The role of mutation bias in adaptive molecular evolution: insights from convergent changes in protein function

Abstract

18An underexplored question in evolutionary genetics concerns the extent to which mutational bias in the 19 production of genetic variation influences outcomes and pathways of adaptive molecular evolution. In the 20 genomes of at least some vertebrate taxa, an important form of mutation bias involves changes at CpG 21 dinucleotides: If the DNA nucleotide cytosine (C) is immediately 5' to guanine (G) on the same coding 22strand, then -depending on methylation status -point mutations at both sites occur at an elevated rate 23relative to mutations at non-CpG sites. Here we examine experimental data from case studies in which it 24has been possible to identify the causative substitutions that are responsible for adaptive changes in the 25 functional properties of vertebrate hemoglobin (Hb). Specifically, we examine the molecular basis of 26 convergent increases in Hb-O2 affinity in high-altitude birds. Using a data set of experimentally verified, 27affinity-enhancing mutations in the Hbs of highland avian taxa, we tested whether causative changes are 28 enriched for mutations at CpG dinucleotides relative to the frequency of CpG mutations among all 29 possible missense mutations. The tests revealed that a disproportionate number of causative amino acid 30replacements were attributable to CpG mutations, suggesting that mutation bias can influence outcomes 31 of molecular adaptation. 32 33 Keywords 34Adaptation; CpG; hemoglobin; high altitude; mutation bias; protein evolution 35 36 65 provides a means of testing whether such changes are random with respect to different classes of 66 site or different classes of mutational change. In vertebrate genomes, transition:transversion bias 67 results in especially high rates of change from one pyrimidine to another (C↔T) or from one 68 purine to another (G↔A). In the genomes of mammals and birds, the dinucleotide CG -often 69 designated "CpG" -is a hotspot of nucleotide point mutations due to the effect of methylation on 70 damage and repair. In mammals, the mutation rate at CpG sites is elevated 10-fold for transition 71 mutations and several-fold for transversions [21, 22]. A recent mutation-accumulation study in 72 birds confirmed a similar increase in mutation rate at CpG sites [23]. Mammalian and avian 73 genomes both exhibit roughly five-fold depletions of CpG dinucleotides, consistent with elevated 74 rates of mutation at such sites [24]. 75 In studies of hemoglobin (Hb) evolution in high-altitude birds, site-directed mutagenesis 76 experiments have documented three cases in which missense mutations at CpG dinucleotides 77 contributed to derived increases in Hb-O2 affinity: 55Ile→Val (I55V) in the β A -globin gene of 78 Andean house wrens (Troglodytes aedon)[25] and parallel 34Ala→Thr substitutions (A34T) in 79 the α A -globin genes of two different passerine species that are native to the Tibetan Plateau, the 80 ground tit (Parus humilis [= Pseudopodoces humilis]) and the grey crested tit (Lophophanes 81 dichrous)[26]. The patterns documented in these three high-altitud...

Oxygenation properties of hemoglobin and the evolutionary origins of isoform multiplicity in an amphibious air-breathing fish, the blue-spotted mudskipper (Boleophthalmus pectinirostris)

“…In many teleost species, the presence of specific isoHbs with functional specializations such as the Root effect (an extreme form of pH-sensitivity that plays a key role in oxygen secretion and general tissue O 2 delivery) exerts an important influence on physiological capacities (Berenbrink, 2007; Rummer et al, 2013; Randall et al, 2014). However, the absence of functional isoHb differentiation in amphibious mudskippers and other facultative air-breathers, and the often pronounced functional heterogeneity in the isoHbs of obligate water-breathers, supports the conclusions of several authors (Fyhn et al, 1979; Ingermann, 1997; Wells, 2009; Storz, 2019) that the overall diversity of co-expressed isoHbs in fish red cells is not generally a strong determinant of physiological versatility or ecological niche breadth.…”

“…In the phylogenies of α- and β-type globins, the fact that adult-expressed mudskipper genes clustered with some embryonically expressed globin genes of other teleosts is not too surprising, as evolutionary changes in stage-specific expression during ontogeny have been well-documented in teleosts (Opazo et al, 2013) and in many tetrapods as well (Opazo et al, 2008; Hoffmann et al, 2010; Storz, 2016; Hoffmann et al, 2018; Storz, 2019).…”

Mutation bias shapes the spectrum of adaptive substitutions

“…A growing body of evidence suggests that specific mutation biases influence the types of genetic changes that cause adaptation [5,[19][20][21][22][23][24][25][26], consistent with a small body of theoretical work on how biases in the introduction of variationboth low-level mutational biases and higher-level systemic biases-are expected to influence evolution [33][34][35][36]. Here, we have developed and applied a general approach to assess how the mutation spectrum shapes the spectrum of adaptive substitutions.…”

Shifts in mutation spectra enhance access to beneficial mutations

“…By altering the pool of mutations available for selection, mutation spectra may determine the genetic basis of adaptation (10,13,14) and drive convergent evolution (15,16). Finally, from a practical standpoint, mutational biases can shape the evolution of resistance to antibiotics (11,17,18) and anticancer drugs (19).…”