title: Evolutionary forward genomics reveals novel insights into the genes and pathways dysregulated in recurrent early pregnancy loss.
abstract: OBJECTIVE
  Are the genes that gained novel expression in the endometria of Eutherian (placental) mammals more likely to be dysregulated in patients with endometrial-associated recurrent early pregnancy loss (REPL)?
  
  
  CONCLUSIONS
  There was a significant enrichment of genes dysregulated in REPL patients among the Eutherian-specific endometrial genes.
  
  
  BACKGROUND
  Pregnancy loss is the most common complication of human pregnancy. REPL has multiple etiologies, including dysregulation of endometrial function, leading to 'suboptimal' implantation. Although the implantation process is tightly regulated in Eutherian (placental) mammals, the molecular factors contributing to dysregulated endometrial gene expression patterns in women with REPL are largely unknown.
  
  
  METHODS
  Endometrial biopsies were obtained from 32 REPL patients during the mid-luteal phase, and evaluated for glandular development arrest based on elevated nuclear cyclin E levels in gland cells, and for out-of-phase endometrial development based on histology. Gene expression levels were measured using Illumina Human HT-12v4 BeadChip arrays.
  
  
  METHODS
  Differentially expressed genes were identified between patients with (i) out-of-phase (n = 10) versus normal (n = 22) histological dating and (ii) abnormally elevated (n = 9) versus normal (n = 23) cyclin E levels in the nuclei of endometrial glands, using a likelihood ratio test. Enrichment of dysregulated genes in REPL endometria among Eutherian-specific genes was tested by permutation. Gene ontology and pathway enrichment analyses were carried out for the dysregulated genes.
  
  
  RESULTS
  Fifty-eight and eighty-one genes were identified as differentially expressed at P < 0.001 in women with out-of-phase histological dating and abnormally elevated glandular cyclin E levels, respectively. Genes that were recruited into endometrial expression during the evolution of pregnancy in Eutherian mammals were significantly enriched for dysregulated genes (P = 0.002 for histology, P = 0.021 for cyclin E), as well as for genes involved in immune response and signaling pathways with essential roles in implantation and endometrial biology.
  
  
  CONCLUSIONS
  Small sample size limits the statistical power to detect dysregulated genes, and the lack of non-REPL control women does not allow us to test for the contribution of these genes to overall risk of REPL.
  
  
  CONCLUSIONS
  Enrichment of functional gene categories, as well as genes gained expression in the Eutherian endometria, help to identify molecular etiologies that contribute to normal functioning of the endometrium. These pathways are also strong candidates for successful pregnancy outcomes. Using the evolutionary history of mammalian gene expression in the endometrial tissue may be a promising approach to discover genes involved in female reproductive disorders.
  
  
  BACKGROUND
  This work is supported by National Institutes of Health (NIH) grant R01 HD21244 to C.O. Authors declare no competing interests.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA Present Address: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Gülüm
authors.initials: G
authors.lastname: Kosova
authors.affiliation: Department of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA Present Address: Department of Obstetrics and Gynecology, The University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Stephenson
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Lynch
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA Department of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA c-ober@bsd.uchicago.edu.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D005075:Biological Evolution; D020964:Embryo Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D006801:Humans; D008183:Luteal Phase / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012098:Reproduction / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
keywords: endometrium; eutherian mammals; forward genomics; recurrent early pregnancy loss; reproductive disorders