Human preterm birth (PTB), a multifactorial syndrome affecting offspring born before 37 completed weeks of gestation, is the leading cause of newborn death worldwide. Remarkably, the degree to which early parturition contributes to mortality in other placental mammals remains unclear. To gain insights on whether PTB is a human-specific syndrome, we examined within- and between-species variation in gestation length across placental mammals and the impact of early parturition on offspring fitness. Within species, gestation length is normally distributed, and all species appear to occasionally give birth before the ‘optimal’ time. Furthermore, human gestation length, like that of many mammalian species, scales proportionally to body mass, suggesting that this trait, like many others, is constrained by body size. Premature humans suffer from numerous cognitive impairments, but little is known of cognitive impairments in other placental mammals. Human gestation differs in the timing of the ‘brain growth spurt’, where unlike many mammals, including closely related primates, the trajectory of human brain growth directly overlaps with the parturition time window. Thus, although all mammals experience early parturition, the fitness costs imposed by the cognitive impairments may be unique to our species. Describing PTB broadly in mammals opens avenues for comparative studies on the physiological and genetic regulators of birth timing as well as the development of new mammalian models of the disease.
Healthy pregnancy depends on proper placentation—including proliferation, differentiation, and invasion of trophoblast cells—which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of Inverted formin 2 (INF2) alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of Inf2 in mice recapitulates maternal and fetal phenotypes of placental insufficiency. Inf2−/− dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. Inf2−/− fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of Inf2 increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for INF2 in trophoblast invasion—a necessary process for placentation—representing a possible future target for improving placentation and fetal outcomes.
Background and objectives The diversity of eutherian reproductive strategies has led to variation in many traits, such as number of offspring, age of reproductive maturity and gestation length. While reproductive trait variation has been extensively investigated and is well established in mammals, the genetic loci contributing to this variation remain largely unknown. The domestic dog, Canis lupus familiaris is a powerful model for studies of the genetics of inherited disease due to its unique history of domestication. To gain insight into the genetic basis of reproductive traits across domestic dog breeds, we collected phenotypic data for four traits, cesarean section rate, litter size, stillbirth rate and gestation length, from primary literature and breeders' handbooks. Methodology By matching our phenotypic data to genomic data from the Cornell Veterinary Biobank, we performed genome-wide association analyses for these four reproductive traits, using body mass and kinship among breeds as covariates. Results We identified 12 genome-wide significant associations between these traits and genetic loci, including variants near CACNA2D3 with gestation length, MSRB3 and MSANTD1 with litter size, SMOC2 with cesarean section rate and UFM1 with stillbirth rate. A few of these loci, such as CACNA2D3 and MSRB3 , have been previously implicated in human reproductive pathologies, whereas others have been associated with domestication-related traits, including brachycephaly ( SMOC2 ) and coat curl ( KRT71 ). Conclusions and implications We hypothesize that the artificial selection that gave rise to dog breeds also influenced the observed variation in their reproductive traits. Overall, our work establishes the domestic dog as a system for studying the genetics of reproductive biology and disease. LAY SUMMARY The genetic contributors to variation in mammalian reproductive traits remain largely unknown. We took advantage of the domestic dog, a powerful model system, to test for associations between genome-wide variants and four reproductive traits (cesarean section rate, litter size, stillbirth rate and gestation length) that vary extensively across breeds. We identified associations at a dozen loci, including ones previously associated with domestication-related traits, suggesting that selection on dog breeds also influenced their reproductive traits.
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