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Expression of type II chorionic gonadotropin genes supports a role in the male reproductive system.

ABSTRACT: Human chorionic gonadotropin (hCG) is a glycoprotein hormone essential to pregnancy. hCG is heterodimeric and functionally defined by its ? subunit. hCG? evolved from the ? subunit of luteinizing hormone in two phases. In the first phase, type I genes (hCG?3, -5, -7, and -8) acquired changes affecting gene expression and extending the proteins' C terminus. In the second phase, type II genes (hCG?1 and -2) were formed by the insertion of a DNA element into the type I 5' end. The insertion includes the small noncoding RNA gene snaR-G and has been predicted to drastically change the protein products encoded. We trace the insertion to the common ancestor of the African great apes and show that it contains transcription signals, including snaR-G. Type II transcripts are predominantly expressed in testis. Contrary to predictions, the product of the major mRNA splice form is hCG?. A novel peptide is encoded by alternatively spliced transcripts. These findings support the view that type II genes evolved in African great apes to function in the male reproductive system.

SUBMITTER: Parrott AM

PROVIDER: S-EPMC3019977 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Expression of type II chorionic gonadotropin genes supports a role in the male reproductive system.

Parrott Andrew M AM Sriram Ganapathy G Liu Yijun Y Mathews Michael B MB

Molecular and cellular biology 20101115 2

Human chorionic gonadotropin (hCG) is a glycoprotein hormone essential to pregnancy. hCG is heterodimeric and functionally defined by its β subunit. hCGβ evolved from the β subunit of luteinizing hormone in two phases. In the first phase, type I genes (hCGβ3, -5, -7, and -8) acquired changes affecting gene expression and extending the proteins' C terminus. In the second phase, type II genes (hCGβ1 and -2) were formed by the insertion of a DNA element into the type I 5' end. The insertion include ...[more]

PMID: 21078876

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Project description:Immunopathological outcomes in Systemic Lupus Erythematosus (SLE; or lupus) are believed to be autoantibody-mediated. Conditions which promote a Th2 skew (such as pregnancy) should encourage antibody production, worsening antibody-mediated diseases while ameliorating Th1/Th17-mediated diseases. Although an increased propensity toward autoreactivity can be observed in pregnant lupus patients and in pregnant lupus-prone mice, whether a unique human pregnancy-specific factor can contribute to such effects is unknown. This study assessed whether human chorionic gonadotropin (hCG, a pregnancy-specific hormone of diverse function) at physiological concentrations could mediate stimulatory influences on immune parameters in non-pregnant, lupus-prone mice, in light of the hormone's ameliorating effects on Th1-mediated autoimmunity in murine models. Results demonstrate that administration of hCG heightened global autoreactivity in such mice; antibodies to dsDNA, RNP68, Protein S, Protein C, β2-glycoprotein 1, and several phospholipids were enhanced, and hormone administration had adverse effects on animal survival. Specifically in splenic cell cultures containing cells derived from lupus-prone mice, hCG demonstrated synergistic effects with TLR ligands (up-modulation of costimulatory markers on B cells) as well as with TCR stimuli (enhanced proliferative responses, enhanced levels of cytokines, and the phosphorylation of p38). In both instances, enhanced synthesis of lupus-associated cytokines was observed, in addition to the heightened generation of autoantibodies reactive toward apoptotic blebs. These results suggest that selective transducive, proliferative, and differentiative effects of hCG on adaptive immune cells may drive autoreactive responses in a lupus environment, and may also potentially provide insights into the association between the presence of higher hCG levels (or the administration of hCG) with the presence (or appearance) of humoral autoimmunity.

Project description:Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (LHB)/Chorionic Gonadotropin Beta (CGB) gene cluster as a model. The placental CGB genes that are essential for implantation have evolved from an ancestral pituitary LHB gene by duplications in the primate lineage.We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp) LHB/CGB regions and hereby present evidence for structural variation resulting in discordant number of CGB genes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions of LHB/CGB cluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped the LHB/CGB gene cluster. The substitution divergence (1.8-2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus approximately 30%). Despite the high sequence identity among LHB/CGB genes, there are signs of functional differentiation among the gene copies. Estimates for dn/ds rate ratio suggested a purifying selection on LHB and CGB8, and a positive evolution of CGB1.If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.

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Expression of type II chorionic gonadotropin genes supports a role in the male reproductive system.

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Expression of type II chorionic gonadotropin genes supports a role in the male reproductive system.

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