Convergent evolution of a genomic rearrangement may explain cancer resistance in hystrico- and sciuromorpha rodents

Yachna Jain,Mohan Lal,Jui Bhattacharya,Kuljeet Singh Sandhu,Meenakshi Bagadia,Harpreet Singh,Keerthivasan Raanin Chandradoss,Anjoom A V

doi:10.1038/s41514-021-00072-9

Abstract

The rodents of hystricomorpha and sciuromorpha suborders exhibit remarkably lower incidence of cancer. The underlying genetic basis remains obscure. We report a convergent evolutionary split of human 3p21.31, a locus hosting a large number of tumour-suppressor genes (TSGs) and frequently deleted in several tumour types, in hystrico- and sciuromorphs. Analysis of 34 vertebrate genomes revealed that the synteny of 3p21.31 cluster is functionally and evolutionarily constrained in most placental mammals, but exhibit large genomic interruptions independently in hystricomorphs and sciuromorphs, owing to relaxation of underlying constraints. Hystrico- and sciuromorphs, therefore, escape from pro-tumorigenic co-deletion of several TSGs in cis. The split 3p21.31 sub-clusters gained proximity to proto-oncogene clusters from elsewhere, which might further nullify pro-tumorigenic impact of copy number variations due to co-deletion or co-amplification of genes with opposing effects. The split of 3p21.31 locus coincided with the accelerated rate of its gene expression and the body mass evolution of ancestral hystrico- and sciuromorphs. The genes near breakpoints were associated with the traits specific to hystrico- and sciuromorphs, implying adaptive significance. We conclude that the convergently evolved chromosomal interruptions of evolutionarily constrained 3p21.31 cluster might have impacted evolution of cancer resistance, body mass variation and ecological adaptations in hystrico- and sciuromorphs.

Highlights

Unlike myomorphs, hystricomorphs and sciuromorphsexhibit extraordinary diversity in body mass, longevity and ecological habitat[1,2,3,4,5,6,7,8,9,10,11,12]
Genomic rearrangements and cancer resistance in naked-mole rat We first identified the instances of genomic rearrangements
Since genome assemblies of naked-mole rat (NMR) are available as collections of large scaffolds and not as deletion or co-amplification of co-positioned tumoursuppressor genes (TSGs) and POG clusters, as proposed elsewhere[45]

Summary

Introduction

Unlike myomorphs (mouse, rat, etc.), hystricomorphs (naked-mole rat, capybara, etc.) and sciuromorphs (squirrels, marmots, etc.)exhibit extraordinary diversity in body mass, longevity and ecological habitat[1,2,3,4,5,6,7,8,9,10,11,12]. It has been proposed that the large body mass and long lifespan are the evolutionary forces that innovate cancer resistance in mammals[13,16,17]. To minimise the risk of cancer, many rodents with large body mass have evolved with repressed telomerase activity to allow replicative senescence that suppresses cancer[13,16]. Tian et al.[14] has shown that NMRs contain high-molecular-mass Hyaluronan (HMM-HA), a component of the extracellular matrix, unlike other mammals which have low-molecular-mass HA (LMM-HA). This was presumably an evolutionary selection for highly elastic skin adapted to the underground habitat. The Kurloff cells in guinea pig are shown to have anti-leukemic activities[28]

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Results

Conclusion