Mihaela Pavlicev

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Verified

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• PhD
• Professor (Full) at University of Vienna

Despite sophisticated mathematical models, the theory of microevolution is mostly treated as a qualitative rather than a quantitative tool. Numerical measures of selection, constraints and evolutionary potential are often too loosely connected to theory to provide operational predictions of the response to selection. In this paper we study the abil...

Objectives The narrow human birth canal evolved in response to multiple opposing selective forces on the pelvis. These factors cannot be sufficiently disentangled in humans because of the limited range of relevant variation. Here, we outline a comparative strategy to study the evolution of human childbirth and to test existing hypotheses in primate...

Among mammals, the extent of placental invasion is correlated with vulnerability to malignancy. Animals with more invasive placentation (e.g. humans) are more vulnerable to malignancy, whereas animals with a non-invasive placenta (e.g. ruminants) are less likely to develop malignant cancer. To explain this correlation, we propose the hypothesis of...

Embryo implantation is the first step in the establishment of pregnancy in eutherian (Placental) mammals. Although viviparity evolved prior to the common ancestor of marsupials and eutherian mammals (therian ancestor), implantation is unique to eutherians. The ancestral therian pregnancy likely involved a short phase of attachment between the fetal...

Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already pres...

Embryo implantation requires tightly coordinated signaling between the blastocyst and the endometrium, and is crucial for the establishment of a uteroplacental unit that persists until term in eutherian mammals. In contrast, marsupials, with a unique life cycle and short gestation, make only brief fetal-maternal contact and lack implantation. To be...

A hallmark of eutherian pregnancy is its dependency on elevated progesterone levels for its entire length. This fact substantially affected the evolution of pregnancy and even the life history of eutherians. Progesterone synthesis by the ovarian corpus luteum, however, long predates all origins of vertebrate viviparity, which requires reconsidering...

Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already pres...

Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already pres...

A hallmark of eutherian pregnancy is its dependency on elevated progesterone levels for its entire length. This fact substantially affected the evolution of pregnancy and even the life history of eutherians. Progesterone synthesis by the ovarian corpus luteum, however, long predates all origins of vertebrate viviparity, which requires reconsidering...

Biological function depends on the composition and structure of the organism, the latter describing the organization of interactions between parts. While cells in multicellular organisms are capable of a remarkable degree of autonomy, most functions do require cell communication: the coordination of functions (growth, differentiation, and apoptosis...

The common human SNP rs3820282 is associated with multiple phenotypes including gestational length and likelihood of endometriosis and cancer, presenting a paradigmatic pleiotropic variant. Deleterious pleiotropic mutations cause the co-occurrence of disorders either within individuals, or across population. When adverse and advantageous effects ar...

Biological function depends on the composition as well as structure of the organism, that is the organization of interactions between its parts. In multicellular organisms, the complex communication between cells is crucial for the coordination of cellular functions (growth, differentiation, apoptosis), compartmentalization of cellular processes wi...

Essays on evolvability from the perspectives of quantitative and population genetics, evolutionary developmental biology, systems biology, macroevolution, and the philosophy of science. Evolvability—the capability of organisms to evolve—wasn't recognized as a fundamental concept in evolutionary theory until 1990. Though there is still some debate a...

Essays on evolvability from the perspectives of quantitative and population genetics, evolutionary developmental biology, systems biology, macroevolution, and the philosophy of science. Evolvability—the capability of organisms to evolve—wasn't recognized as a fundamental concept in evolutionary theory until 1990. Though there is still some debate a...

Essays on evolvability from the perspectives of quantitative and population genetics, evolutionary developmental biology, systems biology, macroevolution, and the philosophy of science. Evolvability—the capability of organisms to evolve—wasn't recognized as a fundamental concept in evolutionary theory until 1990. Though there is still some debate a...

Compared to other primates, modern humans face high rates of maternal and neonatal morbidity and mortality during childbirth. Since the early 20th century, this "difficulty" of human parturition has prompted numerous evolutionary explanations, typically assuming antagonistic selective forces acting on maternal and fetal traits, which has been terme...

The common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants....

In this short paper, we argue that there is a fundamental connection between the medical sciences and evolutionary biology as both are sciences of biological variation. Medicine studies pathological variation among humans (and domestic animals in veterinary medicine) and evolutionary biology studies variation within and among species in general. A...

Synopsis A review of the literature on the anatomy of the lower female genital tract in therian mammals reveals, contrary to the general perception, a large amount of inter-specific variation. Variation in females is anatomically more radical than that in the male genitalia. It includes the absence of whole anatomical units, like the cervix in many...

