Return to the Sea, Get Huge, Beat Cancer: An Analysis of Cetacean Genomes Including an Assembly for the Humpback Whale (Megaptera novaeangliae).

Marc Tollis,Carlo C Maley,Tomas Marques-Bonet,Martine Bèrubè,Nader Pourmand,Per J Palsbøll,Lukas F K Kuderna,Aleah F Caulin,Jacinda D Garcia,Jooke Robbins,Mary J O’Connell,Andrew E Webb

doi:10.1093/molbev/msz099

Abstract

Cetaceans are a clade of highly specialized aquatic mammals that include the largest animals that have ever lived. The largest whales can have ∼1,000× more cells than a human, with long lifespans, leaving them theoretically susceptible to cancer. However, large-bodied and long-lived animals do not suffer higher risks of cancer mortality than humans—an observation known as Peto’s Paradox. To investigate the genomic bases of gigantism and other cetacean adaptations, we generated a de novo genome assembly for the humpback whale (Megaptera novaeangliae) and incorporated the genomes of ten cetacean species in a comparative analysis. We found further evidence that rorquals (family Balaenopteridae) radiated during the Miocene or earlier, and inferred that perturbations in abundance and/or the interocean connectivity of North Atlantic humpback whale populations likely occurred throughout the Pleistocene. Our comparative genomic results suggest that the evolution of cetacean gigantism was accompanied by strong selection on pathways that are directly linked to cancer. Large segmental duplications in whale genomes contained genes controlling the apoptotic pathway, and genes inferred to be under accelerated evolution and positive selection in cetaceans were enriched for biological processes such as cell cycle checkpoint, cell signaling, and proliferation. We also inferred positive selection on genes controlling the mammalian appendicular and cranial skeletal elements in the cetacean lineage, which are relevant to extensive anatomical changes during cetacean evolution. Genomic analyses shed light on the molecular mechanisms underlying cetacean traits, including gigantism, and will contribute to the development of future targets for human cancer therapies.

Highlights

The gene models generated from the first iteration were used to improve the SNAP Hidden Markov Models (HMM), which was used in a second MAKER2 iteration
To assess the quality of annotations that used varying degrees of the three types of evidence, we used annotation editing distances (AED), which measure the difference between a gene call and its aligned evidence
Supplementary Methods Demographic analysis We used the Pairwise Sequential Markovian Coalescent (PSMC) (Li and Durbin 2011) to reconstruct the population history of North Atlantic humpback whales, including the individual sequenced in the current study and a second individual sequenced at ~17X coverage in Árnason et al (2018)

Summary

Introduction

To assess the quality of annotations that used varying degrees of the three types of evidence (expression, protein homology, and ab initio gene prediction), we used annotation editing distances (AED), which measure the difference between a gene call and its aligned evidence Genome annotation We generated gene models for the humpback whale using multiple iterations of MAKER2 (Holt and Yandell 2011) which incorporated (1) direct evidence from the Trinity-assembled transcripts, (2) homology to NCBI proteins from 10 mammals (human, mouse, dog, cow, sperm whale, bottlenose dolphin, orca, bowhead whale, common minke whale, and baiji) and UniProtKB/Swiss-Prot (UniProt Consortium 2015) and (3) ab-initio gene predictions using SNAP (11/29/2013 release; Korf 2004) and Augustus v3.0.2 (Stanke et al 2008).

Results

Conclusion