Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation

Abstract

SUMMARY The North American beaver is an exceptionally long-lived and cancer-resistant rodent species. Here, we report the evolutionary changes in its gene coding sequences, copy numbers, and expression. We identify changes that likely increase its ability to detoxify aldehydes, enhance tumor suppression and DNA repair, and alter lipid metabolism, potentially contributing to its longevity and cancer resistance. Hpgd , a tumor suppressor gene, is uniquely duplicated in beavers among rodents, and several genes associated with tumor suppression and longevity are under positive selection in beavers. Lipid metabolism genes show positive selection signals, changes in copy numbers, or altered gene expression in beavers. Aldh1a1 , encoding an enzyme for aldehydes detoxification, is particularly notable due to its massive expansion in beavers, which enhances their cellular resistance to ethanol and capacity to metabolize diverse aldehyde substrates from lipid oxidation and their woody diet. We hypothesize that the amplification of Aldh1a1 may contribute to the longevity of beavers.

Protocol for gene annotation, prediction, and validation of genomic gene expansion

“…Transcriptome assembly may be available from previous studies or can be assembled de novo from RNA-seq reads by Trinity ( Haas et al., 2013 ). High quality transcriptome assembly can be selected as described in ( Zhang et al., 2021 ).

# Gene structure annotation # (a) Generate MAKER control files # Generate three files with suffix “.ctl”, through which to provide user input maker -CTL # (b) Edit maker_opts.ctl file to provide input parameters genome=<genome_assembly.fa> # choose either eukaryotic or prokaryotic organism_type=<eukaryotic|prokaryotic> # Expressed sequence tags (ESTs) or assembled mRNA est=<transcript_evidence.fa> # Protein sequences from other organisms (e.g., UniProt) protein=<protein.fa> # Gene prediction models snaphmm=<SNAP_trained_model> augustus_species=<augustus_trained_model> # (c) Run MAKER # Run on a single processor by “maker” or on “N” processors by ‘”mpirun -n” maker | mpirun -n N maker # (d) Collect annotation result and merge into a single file cd <maker.ouput> gff3_merge -d <genome_datastore_index.log> -g

Note: Details about gene structure annotation ( Holt and Yandell, 2011 ) can be found at http://gmod.org/wiki/MAKER_Tutorial , https://darencard.net/blog/2017-05-16-maker-genome-annotation/ , and the protocol ( Campbell et al., 2014 ).…”

“… Additional filtering. Gene copies with low protein sequence similarity to other genes within a gene family could be removed ( Keane et al., 2015 ; Zhang et al., 2021 ). The validity of gene prediction can be verified by RNA-seq data generated from either separate or pooled samples of many tissues.…”

“…Finally, we also detail steps to discover functionality of each copy of replicated genes. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021) .…”

Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra

“…Many mechanisms can potentially resolve Peto’s paradox, but they have only been experimentally studied in a few species, such as rodents (Azpurua and Seluanov, 2013; Gorbunova et al, 2012; Liang et al, 2010; Salmon and Akha, 2008; Seluanov et al, 2009; Tian et al, 2019; Zhang et al, 2021), bats (Foley et al, 2018; Kacprzyk et al, 2021; Koh et al, 2019), turtles (Glaberman et al, 2021), elephants (Abegglen et al, 2015; Sulak et al, 2016; Vazquez et al, 2018), and even Drosophila (Garschall et al, 2017; Parkes et al, 1998; Peleg et al, 2016; Shepherd et al, 1989). We and others have shown that elephants, for example, evolved cells that are extremely sensitive to DNA damage (Abegglen et al, 2015; Sulak et al, 2016) at least in part through duplication of tumor suppressor genes (Caulin et al, 2015; Sulak et al, 2016; Tollis et al, 2020; Vazquez et al, 2018; Vazquez and Lynch, 2021); While this burst of tumor suppressor duplication occurred coincident with the evolution of reduced intrinsic cancer risk in Proboscideans (Vazquez and Lynch, 2021), we found that some other mammalian lineages such as the Xenarthra (armadillos, sloths, and anteaters) ( Figure 1A ) may also have evolved reduced intrinsic cancer risk and increased tumor suppressor dosage (Vazquez and Lynch, 2021).…”