Project description:The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1,791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.
Project description:The evolution of human bipedalism exposed the knee to unique biomechanical challenges, requiring changes in knee anatomy giving rise to the modern-day configuration. In order to better understand the relationship between derived knee morphology and the genetic factors associated with osteoarthritis risk, we performed epigenetic profiling of murine forelimb/hindlimb growth plates to identify regulatory elements shaping formation of specific knee structures, identifying signals of ancient positive selection upon which more recent genetic drift overlaps risk-associated loci. Our functional analyses of an osteoarthritis-risk variant within a reproducibly-associated locus establishes a novel model for studying this degenerative disease.
Project description:Regulatory changes are broadly accepted as key drivers of phenotypic divergence. However, identifying regulatory changes that underlie human-specific traits has proven very challenging. Here, we use 63 DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes affecting the face and vocal tract went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-affecting genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract
Project description:Here we report the first recovery, sequencing, and identification of fossil biomineral proteins from a Pleistocene invertebrate. Fossils of the Caribbean stony coral Orbicella annularis retain total hydrolyzable amino acids of a similar composition to extracts from modern O. annularis skeletons and ~10% of the modern skeletal proteome was sequenced by LC-MS/MS over multiple trials in the best-preserved fossil coral specimen. The data are rich in acidic amino acids such as aspartate and glutamate typical of skeletal proteins, and one of the four sequenced fossil proteins, a highly acidic protein, has been previously characterized in modern coral skeletons. A combination of degradation, or amino acid racemization inhibition of trypsin digestion, appears to limit greater recovery. Nevertheless, our workflow determines optimal samples for effective sequencing of fossil coral proteins, allowing comparison of modern and fossil invertebrate protein sequences, and will likely lead to further improvements of the methods. Sequencing of endogenous organic molecules in fossil biominerals provides an ancient record of composition, potentially clarifying evolutionary changes and biotic responses to paleoenvironments.