Placental invasion, preeclampsia risk and adaptive molecular evolution at the origin of the great apes: Evidence from genome-wide analyses
Introduction
In humans, abnormal placental development is associated with a variety of adverse outcomes, including miscarriage, fetal growth restriction, preterm birth, preeclampsia (PE) and eclampsia [1], [2], [3]. PE, with a typical onset of maternal symptoms in the third trimester, is characterized by acute hypertension and proteinuria in the mother. It occurs in 5–7% of all pregnancies, and is a leading cause of maternal mortality [4], [5], [6] for which there is presently no cure other than delivery.
PE is associated with deficiency in spiral artery remodeling, a key step in placental development in which extravillous trophoblast (EVT) cells from placental villi invade the maternal decidua and inner myometrium during the first trimester and replace cells of the uterine artery walls, resulting in vessels with increased diameter, decreased resistance and increased blood flow [7], [8], [9]. Deficiency in EVT invasion and spiral artery remodeling may trigger distinct maternal inflammatory responses which result in the maternal symptoms of PE. PE therefore results from two processes: insufficient placentation, and the maternal response [3].
Various experimental approaches have been used to improve our understanding of PE, spanning from the genetic to the anthropological [6], [9], [10], [11], [12], [13], [14]. Previously, it has been suggested that risk for gestational diseases associated with abnormal placentation, such as PE and postpartum hemorrhage, may be a consequence of the evolution of our particularly invasive placental phenotype [15]. The goal of this study is to develop and apply a new approach to uncovering genes crucial to EVT invasion and spiral artery remodeling, by inferring when these steps in placental development first evolved, and assessing selection on placentally-expressed genes along this branch of the primate phylogeny.
Recent evaluations have revealed that trophoblast invasion depth and spiral artery remodeling are essentially the same in humans, chimpanzees and gorillas [16], [17]. Similarly, isolated accounts of eclamptic pregnancies in gorillas and chimpanzees [18], [19], [20] contest the notion that PE is a uniquely human syndrome [12]. The family Hylobatidae (the gibbons) shares many placental characteristics with Homininae (to which gorillas, chimpanzees and humans belong) including overall discoid shape, hemochorial interhemal interface, and villous fetomaternal interdigitation (Table 1). However, two important characteristics set them apart: shallower trophoblast invasion and the absence of spiral artery remodeling at deeper levels of the myometrium in the gibbons [21], [22]. In Homininae, the deep trophoblast invasion that is responsible for spiral artery remodeling occurs via two routes: interstitial, in which EVT invades from the anchoring villi into the underlying decidua and the inner third of the myometrium, and endovascular, in which EVT migrate through the lumen of the spiral arteries [22], [23]. In gibbons and old world monkeys, EVT invasion occurs primarily via the endovascular route, but penetrates only the decidual region, while the interstitial route appears to be restricted to the basal plate area with no deeper invasion into the decidua, thus leading to the less invasive hemochorial placental phenotype [21], [22], [24].
There is currently no description of the route and depth of trophoblast invasion in orangutans [22], the sister species to the Homininae (Fig. 1) and therefore it is not clear whether increased invasiveness evolved before and/or after the divergence of orangutans from the lineage that gave rise to humans, chimpanzees and gorillas. However, several findings suggest that orangutans may also share our more invasive phenotype: the major histocompatibility complex (MHC) class I antigen HLA-C, which is expressed on EVT in humans and is implicated in spiral artery remodeling via its interactions with uterine natural killer cells, is present in the orangutan but not gibbons or old world monkeys [21], [25], [26], [27]. Furthermore, in one case, massive placental infarcts accompanied by maternal proteinuria and post-partum death led to a diagnosis of “toxemia of pregnancy” in an orangutan [28], hinting that PE may also occur within this species, which might reflect a requirement for increased EVT invasion to achieve a normal, healthy pregnancy.
Given that an increased degree of invasion emerged between the time that gibbons diverged from the great apes and the time that gorillas diverged from chimpanzees and humans (Fig. 1, Table 1), we hypothesize that identification of placentally-expressed genes under positive selection during this period of our evolution could identify novel genes involved in EVT invasion and spiral artery remodeling. While others have examined selection on placentally-expressed genes [29], ours is the first to examine selection specifically during the period when increased invasion evolved. We do not consider selection within the Homininae [27], [30], since trophoblast invasion and spiral artery remodeling show little variation within this group. We focus especially on the Hominidae-origin branch, but also analyze the data for the branch at the origin of Homininae (immediately after the divergence of orangutans), and we note that increases in placental invasiveness may also have occurred along both of these branches.
Section snippets
Methods
Analyses of positive selection on the branch ancestral to Hominidae (humans, chimpanzees, gorillas, and orangutans) and on the branch ancestral to Homininae (humans, chimpanzees, and gorillas) were carried out using the CODEML program in the PAML package using the ratio of non-synonymous to synonymous amino acid substitution for protein-coding DNA (dN/dS ratio). The dN/dS ratio is a commonly-used indicator of selective pressure acting on protein-coding genes. The rationale is that natural
Results
DAVID functional clustering analysis of genes under positive selection with p < 0.05 (n = 295 from the branch ancestral to Hominidae shown in Supplementary Table 1, and n = 264 from the branch ancestral to Homininae shown in Supplementary Table 2) identified several molecular pathways, gene function categories and disease contexts that were relevant to processes important in placentation.
Clusters functionally related, or potentially related, to placentation are summarized in Table 2.
Discussion
Genes under positive selection on the branch ancestral to the great apes included genes with verified or hypothesized roles in EVT invasion and spiral artery remodeling. This set of genes is thus implicated by evolutionary and physiological-developmental evidence in the emergence of a more invasive hemochorial phenotype. The most highly enriched clusters of genes included those involved in immune function, particularly in relation to the immunoglobulin-like proteins and MHC class I antigen
Conclusions
We describe a novel approach that identifies genes, pathways and specific amino acid sites under positive selection during the evolution of the particularly invasive placenta of the great apes. This approach is valuable in that it provides a novel set of candidate genes, and candidate functional amino acid sites, for further investigation with respect to roles in the evolution of placental invasiveness, spiral artery remodeling and PE risk.
Interpretation of these results is subject to several
Acknowledgments
This research has been enabled by the use of computing resources provided by WestGrid and Compute/Calcul Canada, and the IRMACS centre at Simon Fraser University. Our work was also supported by a Canadian Institutes of Health Research Master's Award (Frederick Banting and Charles Best Canada Graduate Scholarships) to EJC, as well as the Nelly Auersperg Award from the Women's Health Research Institute of British Columbia to JKC and NSERC Operating Grants to JKC and BJC.
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