Integrating Diverse Types of Genomic Data to Identify Genes that Underlie Adverse Pregnancy Phenotypes

Abstract

Progress in understanding complex genetic diseases has been bolstered by synthetic approaches that overlay diverse data types and analyses to identify functionally important genes. Pre-term birth (PTB), a major complication of pregnancy, is a leading cause of infant mortality worldwide. A major obstacle in addressing PTB is that the mechanisms controlling parturition and birth timing remain poorly understood. Integrative approaches that overlay datasets derived from comparative genomics with function-derived ones have potential to advance our understanding of the genetics of birth timing, and thus provide insights into the genes that may contribute to PTB. We intersected data from fast evolving coding and non-coding gene regions in the human and primate lineage with data from genes expressed in the placenta, from genes that show enriched expression only in the placenta, as well as from genes that are differentially expressed in four distinct PTB clinical subtypes. A large fraction of genes that are expressed in placenta, and differentially expressed in PTB clinical subtypes (23-34%) are fast evolving, and are associated with functions that include adhesion neurodevelopmental and immune processes. Functional categories of genes that express fast evolution in coding regions differ from those linked to fast evolution in non-coding regions. Finally, there is a surprising lack of overlap between fast evolving genes that are differentially expressed in four PTB clinical subtypes. Integrative approaches, especially those that incorporate evolutionary perspectives, can be successful in identifying potential genetic contributions to complex genetic diseases, such as PTB.

Fig 1. Overview of the scheme for identifying convergence between genes under positive selection and those associated with expression differences in normal pregnancy and various syndromes.

Convergence between different data set was determined by overlaying gene sets from each of the data categories using Venn diagram. Genes that fall in overlapping sets were functionally annotated using PANTHER web tool. Key: CAC, Coding Accelerated Changes; EPS, European Positive Selection; HARs, Human Accelerated Regions; PEG, Placental Expressed Genes; PED, Preeclampsia Expressed Differential; LED, Labor Expressed Differential; PPROM, Preterm Premature Rupture of Membranes; sPTB, Spontaneous Preterm Birth.

Fig 2. Overlap between genes expressed in placenta and those that have undergone fast evolution.

Fig 3. Overlap between the genes enriched in the placenta and those that are fast evolving in the human genome.

Similar diagrams are shown for four tissues (cerebral cortex, thyroid, salivary, and bone marrow) that exhibit patterns of significant enrichment of fast evolving genes.

Fig 4. Overlap between genes differentially expressed in four PTB clinical subtypes (large diagram; collated by Eidem et al. 2015), and the overlaps between each of these clinical subtypes and fast evolving genes.