Immune Regulation in Eutherian Pregnancy: Live Birth Coevolved with Novel Immune Genes and Gene Regulation.

Novel regulatory elements that enabled expression of pre-existing immune genes in reproductive tissues and novel immune genes with pregnancy-specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade-offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade-offs) played a pivotal role in refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal-fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus.

Signatures of Recent Positive Selection in Enhancers Across 41 Human Tissues.

Evolutionary changes in enhancers are widely associated with variation in human traits and diseases. However, studies comprehensively quantifying levels of selection on enhancers at multiple evolutionary periods during recent human evolution and how enhancer evolution varies across human tissues are lacking. To address these questions, we integrated a dataset of 41,561 transcribed enhancers active in 41 different human tissues (FANTOM Consortium) with whole genome sequences of 1,668 individuals from the African, Asian, and European populations (1000 Genomes Project). Our analyses based on four different metrics (Tajima's D, FST, H12, nSL) showed that ∼5.90% of enhancers showed evidence of recent positive selection and that genes associated with enhancers under very recent positive selection are enriched for diverse immune-related functions. The distributions of these metrics for brain and testis enhancers were often statistically significantly different and in the direction suggestive of less positive selection compared to those of other tissues; the same was true for brain and testis enhancers that are tissue-specific compared to those that are tissue-broad and for testis enhancers associated with tissue-enriched and non-tissue-enriched genes. These differences varied considerably across metrics and tissues and were generally in the form of changes in distributions' shapes rather than shifts in their values. Collectively, these results suggest that many human enhancers experienced recent positive selection throughout multiple time periods in human evolutionary history, that this selection occurred in a tissue-dependent and immune-related functional context, and that much like the evolution of their protein-coding gene counterparts, the evolution of brain and testis enhancers has been markedly different from that of enhancers in other tissues.

The Impact of Natural Selection on the Evolution and Function of Placentally Expressed Galectins.

Immunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal-fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins, both across mammals and within humans, we conducted a series of between- and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage- and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.

Examination of Signatures of Recent Positive Selection on Genes Involved in Human Sialic Acid Biology.

Sialic acids are nine carbon sugars ubiquitously found on the surfaces of vertebrate cells and are involved in various immune response-related processes. In humans, at least 58 genes spanning diverse functions, from biosynthesis and activation to recycling and degradation, are involved in sialic acid biology. Because of their role in immunity, sialic acid biology genes have been hypothesized to exhibit elevated rates of evolutionary change. Consistent with this hypothesis, several genes involved in sialic acid biology have experienced higher rates of non-synonymous substitutions in the human lineage than their counterparts in other great apes, perhaps in response to ancient pathogens that infected hominins millions of years ago (paleopathogens). To test whether sialic acid biology genes have also experienced more recent positive selection during the evolution of the modern human lineage, reflecting adaptation to contemporary cosmopolitan or geographically-restricted pathogens, we examined whether their protein-coding regions showed evidence of recent hard and soft selective sweeps. This examination involved the calculation of four measures that quantify changes in allele frequency spectra, extent of population differentiation, and haplotype homozygosity caused by recent hard and soft selective sweeps for 55 sialic acid biology genes using publicly available whole genome sequencing data from 1,668 humans from three ethnic groups. To disentangle evidence for selection from confounding demographic effects, we compared the observed patterns in sialic acid biology genes to simulated sequences of the same length under a model of neutral evolution that takes into account human demographic history. We found that the patterns of genetic variation of most sialic acid biology genes did not significantly deviate from neutral expectations and were not significantly different among genes belonging to different functional categories. Those few sialic acid biology genes that significantly deviated from neutrality either experienced soft sweeps or population-specific hard sweeps. Interestingly, while most hard sweeps occurred on genes involved in sialic acid recognition, most soft sweeps involved genes associated with recycling, degradation and activation, transport, and transfer functions. We propose that the lack of signatures of recent positive selection for the majority of the sialic acid biology genes is consistent with the view that these genes regulate immune responses against ancient rather than contemporary cosmopolitan or geographically restricted pathogens.