Criticisms of the “container” model of pregnancy picturing female and embryo as separate entities multiply in various philosophical and scientific contexts during the last decades. In this paper, we examine how this model underlies received views of pregnancy in evolutionary biology, in the characterization of the transition from oviparity to vivip...

Mammalian pregnancy evolved in the therian stem lineage, that is, before the common ancestor of marsupials and eutherian (placental) mammals. Ancestral therian pregnancy likely involved a brief phase of attachment between the fetal and maternal tissues followed by parturition—similar to the situation in most marsupials including the opossum. In all...

The field of evolution and development consists of two main approaches, the first, the evolutionary developmental approach studying changes in development, and the second, the developmental evolutionary approach, studying how developmental properties affect the evolutionary process, thus using a systems-biological approach to integrate development...

Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter...

Gene regulation in the germline ensures the production of high-quality gametes, long-term maintenance of the species, and speciation. Germline transcriptomes undergo dynamic changes after the mitosis-to-meiosis transition in males and have been subject to evolutionary divergence among mammals. However, the mechanism that underlies germline regulato...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Among mammals, placental invasion is correlated with vulnerability to malignancy. Animals with more invasive placentation (for example, humans) are more vulnerable to malignancy. To explain this correlation, we propose the hypothesis of ‘Evolved Levels of Invasibility’ proposing that the evolution of invasibility of stromal tissue affects both plac...

Evolution of highly invasive placentation in the stem lineage of eutherians and subsequent extension of pregnancy set eutherians apart from other mammals, i.e., marsupials with short-lived placentas, and oviparous monotremes. Recent studies suggest that eutherian implantation evolved from marsupial attachment reaction, an inflammatory process induc...

The question of how to conceive of the relation between the pregnant female and the embryo has become a recent focus of debate in the philosophical literature. Here we consider this problem in the context of current debates on individuality in the philosophy of biology by looking at how pregnancy is individuated in different disciplinary contexts....

Significance The existence of female orgasm is intriguing for 2 reasons: On the one hand, female orgasm is not necessary for female reproductive success, and on the other hand, this neuro-endocrine reflex is too complex to be an evolutionary accident. This led to many proposed evolutionary explanations, most of which have little empirical support....

Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). Afte...

In human pregnancy, recognition of an embryo within the uterus is essential to support the fetus through gestation. In most marsupials, such as the opossums, pregnancy is shorter than the oestrous cycle and the steroid hormone profile during pregnancy and oestrous cycle are indistinguishable. For these reasons, it was assumed that recognition of pr...

Without cesarean delivery, obstructed labor due to a disproportion of the fetus and the maternal birth canal can result in maternal and fetal injuries or even death. The precise frequency of obstructed labor is difficult to estimate because of the widespread use of cesarean delivery for indications other than proven cephalopelvic disproportion, but...

Photographs of articulated bony pelves of representatives of all major mammalian (marsupial and placental) groups. Sexual dimorphism (or the lack thereof) can also be observed by comparing male and female specimens.

Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). Afte...

Appendix S1: Supporting information Figures

Table S2 Supporting information Table S2. The number of species by higher‐order taxon used to produce each Figure in the main text, including the data source.

Table S1 Supporting information Table S1. Data on neonatal and female body mass for 284 mammalian species. Data for 266 species were taken from Tague (2016), and data for an additional twelve species (highlighted in yellow) were collated from the indicated sources. When no reference is given, data are from Tague (2016).

The narrow human birth canal evolved in response to multiple opposing selective forces on the pelvis. These factors cannot be sufficiently disentangled in humans because of the limited range of relevant variation. We outline a comparative strategy to study the evolution of human childbirth and to test existing hypotheses in primates and other mamma...

Decidual stromal cells differentiate from endometrial stromal fibroblasts (ESFs) under the influence of progesterone and cyclic adenosine monophosphate (cAMP) and are essential for implantation and the maintenance of pregnancy. They evolved in the stem lineage of placental (eutherian) mammals coincidental with the evolution of implantation. Here we...

Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expre...

( N Engl J Med. 2017;377(12):1156–1167) Preterm birth is the leading cause of death in neonates and children above 5 years of age. Its definition, birth before 37 completed weeks of gestation, is a dichotomous trait based on a somewhat arbitrary cutoff of weeks’ gestation, rather than time of birth or a level of fetal maturity. Therefore, in the pr...

