Evolution of the Chorionic Gonadotropin β Genes in Primates

Abstract

Several genes associated with reproduction have been duplicated during primate evolution and evolved under positive selection. Chorionic gonadotropin hormone (HCG) produced by trophoblast cells has emerged in primates and assists maternal physiology to establish pregnancy. CGB gene, coding for the HCG β subunit has evolved through a duplication of the ancestral lutenizing hormone β (LHB) gene 55–35 million years ago. Only a few sequence changes in the duplicate locus were required to result in a novel CGB gene with different tissue‐specificity and function. Evolution of the LHB/CGB genomic region has been accompanied by active genome dynamics either as series of additional duplications in Old World monkeys and apes, or as functional modifications of genes in New World monkeys. Duplicated, highly homologous genes with diverged functions are maintained through a balance between selective pressures targeted to their specific functions and evolution in consort facilitated by interlocus gene conversion.

Key Concepts

  • Several genes associated with female and male reproduction have been shown to be duplicated during primate evolution and evolve under positive selection.

  • Chorionic gonadotropin hormone (HCG) produced by the trophoblast cells has emerged in primates and acts as a key hormone to assist maternal physiology to establish pregnancy.

  • Primate‐specific CGB gene, coding for the β subunit of HCG has emerged through a duplication of the ancestral lutenizing hormone β (LHB) gene approximately 55–35 million years ago.

  • Only a few sequence changes in the duplicate locus were required to result in a novel CGB gene with different tissue‐specificity, expression pattern and function.

  • Evolution of the LHB/CGB genomic region in primates has been accompanied by active genome dynamics either as a series of additional duplications in the lineage to OWM and apes, or as functional modifications of the gene loci in NWM.

  • Comparison of the human and chimpanzee LHB/CGB gene clusters identified large species‐specific parallel rearrangement events, resulting in lineage‐specific number of CGB gene copies (five versus six genes in chimpanzee compared to human).

  • Duplicated genes tend to evolve in consort facilitated by active interlocus gene conversion increasing and preserving sequence similarity among the gene copies.

  • Intraspecies gene conversion events have led to a higher human–chimpanzee divergence between duplicated LHB/CGB genes compared to the available data for unique genomic regions.

  • Duplicated, highly homologous genes with diverged functions are maintained through balancing interlocus gene conversion activity with selective pressure targeting their specific functions.

Keywords: chorionic gonadotropin β genes; primates; placenta; gene duplication; concerted evolution

Figure 1.

Human Luteinizing hormone β (LHB)/chorionic gonadotropin β (CGB) genes. (a) The structure and functional characteristics of LHB (gene length 1111 bp), HCG β coding (CGB, CGB5, CGB8, CGB7; 1467 bp) and HCG β noncoding genes (CGB1, CGB2; 1366 bp). Exonic regions coding for the signal peptide and mature peptide are depicted as pink and red boxes, respectively. Untranslated regions are marked as white boxes. Compared to the ancestral LHB, the derived CGB genes have a longer 5′‐UTR as well as elongated exon 3 giving rise to a longer mature peptide (Talmadge et al., ). HCG β noncoding genes CGB1 and CGB2 genes have emerged in the common ancestor of African great apes through an insertion of a DNA fragment that replaced part of the proximal end of the promoter and the entire 5′‐UTR of the HCG β coding gene (Bo and Boime, ; Hallast et al., ; Hollenberg et al., ). This insertion created an alternative 5′‐UTR and a novel exon 1 as well as abrupted the open reading frame leading to one base pair frame‐shift for exons 2 and 3. The predicted protein of HCG β noncoding genes has not been isolated. (b) Comparison of the coding sequences of LHB and CGB5 genes using nucleotide alignment. Nucleotide identities and differences are indicated by dashes and gaps, respectively. The one‐letter amino acid code above (LH β subunit) and below (HCG β subunit) the nucleotide sequences indicates encoded proteins. Divergent amino acid positions between LH β and HCG β subunits are indicated in red. Blue arrow indicates 1 bp deletion in duplicated CGB genes, which leads to a read‐through of the ancestral LHB stop‐codon and elongation of the open reading frame of HCG β genes by 24 aminoacids. The N‐glycosylation sites are marked with (*), O‐glycosylation sites with (°).

Figure 2.

Evolution of the LHB/CGB cluster (modified from Hallast et al., ). (a) A simplified schematic presentation of the emergence of CGB genes through duplication of the ancestral LHB gene in primate lineage. (b) Structure of the LHB/CGB cluster in human (Hu) and chimpanzee (Ch). In addition to the high DNA sequence identity between the duplicated LHB/CGB genes (85–99%), the intergenic regions (marked A–E) are also rich in direct and inverted duplicated genomic fragments. Identical colour codes refer to the DNA segments with highly similar sequences, direction of the DNA sequence is indicated as on the sense strand. Sequence identity among intergenic regions is 81% for A and E, 96% for C and C′ and ranges 81–98% for B, B′ and D. The HuLHB/CGB and the ChLHB/CGB gene clusters differ in a large species‐specific duplication event, which has led to the discordant copy number of HCG β coding genes in two species (Hallast et al., ). (c) Location of the non‐coding small NF90‐associated RNA genes, SNAR‐G1 and SNAR‐G2 within the upstream region of HCG β noncoding CGB1‐like genes in human. Coding segments and untranslated regions of the predicted CGB1 and CGB2 proteins are denoted as red and white boxes, respectively. Blue boxes mark the discovered SNAR‐G1 and SNAR‐G2 genes (Parrott and Mathews, ). The direction of transcription of each gene is indicated by black triangles. Modified from Hallast et al..

Figure 3.

Phylogenetic tree based on the genomic DNA sequences of primate LHB/CGB genes, which have been published or were available at NCBI GenBank. Neighbour‐joining tree was constructed by MEGA4 (Kumar et al., ; Tamura et al., ) using Kimura's two‐parameter model and pairwise deletion of gaps. Bootstrap support values are shown at the nodes (1000 replications). Full gene sequences were available for human (GenBank NG_000019), chimpanzee (Pan troglodytes; Hallast et al., ), Macaca mulatta (GenBank AC202849), Saimiri sciureus, Saguinus fuscicollis, Saguinus oedipus, Callithrix jacchus and Cebus apella (AM996851‐AM996855), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus; (Hallast et al., )). Partial gene sequences (from the first intron to the end of third exon) for the rest of the species were derived from (Maston and Ruvolo, ) and are denoted with (*). Three M. mulattaCGB genes are marked a, b, c (**) as the ancestral status of the genes is not clear.

Abbreviations: Atr ‐ Aotus trivirgatus; Cap ‐ Cebus apella; Cgu ‐ Colobus guereza; Cja ‐ Callithrix jacchus; Cmo ‐ Callicebus moloch; Dma ‐ Daubentonia madagascariensis; Ggo ‐ Gorilla gorilla; Gse ‐ Galago senegalensis; Hsa ‐ Homo sapiens; Lta ‐ Loris tardigradus; Mmu ‐ Macaca mulatta; Pob ‐ Presbytis obscura; Ppy ‐ Pongo pygmaeus; Ptr ‐ Pan troglodytes; Sfu ‐ Saguinus fuscicollis; Soe ‐ Saguinus oedipus; Ssc ‐ Saimiri sciureus; Tba ‐ Tarsius bancanus; Vva ‐ Varecia variegata

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Further Reading

Bailey JA and Eichler EE (2006) Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Reviews Genetics 7: 552–564.

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Hallast, Pille, and Laan, Maris(Sep 2009) Evolution of the Chorionic Gonadotropin β Genes in Primates. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021966]