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Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine

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Abstract

Studies of the process of pseudogenization have widened our understanding of adaptive evolutionary change. In Rabbit, an alteration at the second extra-cellular loop of the CCR5 chemokine receptor was found to be associated with the pseudogenization of one of its prime ligands, the chemokine CCL8. This relationship has raised questions about the existence of a causal link between both events, which would imply adaptive gene loss. This hypothesis is evaluated here by tracing back the history of the genetic modifications underlying the chemokine pseudogenization. The obtained data indicate that mutations at receptor and ligand genes occurred after the lineage split of New World Leporids versus Old World Leporids and prior to the generic split of the of Old World species studied, which occurred an estimated 8–9 million years ago. More important, they revealed the emergence, before this zoographical split, of a “slippery” nucleotide motif (CCCCGGG) at the 3′ region of CCL8-exon2. Such motives are liable of generating +1G or −1G frameshifts, which could, however, be overcome by “translesion” synthesis or somatic reversion. The CCL8 pseudogenization in the Old World lineage was apparently initiated by three synapomorphic point mutations at the exon2-intron2 boundary which provide at short range premature terminating codons, independently of the reading frame imposed by the slippery motif. The presence of this motif in New World Leporids might allow verifying this scenario. The importance of CCL8−CCR5 signaling in parasite–host interaction would suggest that the CCL8 knock-out in Old World populations might be related to changes in pathogenic environment.

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Abbreviations

CCL :

CC chemokine ligand

CCR :

CC chemokine receptor

WGS:

Whole genome sequence

Mya:

Million years ago

MYXV:

Myxoma virus

PCR:

Polymerase chain reaction

PTC:

Premature terminating codon

pPTC:

Potential PTC

NMD:

Nonsense-mediated mRNA decay

PPT:

PolyPurine track

ISE:

Intronic splicing enhancer

M&M:

Materials and methods

OWL:

Old World Leporids (Leporid species originating of the Palearctic region, does not include Lepus)

NWL:

New World Leporids (idem for the Nearctic region, includes Lepus)

Rabbit:

Oryctolagus cuniculus

Pika:

Ochotona princeps

nc:

Nucleotide

bp:

Base pair

K bp:

1000 bp

aa:

Amino acid

fs:

Frameshift

i.e.,:

In extensor, more in detail

e.g.,:

Exempli gratia, for example

cf:

Confer

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Acknowledgments

This work was partially supported by the funds from the FEDER (Fundo Europeu de Desenvolvimento Regional) through the Programa Operacional Factores de Competitividade (COMPETE program; FCOMP-01-0124-FEDER-028286) and the Portuguese national funds through FCT (Fundação para a Ciência e a Tecnologia; research project PTDC/BIA-ANM/3963/2012). FCT also supported the FCT Investigator Grant of JA (ref.: IF/01396/2013). “Genomics Applied To Genetic Resources” cofinanced by the North Portugal Regional Operational Program 2007/2013 (ON.2-O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF), also supported this work.

Authors contribution

WvdL conceived the study and carried out the literature research, data mining and analysis, drafting, and editing of the manuscript. The new data of present report were produced by MJM who succeeded in the extraction of and PCR amplification of genomic DNA of the used tissues of Pentalagus furnessi which was collected and conditioned by FY. AML carried out the cDNA work, establishing the transcription of CCL8 in NWL. as well as the cloning of the specimen presenting an allelic −fs. PJE is the leader and JA an inspiring member of the CIBIO Immunogenetics, Microbes and Infectious Diseases research group (IMID).

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Authors and Affiliations

  1. CIBIO-UP, Centro de Investigação em Biodiversidade e Recursos Genéticos, InBIO Laboratório Associado, Campus Agrário de Vairão, Universidade do Porto, 4485–661, Vairão, Portugal

    Wessel van der Loo, Maria João Magalhaes, Ana Lemos de Matos, Joana Abrantes & Pedro J. Esteves

  2. Departamento de Zoologia e Antropologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

    Wessel van der Loo, Ana Lemos de Matos & Pedro J. Esteves

  3. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA

    Ana Lemos de Matos

  4. Agriculture Forestry and Fisheries Research Council, Tsukuba, Japan

    Fumio Yamada

  5. Centro de Investigação em Tecnologias da Saúde, IPSN, CESPU, 4585–116, Gandra, Portugal

    Pedro J. Esteves

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  1. Wessel van der Loo
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  2. Maria João Magalhaes
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  3. Ana Lemos de Matos
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  4. Joana Abrantes
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  5. Fumio Yamada
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  6. Pedro J. Esteves
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Corresponding author

Correspondence to Wessel van der Loo.

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Endnotes

Species names are capitalized when used to avoid irrelevant repetitions of scientific names (such as European rabbit or Oryctolagus cuniculus). Thus, “Rabbit genome” or “Rabbit sequences” but “rabbits were collected.” By analogy, we write Human, Pika, etc. depending on context (cf http://mailman.nhm.ku.edu/pipermail/taxacom/2005-March/010154.html).

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van der Loo, W., Magalhaes, M.J., de Matos, A.L. et al. Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine. J Mol Evol 83, 12–25 (2016). https://doi.org/10.1007/s00239-016-9747-7

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