Complex signatures of locus-specific selective pressures and gene conversion on Human Growth Hormone/Chorionic Somatomammotropin genes

Abstract

Reduced birth weight and slow neonatal growth are risks correlated with the development of common diseases in adulthood. The Human Growth Hormone/Chorionic Somatomammotropin (hGH/CSH) gene cluster (48 kb) at 17q22-24, consisting of one pituitary-expressed postnatal (GH1) and four placental genes (GH2, CSH1, CSH2 and CSHL1) may contribute to common variation in intrauterine and infant growth, and also to the regulation of feto-maternal and adult glucose metabolism. In contrast to GH1, there are limited genetic data on the hGH/CSH genes expressed in utero. We report the first survey of sequence variation encompassing all five hGH/CSH genes. Resequencing identified 113 SNPs/indels (ss86217675-ss86217787 in dbSNP) including 66 novel variants, and revealed remarkable differences in diversity patterns among the homologous duplicated genes as well as between the study populations of European (Estonians), Asian (Han Chinese) and African (Mandenkalu) ancestries. A dominant feature of the hGH/CSH region is hyperactive gene conversion, with the rate exceeding tens to hundreds of times the rate of reciprocal crossing-over and resulting in near absence of linkage disequilibrium. The initiation of gene conversion seems to be uniformly distributed because the data do not predict any recombination hotspots. Signatures of different selective constraints acting on each gene indicate functional specification of the hGH/CSH genes. Most strikingly, the GH2 coding for placental growth hormone shows strong intercontinental diversification (Fst= 0.41-0.91; p<10−6) indicative of balancing selection, whereas the flanking CSH1 exhibits low population differentiation (Fst=0.03-0.09), low diversity (non-Africans π=8-9 × 10−5, Africans π= 8.2 × 10−4), and one dominant haplotype worldwide, consistent with purifying selection. The results imply that the success of an association study targeted to duplicated genes may be enhanced by prior resequencing of the study population in order to determine polymorphism distribution and relevant tag-SNPs.

High divergence in primate-specific duplicated regions: Human and chimpanzee Chorionic Gonadotropin Betagenes

“…So far, only a limited number of reports has been published that focus on detailed variation patterns of duplicated gene families in primates ( MHC , Globin , GH/CSH and LHB/CGB genes) [ 7 , 29 , 81 - 83 ]. However, the common observation is that compared to single-copy segments, duplicated regions tend to exhibit higher interspecies diversity that could be explained by relaxed selective pressures and/or gene conversions spreading mutations.…”

Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations

“…The human CGB8 and CGB5 genes are located among the seven duplicate genes within the LHB/CGB gene cluster. Major complications in targeting duplicated genes in association studies are high sequence similarity (>92%), high diversity, large number of population-specific variants and low LD due to high gene conversion activity (19, 33). These characteristics make it technically challenging to select reliable tag-SNPs and establish genotyping methods capable of targeting unique SNPs in duplicated genes.…”

Extensive load of somatic CNVs in the human placenta

“…On the other hand, there is increasing evidence of placenta to act as an extra-embryonic organ with important contribution to the growth, programming and development of the fetus, as well as to the maternal gestational metabolism 1 . Rapid development of placenta among mammals has been explained by the plasticity of the placental genome modulated by two evolutionary mechanisms – co-option and adaptive evolution of ancient genes involved in growth and metabolism 2 3 and emergence of novel placental genes by locus duplication events 4 5 .…”