In human females, direct or indirect stimulation of the clitoris plays a central role in reaching orgasm. A majority of women report that penetrative coitus alone is insufficient for triggering orgasm, puzzling researchers who expect orgasm to be an outcome of procreative intercourse. In the present paper, we turn our attention to the evolutionary...

( N Engl J Med . 2017;377(12):1156–1167) Preterm birth is the leading cause of death in neonates and children younger than 5 years of age. Its definition, birth before 37 completed weeks of gestation, is a dichotomous trait based on a somewhat arbitrary cutoff of weeks’ gestation, rather than time of birth or a level of fetal maturity. Therefore, i...

(Abstracted from N Engl J Med 2017;377:1156–1167) Preterm birth, caused by idiopathic onset of uterine contractions or rupture of fetal membranes, is a major risk factor for death in neonates and children younger than 5 years. Although there is evidence that preterm birth and gestational duration are affected by both maternal and fetal genomes, rob...

Significance The cliff-edge model explains the evolutionary persistence of relatively high incidences of fetopelvic disproportion (FPD), the mismatch of fetal and maternal dimensions during human childbirth. It also predicts that FPD rates have increased evolutionarily since the regular use of Caesarean sections. Here we show that the model also ex...

Background Despite evidence that genetic factors contribute to gestational length and preterm birth, robust associations with genetic variants have not been identified. We hypothesized that analyzing larger data sets with gestational length information by genomewide association would reveal trait-influencing variants. Methods We performed a genome...

Humans are one of the few mammalian viviparous species in which pregnancy is extended beyond the luteal phase, the phase during which progesterone is synthesized by the maternal ovary. Instead, it is the fetal placenta that produces progesterone throughout the latter 2 trimesters of human pregnancy. The placenta is developmentally crucial for repro...

Transposable element (TE)-derived sequences make up approximately half of most mammalian genomes, and many TEs have been co-opted into gene regulatory elements. However, we lack a comprehensive tissue- and genome-wide understanding of how and when TEs gain regulatory activity in their hosts. We evaluated the prevalence of TE-derived DNA in enhancer...

Organismal function is, to a great extent, determined by interactions among their fundamental building blocks, the cells. In this work, we studied the cell-cell interactome of fetal placental trophoblast cells and maternal endometrial stromal cells, using single-cell transcriptomics. The placental interface mediates the interaction between two semi...

Development translates genetic variation into a multivariate pattern of phenotypic variation, distributing it among traits in a nonuniform manner. As developmental processes are largely shared within species, this suggests that heritable phenotypic variation will be patterned similarly, in spite of the different segregating alleles. To investigate...

It has been hypothesized that one of the main reasons evolution has been able to produce such impressive adaptations is because it has improved its own ability to evolve -- "the evolution of evolvability". Rupert Riedl, for example, an early pioneer of evolutionary developmental biology, suggested that the evolution of complex adaptations is facili...

Significance Compared with other primates, human childbirth is difficult because the fetus is large relative to the maternal pelvic canal. It is a long-standing evolutionary puzzle why the pelvis has not evolved to be wider, thus reducing the risk of obstructed labor. We present a mathematical model that explains the high rates of fetopelvic dispro...

Cell types are the basic building blocks of multicellular organisms and are extensively diversified in animals. Despite recent advances in characterizing cell types, classification schemes remain ambiguous. We propose an evolutionary definition of a cell type that allows cell types to be delineated and compared within and between species. Key to ce...

Pleiotropy, the involvement of a gene in development and variation of multiple traits, is a concept considerable appreciation in developmentally as well as statistically oriented fields of evolutionary biology. Here I argue that this feature makes pleiotropy a particularly suitable guiding topic for connecting the two branches of evolutionary biolo...

The evolutionary explanation of female orgasm has been difficult to come by. The orgasm in women does not obviously contribute to the reproductive success, and surprisingly unreliably accompanies heterosexual intercourse. Two types of explanations have been proposed: one insisting on extant adaptive roles in reproduction, another explaining female...

The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stem lineage of eutherian mammals ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type "neo-ESF" in contrast to "paleo-ESF" which are homologous to eutherian ES...

Developmental stability and canalization describe the ability of developmental systems to minimize phenotypic variation in the face of stochastic micro-environmental effects, genetic variation and environmental influences. Canalization is the ability to minimize the effects of genetic or environmental effects, while developmental stability is the a...

With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into...

Evolutionary constraint due to pleiotropy refers to a situation in which mutations in genes shared among traits generate trait covariance; therefore, traits that are not directly exposed to selective challenge show a correlated response. When such a correlated response is deleterious, it may constrain the trait from evolving. Here, we argue that th...

Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. T...

Independent selection response of a trait is contingent on the availability of genetic variation that is not entangled with other traits. Mechanistically, such variational individuation in spite of shared genome results from gene regulation. Changes that increase individuation of traits are likely caused by gene regulatory changes. Yet the effect o...

The molecular mechanisms controlling human birth timing at term, or resulting in preterm birth, have been the focus of considerable investigation, but limited insights have been gained over the past 50 years. In part, these processes have remained elusive because of divergence in reproductive strategies and physiology shown by model organisms, maki...

This chapter first argues that both gene-centered explanatory models and developmental or systems-level explanatory models to causality are justified. Using simple insights from population genetics, it shows that gene-based models adequately capture situations where very similar organisms are compared, or where differences between closely related o...

The control of normal birth timing in mammals and the fundamental signals that initiate preterm birth in humans are critical areas of scientific investigation. Preterm birth is the leading cause of infant mortality throughout the world, and the single greatest challenge in women's and children's health today. Despite the recognised importance of th...

Preterm birth and its complications remain one of the most challenging problems in neonatology. Although preventative strategies to reduce preterm birth have been a longstanding goal, limited progress has been achieved in reducing its incidence. In part, the barriers to designing better interventions to prevent preterm birth have reflected our inco...

Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution...

Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the l...

Abstract Ontogenetic and static allometries describe how a character changes in size when the size of the organism changes during ontogeny and among individuals measured at the same developmental stage, respectively. Understanding the relationship between these two types of allometry is crucial to understanding the evolution of allometry and, more...

To explain the evolution of complex organisms by random mutation, drift, and selection is not a trivial task. This becomes obvious if we imagine an organism in which most genes affect most traits and all mutations are immediately expressed in the phenotype. Most of the mutations will be deleterious. Computer programmers experienced a similar proble...

Obesity, in addition to being associated with metabolic diseases, such as diabetes, has also been found to lower the risk of osteoporotic fractures. The relationship between obesity and bone trabecular structure is complex, involving responses to mechanical loading and the effects of adipocyte-derived hormones, both directly interacting with bone t...

Development and physiology translate genetic variation into phenotypic variation and determine the genotype-phenotype map, such as which gene affects which character (pleiotropy). Any genetic change in this mapping reflects a change in development. Here, we discuss evidence for variation in pleiotropy and propose the selection, pleiotropy and compe...

The mechanisms translating genetic to phenotypic variation determine the distribution of heritable phenotypic variance available to selection. Pleiotropy is an aspect of this structure that limits independent variation of characters. Modularization of pleiotropy has been suggested to promote evolvability by restricting genetic covariance among unre...

The genotype-phenotype (GP) map consists of developmental and physiological mechanisms mapping genetic onto phenotypic variation. It determines the distribution of heritable phenotypic variance on which selection can act. Comparative studies of morphology as well as of gene regulatory networks show that the GP map itself evolves, yet little is know...

A basic assumption of the Darwinian theory of evolution is that heritable variation arises randomly. In this context, randomness means that mutations arise irrespective of the current adaptive needs imposed by the environment. It is broadly accepted, however, that phenotypic variation is not uniformly distributed among phenotypic traits, some trait...

Directional epistasis describes a situation in which epistasis consistently increases or decreases the effect of allele substitutions, thereby affecting the amount of additive genetic variance available for selection in a given direction. This study applies a recent parameterization of directionality of epistasis to empirical data. Data stems from...

We previously mapped Adip1, an obesity quantitative trait locus (QTL), to the central portion of murine chromosome 1 containing the calpain-10 (Capn10) gene. Human studies have associated calpain-10 (CAPN10) variants with type 2 diabetes and various metabolic traits. We performed a quantitative hybrid complementation test (QHCT) to determine whethe...

Resumimos los primeros datos de radiotelemetría obtenidos para la subespecie siberiana Accipiter gentilis albidus. Un macho adulto fue seguido inmediatamente después de haber perdido su nidada ante un mamífero depredador en el verano de 2002. El seguimiento por medio de un transmisor de radio permitió obtener 103 ubicaciones del ave en siete días....

The potential and direction of phenotypic evolution is constrained by the distribution of genetic variation for the traits as described by the phenotypic (P) and genetic covariance matrices (G). The rank of the covariance matrix reflects the number of independent variational dimensions of the phenotype. Covariance matrices with less than full rank...