RT Journal Article
SR Electronic
T1 Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 816827
DO 10.1101/816827
A1 Abigail L. LaBella
A1 Abin Abraham
A1 Yakov Pichkar
A1 Sarah L. Fong
A1 Ge Zhang
A1 Louis J. Muglia
A1 Patrick Abbot
A1 Antonis Rokas
A1 John A. Capra
YR 2019
UL http://biorxiv.org/content/early/2019/10/25/816827.abstract
AB Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. However, there is no framework to comprehensively evaluate how these traits evolved or to explore the relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we develop an approach to test for signatures of diverse evolutionary forces, including multiple types of selection, and apply it to genomic 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 evolutionary sequence conservation (consistent with the action of negative selection), excess population differentiation (local adaptation), accelerated evolution (positive selection), and balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop hypotheses about how these genomic regions contribute to sPTB risk. In summary, we introduce an approach for inferring the spectrum of evolutionary forces acting on genomic regions associated with complex disorders. When applied to sPTB-associated genomic regions, this approach both improves our understanding of the potential roles of these regions in pathology and illuminates the mosaic nature of evolutionary forces acting on genomic regions associated with sPTB.