Segmental duplications and gene conversion: Human luteinizing hormone/chorionic gonadotropin β gene cluster

Hallast, Pille; Nagirnaja, Liina; Margus, Tõnu; Laan, Maris

doi:10.1101/gr.4270505

Cited by 68 publications

(81 citation statements)

References 63 publications

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“…This CGB/ LHB gene cluster arose from the only ancestral LHB gene with segmental duplications, which is evolutionarily conserved and is only expressed in human and nonhuman primates [7]. With regard to evolution, the CGB7 and CGB6 subunits are described as the oldest phenotypic CGB variations, whereas the CGB5, CGB3, and CGB8 nucleotide structure variations comply with more recent gene locus development for hormone transcription and translation [8,9].…”

Section: Introductionmentioning

confidence: 99%

Expression and Production of Human Chorionic Gonadotropin (hCG) in the Normal Secretory Endometrium: Evidence of CGB7 and/or CGB6 Beta hCG Subunit Gene Expression1

Zimmermann

Ackermann²,

Alexander

2012

Biology of Reproduction

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We have previously confirmed glandular cell CGB and CGA subunit mRNA gene expression as well as the expression of their dimeric and single-subunit human chorionic gonadotropin (hCG) proteins in normal secretory transformed endometrium. The objective of this study was to investigate the endometrial epithelial gene locus of the human hCG/LH gene cluster from CGB genes responsible for gene expression. For this study, endometrial specimens were selected from women characterized using our endometrium score and hCG staining index that had normal secretory transformed endometrium and optimal hCG staining. Using full-length CGB mRNA sequence analysis, we found that epithelial CGB is (co)expressed as the product of gene locus CGB7 and CGB6 (48%), as single CGB7 (42%), or to a lower percentage as single CGB6 (10%). In addition to known differences between these genes and CGB5, the nucleotide sequence of the mRNA differs between CGB7 and CGB6 in the untranslated promoter region and in translated exon 2. Immunohistochemical results show that endometrial joint CGB7 and CGB6, single CGB7, and single CGB6 mRNA expression lead to the release of endometrial hCG. Genespecific antibodies for CGB7 reveal secretory endometrial hCG production, which is not observed for gene-specific CGB5 antibodies, whereas the placenta is positive for CGB5 and negative for CGB7 antibody as revealed by immunohistochemistry and Western blot hCG isoform analysis. Only endometrial CGB7 expression seems to be supported specifically by secretory endometrial transcription factors. In conclusion, epithelial hCG is expressed and produced as CGB7 and/or CGB6 but not CGB5, and it is produced together with CGA as a secretory transformation marker in the normal secretory phase endometrium.endometrium, female reproduction tract, human chorionic gonadotropin (hCG/hCG receptor), menstrual cycle, uterus

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Section: Introductionmentioning

confidence: 99%

Expression and Production of Human Chorionic Gonadotropin (hCG) in the Normal Secretory Endometrium: Evidence of CGB7 and/or CGB6 Beta hCG Subunit Gene Expression1

Zimmermann

Ackermann²,

Alexander

2012

Biology of Reproduction

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“…Compared to WT‐LH, V‐LH has higher number of sialic acid residues and indeed, its measured half‐life is approximately 40% longer (half‐life: WT‐LH 108 min, V‐LH 148 min; Wide et al ., 2010). The V‐LHβ polymorphism was suggested to have originated through an ancient gene conversion event, where one of the hCGβ encoding CGB genes has acted as a conversion donor and the LHB gene as an acceptor of the respective genomic fragment (Hallast et al ., 2005). The concerted substitutions in V‐LH exon 2 leading to Trp8Arg/Ile15Thr correspond to the nucleotide sequence in the respective positions of all six CGB genes (Nagirnaja et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Sequencing analysis was performed as described by Hallast et al . (2005). There was no difference in the results of the three methods used for confirming V‐LH status.…”

Section: Methodsmentioning

confidence: 99%

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

et al. 2015

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SummaryLuteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V‐LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β‐subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V‐LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V‐LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V‐LH was detected by genotyping of the underlying DNA polymorphisms using PCR‐RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta‐analysis. No significant difference was detected between young men and infertility patients for the V‐LH allele frequency (11.0 vs. 9.3%, respectively). V‐LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta‐analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V‐LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB ‐211G/T, FSHR Asn680Ser, FSHR ‐29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V‐LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V‐LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

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“…The region of chromosome 19 containing CG␤ genes has undergone extensive duplication of an ancestral LH␤ gene in primates (41) and represents a hot spot of human genomic diversity (21). Type II CG␤ genes originated through replacement of a portion of an ancestral type I CG␤ gene with a composite of chromosome 19 and 18 and Alu sequences, replacing the type I proximal promoter and 5Ј UTR sequence with a novel promoter containing a small noncoding RNA gene.…”

Section: Discussionmentioning

confidence: 99%

Expression of Type II Chorionic Gonadotropin Genes Supports a Role in the Male Reproductive System

Parrott

Sriram

Liu

et al. 2011

Molecular and Cellular Biology

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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.

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Segmental duplications and gene conversion: Human luteinizing hormone/chorionic gonadotropin β gene cluster

Cited by 68 publications

References 63 publications

Expression and Production of Human Chorionic Gonadotropin (hCG) in the Normal Secretory Endometrium: Evidence of CGB7 and/or CGB6 Beta hCG Subunit Gene Expression1

Expression and Production of Human Chorionic Gonadotropin (hCG) in the Normal Secretory Endometrium: Evidence of CGB7 and/or CGB6 Beta hCG Subunit Gene Expression1

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

Expression of Type II Chorionic Gonadotropin Genes Supports a Role in the Male Reproductive System

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