A tale of two genes: divergent evolutionary fate of haptoglobin and hemopexin in hemoglobinless antarctic icefishes

Abstract

The evolution of Antarctic notothenioid fishes in the isolated freezing Southern Ocean has led to remarkable trait gains and losses. One of the most extraordinary was the loss of the major oxygen carrier hemoglobin (Hb) in the icefishes (family Channichthyidae). Although the mechanisms of this loss and the resulting compensatory changes have been well studied, the impact of Hb loss on the network of genes that once supported its recycling and disposal has remained unexplored. Here, we report the functional fate and underlying molecular changes of two such key Hb-supporting proteins across the icefish familyhaptoglobin (Hp) and hemopexin (Hx), crucial in removing cytotoxic free Hb and heme, respectively. Hp plays a critical role in binding free Hb for intracellular recycling and absent its primary client, icefish Hp transcription is now vanishingly little, and translation into a functional protein is nearly silenced. Hp genotype degeneration has manifested in separate lineages of the icefish phylogeny with three distinct nonsense mutations and a deletion frame shift, as well as mutated polyadenylation signal sequences. Thus, Hb loss appears to have diminished selective constraint on Hp maintenance, resulting in its stochastic, co-evolutionary drift towards extinction. Hx binds free heme for iron recycling in hepatocytes. In contrast to Hp, Hx genotype integrity is preserved in the icefishes and transcription occurs at levels comparable to those in the red-blooded notothenioids. The persistence of Hx likely owes to continued selective pressure for its function from mitochondrial and non-Hb cellular hemoproteins.

Developmental constraint shaped genome evolution and erythrocyte loss in Antarctic fishes following paleoclimate change

“…Adding to the physiological calculus are mutations of key erythroid genes in the genomes of these fishes. We and others have identified lossof-function alleles in the alpha-and beta-globins [8][9][10], alas2, hemgn, haptoglobin [16] and myoglobin [12] that have risen to fixation in some, if not all, icefish species. These mutations are likely to constrain the adaptive landscape of icefishes and to render impossible the re-evolution of erythroid function as the SO warms.…”

“…Myoglobin expression is also absent from the hearts of 6 out of 16 icefish species, although mutated myoglobin genes remain in their genomes [12][13][14][15]. Furthermore, several genes encoding hemoglobin scavenging proteins, such as haptoglobin, have accumulated deleterious mutations and are expressed at reduced levels by icefishes [16]. Early work by Hureau et al [17] and by Barber et al [18] revealed that icefishes possess small numbers of…”

Quantitative Proteomics and Network Analysis of Differentially Expressed Proteins in Proteomes of Icefish Muscle Mitochondria Compared with Closely Related Red-Blooded Species

“…We also show that hemopexin (Hx) protein is reduced in the WMM of icefish. It was previously shown that Hx transcription occurs at levels comparable to those in the red-blooded notothenioids; however, it seems possible that there is a discrepancy between transcript and protein levels of Hx [ 80 ]. Cytochrome c oxidase (CO) is an important haem-containing protein just like haemoglobin and in our study was also found to be much reduced in icefish RMM.…”

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

“…Compared with hundreds of red blooded notothenioids, these ice fish have very little Hp and its translation into a functional protein has actually been silenced [128]. Overtime, a degeneration of the Hp genotype manifested in a separate lineage.…”