High altitude, natural selection, & birth weight: Is small good or bad

Fetal growth is slowed at high altitude (HA) and preeclampsia more common. Populations of multi-generational residence at HA show a decrease in fetal growth at high altitude, but the decrease is less than that seen in relative newcomers to HA. There is debate as to whether decreased birth weight at HA has been selected for or against. Previously, direct tests of the genetic adaptations in pregnancy to HA have been unavailable. We explored the relationship between genes that show evidence of natural selection and their effect on phenotype by (1) identifying hypoxia-related gene regions that showed evidence of natural selection through the analysis of genome-wide SNP microarray data, and (2) searching for association between genotypes at candidate loci, circulating gene product (protein) levels, uterine artery (UA) blood flow and other pregnancy phenotypes at HA. In 50 multi-generational HA Andeans compared to low-altitude control populations (Amerindians and Han Chinese), five hypoxia-related gene regions showed differential expression of alleles in Andeans. In 55 multi-generational HA pregnant Andeans, CDH1 gene region SNP genotypes were associated with UA blood flow. Soluble CDH (sCDH1) correlated with CDH1 genotype and also with UA blood flow. Additionally, AMPKa1 genotype was strongly associated with gestational age at birth and ARNT2 was associated with birth weight. In all cases, alleles more frequently found in Andeans were positively associated with UA blood flow, gestational age at birth, or birth weight, suggesting evolution at HA may have selected for increased birth weight, as opposed to "small-but-healthy" babies, in adapted populations.