Duo Xu

Archaic hominin introgression in Africa contributes to functional salivary MUC7 genetic variation

Abstract One of the most abundant proteins in human saliva, mucin-7, is encoded by the MUC7 gene, which harbors copy number variable subexonic repeats (PTS-repeats) that affect the size and glycosylation potential of this protein. We recently documented the adaptive evolution of MUC7 subexonic copy number variation among primates. Yet, the evolution of MUC7 genetic variation in humans remained unexplored. Here, we found that PTS-repeat copy number variation has evolved recurrently in the human lineage, thereby generating multiple haplotypic backgrounds carrying five or six PTS-repeat copy number alleles. Contrary to previous studies, we found no associations between the copy number of PTS-repeats and protection against asthma. Instead, we revealed a significant association of MUC7 haplotypic variation with the composition of the oral microbiome. Furthermore, based on in-depth simulations, we conclude that a divergent MUC7 haplotype likely originated in an unknown African hominin population and introgressed into ancestors of modern Africans.

Atopic Dermatitis Susceptibility Variants in Filaggrin Hitchhike Hornerin Selective Sweep

Human skin has evolved rapidly, leaving evolutionary signatures in the genome. The filaggrin (FLG) gene is widely studied for its skin-barrier function in humans. The extensive genetic variation in this gene, especially common loss-of-function (LoF) mutations, has been established as primary risk factors for atopic dermatitis. To investigate the evolution of this gene, we analyzed 2,504 human genomes and genotyped the copy number variation of filaggrin repeats within FLG in 126 individuals from diverse ancestral backgrounds. We were unable to replicate a recent study claiming that LoF of FLG is adaptive in northern latitudes with lower ultraviolet light exposure. Instead, we present multiple lines of evidence suggesting that FLG genetic variation, including LoF variants, have little or no effect on fitness in modern humans. Haplotype-level scrutinization of the locus revealed signatures of a recent selective sweep in Asia, which increased the allele frequency of a haplotype group (Huxian haplogroup) in Asian populations. Functionally, we found that the Huxian haplogroup carries dozens of functional variants in FLG and hornerin (HRNR) genes, including those that are associated with atopic dermatitis susceptibility, HRNR expression levels and microbiome diversity on the skin. Our results suggest that the target of the adaptive sweep is HRNR gene function, and the functional FLG variants that involve susceptibility to atopic dermatitis, seem to hitchhike the selective sweep on HRNR. Our study presents a novel case of a locus that harbors clinically relevant common genetic variation with complex evolutionary trajectories.

The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence

BackgroundA common, 32kb deletion of LCE3B and LCE3C genes is strongly associated with psoriasis. We recently found that this deletion is ancient, predating Human-Denisovan divergence. However, it was not clear why negative selection has not removed this deletion from the population.ResultsHere, we show that the haplotype block that harbors the deletion (i) retains high allele frequency among extant and ancient human populations; (ii) harbors unusually high nucleotide variation (π, P < 4.1 × 10−3); (iii) contains an excess of intermediate frequency variants (Tajima’s D, P < 3.9 × 10−3); and (iv) has an unusually long time to coalescence to the most recent common ancestor (TSel, 0.1 quantile).ConclusionsOur results are most parsimonious with the scenario where the LCE3BC deletion has evolved under balancing selection in humans. More broadly, this is consistent with the hypothesis that a balance between autoimmunity and natural vaccination through increased exposure to pathogens maintains this deletion in humans.

VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences

BackgroundConstructing alignments and phylogenies for a given locus from large genome sequencing studies with relevant outgroups allow novel evolutionary and anthropological insights. However, no user-friendly tool has been developed to integrate thousands of recently available and anthropologically relevant genome sequences to construct complete sequence alignments and phylogenies.ResultsHere, we provide VCFtoTree, a user friendly tool with a graphical user interface that directly accesses online databases to download, parse and analyze genome variation data for regions of interest. Our pipeline combines popular sequence datasets and tree building algorithms with custom data parsing to generate accurate alignments and phylogenies using all the individuals from the 1000 Genomes Project, Neanderthal and Denisovan genomes, as well as reference genomes of Chimpanzee and Rhesus Macaque. It can also be applied to other phased human genomes, as well as genomes from other species. The output of our pipeline includes an alignment in FASTA format and a tree file in newick format.ConclusionVCFtoTree fulfills the increasing demand for constructing alignments and phylogenies for a given loci from thousands of available genomes. Our software provides a user friendly interface for a wider audience without prerequisite knowledge in programming. VCFtoTree can be accessed from https://github.com/duoduoo/VCFtoTree_3.0.0.

Structural Variants in Ancient Genomes

The last decade has witnessed a myriad of advancements in the field of genomics, drastically changing our understanding of how genomes evolve; how genetic variation is maintained, gained, and lost; and how this variation affects gene function. In our opinion, the most relevant conceptual development has to be the renewed appreciation of the impact of genomic structural variation within species and across different species. In parallel, our newly gained ability to sequence the genomes collected from ancient populations has revolutionized how we conduct population and evolutionary genetics analyses. Combining these two exciting developments, we argue that studying the structural variation in ancient genomes will open new doors to previously unexplored areas of mammalian genome evolution. In this review, we summarize some of the recent developments in this field, most of which comes from studies in humans, and give an example where we determined the Neanderthal origins of a polymorphic gene deletion in humans combining information from modern and ancient genomes.