Insights into the evolution of longevity from the bowhead whale genome

Abstract

The bowhead whale (Balaena mysticetus) is estimated to live over 200 years and is possibly the longest-living mammal. These animals should possess protective molecular adaptations relevant to age-related diseases, particularly cancer. Here, we report the sequencing and comparative analysis of the bowhead whale genome and two transcriptomes from different populations. Our analysis identifies genes under positive selection and bowhead-specific mutations in genes linked to cancer and aging. In addition, we identify gene gain and loss involving genes associated with DNA repair, cell-cycle regulation, cancer, and aging. Our results expand our understanding of the evolution of mammalian longevity and suggest possible players involved in adaptive genetic changes conferring cancer resistance. We also found potentially relevant changes in genes related to additional processes, including thermoregulation, sensory perception, dietary adaptations, and immune response. Our data are made available online (http://www.bowhead-whale.org) to facilitate research in this long-lived species.

Graphical abstract

Figure 1

Phylogeny of Mammals Used in Codon-Based Maximum Likelihood Comparison of Selective Pressure Variation The number of candidate genes under positive selection on each lineage is indicated.

Figure 2

Multiple Protein Sequence Alignments of HDAC2 and UCP1 (A) Partial alignment of bowhead HDAC2 with mammalian orthologs. Unique bowhead residues are highlighted at human positions 68, 95, and 133. (B) Partial alignment of whale UCP1 with mammalian orthologs. Conserved regions involved in UCP1 are marked in red.

Figure 3

Gene Family Expansion and PCNA (A) Gene family expansion. Numbers in red correspond to the predicted number of gene expansion events during mammalian evolution. Mean divergence time estimates were used from TimeTree (Hedges et al., 2006) for scaling. (B) Multiple sequence alignment of PCNA residues 28–107, showing bowhead whale-specific duplication (gene IDs: bmy 16007 and bmy 21945). Lineage-specic amino acids in the duplicated PCNA of bowhead whales are highlighted in red. (C) Crystal structure of the PCNA (green) and FEN-1 (yellow) complex. Lineage-specific residues on the PCNA structure are colored in red. A zoom in on the structures reveals a putative interaction between two β sheets, one within PCNA and another within FEN-1. This interaction may be altered through a second interaction between the PCNA β sheet and a lineage-specic change from glutamine to histidine within PCNA. Distance measurements between pairs of atoms are marked in black. PDB accession number: 1UL1. See also Table S3 and Figure S3.