Currently, there is no comprehensive framework to evaluate the evolutionary forces acting on genomic regions associated with human complex traits and contextualize the relationship between evolution and molecular function. Here, we develop an approach to test for signatures of diverse evolutionary forces on trait-associated genomic regions. We apply our method to regions associated with spontaneous preterm birth (sPTB), a complex disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary signatures including conservation, excess population differentiation, accelerated evolution, and balanced polymorphism. Furthermore, we integrate evolutionary context with molecular evidence to hypothesize how these regions contribute to sPTB risk. Finally, we observe enrichment in signatures of diverse evolutionary forces in sPTB-associated regions compared to genomic background. By quantifying multiple evolutionary forces acting on sPTB-associated regions, our approach improves understanding of both functional roles and the mosaic of evolutionary forces acting on loci. Our work provides a blueprint for investigating evolutionary pressures on complex traits.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We further find significantly higher language transmission rates for matrilineal groups as compared to patrilineal. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

No 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...

Objectives: Genes and languages both contain signatures of human evolution, population movement, and demographic history. Cultural traits like language are transmitted by interactions between people, and these traits influence how people interact. In particular, if groups of people differentiate each other based on some qualities of their cultures, and if these qualities are passed to the next generation, then this differentiation can result in barriers to gene flow. Previous work finds such barriers to gene flow between groups that speak different languages, and we explore this phenomenon further: can more subtle cultural differences also produce genetic structure in a population? We focus on whether subtle, dialect-level linguistic differences in England have influenced genetic population structure, likely by affecting mating preferences. Materials and Methods:We analyze spatially dense linguistic and genetic data-both of which independently contain spatially structured variation in England-to examine whether the cultural differences represented by variation in English phonology colocalize with higher genetic rates of change.Results: We find that genetic variation and dialect markers have similar spatial distributions on a country-wide scale, and that throughout England, linguistic boundaries colocalize with the boundaries of genetic clusters found using fineSTRUCTURE.Discussion: This gene-language covariation, in the absence of geographic barriers that could coordinate cultural and genetic differentiation, suggests that similar social forces influenced both dialect boundaries and the genetic population structure of England.