This is the accepted manuscript version. It will be embargoed until 12 months after publication by RSC. The final version is available from RCS at http://rstb.royalsocietypublishing.org/content/370/1663/20140071.longHuman birth weight is subject to stabilizing selection. Large babies are at
risk of obstetric complications such as obstructed labour, which endangers
both mother and child. Small babies are also at risk with reduced survival.
Fetal growth requires remodeling of maternal spiral arteries to provide an
adequate maternal blood supply to the placenta. This arterial
transformation is achieved by placental trophoblast cells, which invade into
the uterine wall. Under invasion is associated with fetal growth restriction;
but if invasion is excessive large babies can result. A growing body of
evidence suggests that this process is controlled by interactions between KIR
receptors expressed on maternal uterine NK cells (uNK) and their
corresponding HLA-C ligands on invading trophoblast. Mothers with the KIR
AA genotype and a fetus with a paternal HLA-C2 allele tend to have small
babies, because this combination inhibits cytokine secretion by uNK.
Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more
likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases
secretion of cytokines that enhance trophoblast invasion. We conclude that
specific combinations of the highly polymorphic gene systems, KIR and HLAC,
contribute to successful reproduction by maintaining birth weight
between two extremes.This work was supported by
funding from the Wellcome Trust [090108/Z/09/Z], [085992/Z/08/Z] and
the British Heart Foundation [PG/09/077/27964]. This work was also
supported by a Frederick National Laboratory for Cancer Research Contract
[HHSN261200800001E] and by the Intramural Research Program of National
Institutes of Health, Frederick National Laboratory, Center for Cancer
Research. The authors also thank the Centre for Trophoblast Research,
Cambridge for generous support