An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

Stanford University, United States of America
PLoS Genetics (Impact Factor: 7.53). 04/2011; 7(4):e1001365. DOI: 10.1371/journal.pgen.1001365
Source: PubMed


Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

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    • "Bacteria also produce phospholipase A2 that increases matrix metalloproteinase 1 and 3 (MMP1 and MMP3), leading to ECM degradation [8], [9]. Molecular studies on the development of PPROM have been undertaken [10], with a focus on genes that are involved with inflammation [11]–[14], including TNFα [15]–[17], FAS, which is member 6 gene of the tumor necrosis factor receptor superfamily [9], [18], and Toll-like receptor (TLR) [19], [20]. TNF-α induces apoptosis in PPROM, through binding to the TNF receptor [13]–[15] and activating a proteolytic cascade via the FAS-caspase pathway [9]. "
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    ABSTRACT: Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "A previous study by Plunkett et al . ( 2011) identified three common tag SNPs, rs11686474 , rs11680730 and rs12473815 , that were significantly associated with preterm birth with odds ratios of 1 . 76 – 1 . 82 in a Finnish cohort . We observed a slight decline in the odds ratios of these same tag SNPs to 1 . 58 – 1 . 59 . The lower odds ratios are due to subtle differences in alle"
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    ABSTRACT: Preterm birth is a complex disorder defined by gestations of less than 37 weeks. While preterm birth is estimated to have a significant genetic component, relative few genes have been associated with preterm birth. Polymorphism in one such gene, follicle-stimulating hormone receptor (FSHR), has been associated with preterm birth in Finnish and African American mothers but not other populations. To refine the genetic association of FSHR with preterm birth we conducted a fine-mapping study at the FSHR locus in a Finnish cohort. We sequenced a total of 44 kb, including protein-coding and conserved non-coding regions, in 127 preterm and 135 term mothers. Overall, we identified 288 single nucleotide variants and 65 insertion/deletions of 1-2 bp across all subjects. While no common SNPs in protein-coding regions were associated with preterm birth, including one previously associated with timing of fertilization, multiple SNPs spanning the first and second intron showed the strongest associations. Analysis of the associated SNPs revealed that they form both a protective (OR = 0.50, 95% CI = 0.25-0.93) as well as a risk (OR = 1.89, 95% CI = 1.08-3.39) haplotype with independent effects. In these haplotypes, two SNPs, rs12052281 and rs72822025, were predicted to disrupt ZEB1 and ELF3 transcription factor binding sites, respectively. Our results show that multiple haplotypes at FSHR are associated with preterm birth and we discuss the frequency and structure of these haplotypes outside of the Finnish population as a potential explanation for the absence of FSHR associations in some populations.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "influencing PTB; subsequently, variants in a positional candidate gene IGF1R were shown to be associated with PTB. Recently, using an evolutionary genomic approach, Plunkett et al. (2011) tested several accelerated genes and found evidence for significant association of variants in FSHR with PTB. Despite such advances in our understanding of the etiology of prematurity , knowledge on specific, major genetic determinants of PTB is extremely limited. "
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    ABSTRACT: Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the United States (US), using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1,302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An approximately 10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2)±SE: 0.75±0.20) and significant (P=4.5 x 10(-5)), after adjusting for the significant effects of birth weight and birth order. We found significant evidence for linkage of PTB (LOD=3.6; nominal P=2.3 x 10(-5); empirical P=1.0 x 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q, and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.
    Full-text · Article · May 2013 · Molecular Human Reproduction
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