations in the polar bear lineage, may have enabled the rapid adaptation of polar bears to their new Arctic environment. Keywords: Polar bear, Adaptation, Arctic, Genomics, Selection Background ecology, behaviour, and morphology. This rapid evolu- The divergence of polar bears (Ursus maritimus) from tion was proven even more substantial by stable isotope brown bears (Ursus arctos) and their adaptation to a analysis of an ancient polar bear jawbone from Svalbard, novel environment and lifestyle in the Arctic is a well- indicating that the species had already adapted to a mar- known example of rapid evolution [1, 2]. Despite having ine diet and life in the High Arctic by at least 110 kya diverged relatively recently (ca. 479–343 thousand years [3]. Therefore, in perhaps as little as 20,000 generations, ago (kya)) [1], polar bears evolved a novel and distinct polar bears evolved a suite of unique adaptations that enable them to maintain homeostasis under low temper- atures, occupy a hypercarnivorous niche, subsist on a * Correspondence: [email protected]; [email protected] † diet of primarily seals and their blubber [4], process Jose Alfredo Samaniego Castruita and Michael V. Westbury contributed equally to this work. lipids as their predominant energy source [5, 6], and GLOBE Institute, University of Copenhagen, Copenhagen, Denmark © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Samaniego Castruita et al. BMC Genomics (2020) 21:543 Page 2 of 8 camouflage into their surroundings with pigment-free is no introgressive admixture/ILS at these loci (Sup- fur [7]. plementary Figs. 1–5and7–12). However, for The rapid adaptation of such an iconic species has EDH3, seven of the brown bears cluster within the sparked a number of studies seeking to unravel the gen- diversity of polar bears, indicating some level of omic underpinnings through the use of various datasets introgression or ILS around this gene (Supplemen- and analyses [1, 2, 8]. Both Miller et al. [2] and Liu et al. tary Fig. 6). The seven brown bears were all from [1], investigated whole-genome datasets to uncover gen- the Admiralty, Baranof, and Chichagof islands in Al- omic regions showing signatures of selection. Together, aska, an area known to be inhabited by introgressed these studies revealed different yet complementary sets brown bears [9]. We therefore excluded EDH3 from of genes, pathways, and phenotypes that were likely further analysis. shaped by natural selection during polar bear evolution. Genes showing the strongest signal of positive selection Non-synonymous differences between polar bears and are involved in adipose tissue development, fatty acid brown bears metabolism, heart function, and fur pigmentation [1], in- For this analysis, we only considered dinucleotide sites dicating these are key processes in polar bear adaptation coding for non-synonymous amino acid changes. Firstly, to the Arctic. we calculated the percentages of sites fixed within polar Using all currently available nuclear genomes from bears (Table 1), which ranged between 10 of 8424 cod- polar bears (n = 109) and brown bears (n = 33), we set ing sites (0.12%) in FCGBP to 18 of 3957 coding sites out to determine the nature of the polar bear-specific (0.45%) in LAMC3. We compared this to the number of amino acid changes in the top genes showing the stron- sites also fixed in brown bears for an alternative allele. gest signal of positive selection in the polar bear lineage Seven out of the eleven genes contained sites showing as reported by Liu et al., (Table 1 and supplementary this pattern (Table 1). More specific information regard- Table S1)[1]. This increase in sample number and ing gene positions, amino acid changes, and allele counts spatial coverage enabled us to more comprehensively in- can be found in supplementary Table S2. vestigate the origins of polar bear-specific substitutions. By comparing the target gene regions across the two Fixed derived missense mutations in polar bear species based on this comprehensive dataset, we (i) de- To understand the origins of the variants fixed in the termine the number and location of missense substitu- polar bear lineage relative to brown bears (i.e. whether tions specific to the polar bear lineage (ii) address they are derived or ancestral), we compared the polar whether the polar bear variants derive from standing bear and brown bear alleles to the giant panda (Ailuro- variation or de novo mutations, (iii) evaluate whether poda melanoleuca) reference sequence, assuming the an- the variants fixed in polar bears may lead to functional cestral variant is retained in the panda. This was to changes in the genes. reduce any noise caused by changes occurring in the brown bear lineage after its divergence from polar bears. Results Therefore, we only included sites where polar bears ac- Population structure and admixture quired a derived allele, while brown bears retained the To gain a better understanding of whether selection ancestral state. Seven of the eleven genes of interest had acted upon standing variation in the polar/brown bear at least one site showing this pattern (Table 1, Fig. 1). ancestral lineage or on de novo mutations in the polar The number of such sites varied from zero (CUL7, bear lineage, we first needed to determine whether de- FCGBP, LAMC3, and XIRP1) to twelve (TTN). More rived variants were already present in the ancestral gene specific information regarding the gene positions and al- pool. However, as admixture from polar bears into lele counts can be found in supplementary Table S3. brown bears has been well documented [1, 2, 9–11], we first investigated admixture at our selected genes. If any Influence on protein structure introgression from polar bears persists in the brown bear To evaluate whether the fixed derived amino acid gene pool, inferences of the origins of these variants changes in polar bears (also fixed for the ancestral allele (standing variation or de novo) may be biased. To do in brown bears) had any functional influence on the pro- this, we ran independent PCAs on each of the twelve tein function, we implemented three independent ana- genes analysed including the 50 kb flanking regions up lyses to predict the functional effects of the amino acid and downstream of the genes. change in humans. Amino acid changes that appeared to Clear genetic differentiation between polar bears and have a functional influence according to at least one of brown bears has been shown at a genome-wide scale [1, the three tests were found in four genes, with varying 2]. For eleven of the twelve genes, polar bears and brown numbers of sites displaying this in each gene, TTN (9 bears form separate clusters, which we expect if there sites), LYST (3 sites),
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