Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Abstract

35Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has 36 evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and 37 related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. 38 However, there is no framework to comprehensively evaluate how these traits evolved or to explore the 39 relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we 40develop an approach to test for signatures of diverse evolutionary forces, including multiple types of 41 selection, and apply it to genomic regions associated with spontaneous preterm birth (sPTB), a complex 42 disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary 43 signatures including evolutionary sequence conservation (consistent with the action of negative selection), 44 excess population differentiation (local adaptation), accelerated evolution (positive selection), and 45 balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse 46 functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop 47 54Mammalian pregnancy requires the coordination of multiple maternal and fetal tissues 1,2 and extensive 55 modulation of the maternal immune system so that the genetically distinct fetus is not immunologically 56 rejected 3 . Given this context, pregnancy-related phenotypes and disorders are likely to have experienced 57 diverse selective pressures. This is particularly likely on the human lineage where pregnancy has been 58 shaped by unique human adaptations such as bipedality and enlarged brain size 4-8 . One major disorder of 59 pregnancy is preterm birth (PTB), a complex multifactorial syndrome 9 that affects 10% of pregnancies in 60 the United States and more than 15 million pregnancies worldwide each year 10,11 . PTB leads to increased 61 infant mortality rates and significant short-and long-term morbidity [11][12][13][14] . Risk for PTB varies 62 substantially with race, environment, comorbidities, and genetic factors 15 . PTB is broadly classified into 63 iatrogenic PTB, when it is associated with medical conditions such as preeclampsia (PE) or intrauterine 64 growth restriction (IUGR), and spontaneous PTB (sPTB), which occurs in the absence of preexisting 65 medical conditions or is initiated by preterm premature rupture of membranes [16][17][18][19] . The biological 66 pathways contributing to sPTB remain poorly understood 9 , but diverse lines of evidence suggest that 67 maternal genetic variation is an important contributor 20-24 . 68The complexity of human pregnancy and association with unique human adaptations raise the hypothesis 69 that genetic variants associated with birth timing and sPTB have been shaped by diverse evolutionary 70 forces. Consistent with this hypothesis, several immune genes involved in pregnancy have signatures of 71 recent purifyin...

Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

“…Gene expression changes at the maternal-fetal interface underlie evolutionary differences in pregnancy ( Hou et al, 2012 ; Lynch et al, 2015 ; Armstrong et al, 2017 ), and thus likely also pathologies of pregnancy such as infertility, recurrent spontaneous abortion ( Kosova et al, 2015 ), preeclampsia ( Elliot, 2017 ; Arthur, 2018 ; Varas Enriquez et al, 2018 ), and preterm birth ( Plunkett et al, 2011 ; Swaggart et al, 2015 ; LaBella, 2019 ). Here, we assembled a collection of gene expression data from the pregnant/gravid maternal-fetal interface of tetrapods and used evolutionary methods to reconstruct gene expression changes during the origins of mammalian pregnancy.…”

Evolutionary transcriptomics implicatesHAND2in the origins of implantation and regulation of gestation length

“…Gene expression changes at the maternal-fetal interface underlie evolutionary differences in pregnancy (Hou et al ., 2012; Lynch et al ., 2015; Armstrong et al ., 2017), and thus likely also pathologies of pregnancy such as infertility, recurrent spontaneous abortion (Kosova et al ., 2015), preeclampsia (Elliot, 2017; Arthur et al ., 2018; Varas Enriquez, McKerracher and Elliot, 2018) and preterm birth (Plunkett et al ., 2011; Swaggart, Pavlicev and Muglia, 2015; LaBella et al ., 2019). Here, we assembled a collection of gene expression data from the pregnant/gravid maternal-fetal interface of tetrapods and used evolutionary methods to reconstruct gene expression changes during the origins of mammalian pregnancy.…”