Biology subjects

Köhler, K.

Publications and source records attributed to Köhler, K..

4 recordsLinked to original sources

bioRxiv2026

Accelerated Evolution of Context-Dependent Gene Expression in Primate Immune Cells

Regulatory variation is widely recognized as a driver of evolution within and between species, including in the primate lineage. Evidence for potentially adaptive regulatory evolution in primates comes from both sequence-based tests for selection and cross-species comparisons of gene expression. However, comparative studies of gene expression have tended to focus on baseline cellular states, despite growing evidence that context-dependent gene regulation is important. Here, we investigate the evolution of gene expression in lymphoblastoid cell lines (LCLs) from 6 primate lineages (humans, chimpanzees, bonobos, western gorillas, Sumatran orangutans, and rhesus macaques) using data from both control and 5 perturbed cellular conditions (n=22-25 individuals per condition). Analyzing baseline expression data, we find that genes involved in immunity often exhibit lineage-specific transcriptional shifts, and that these genes occur near regions with lineage-specific sequence acceleration and lineage-specific epigenomic states. However, the subset of genes that respond to in vitro perturbations have evolved at significantly higher rates than environmentally-insensitive genes, a finding we replicate in an independent four-species dataset of primary white blood cells (n=26). Together, our findings support the argument that focusing on baseline states alone provides a biased view of gene regulatory evolution, and suggest that studying gene regulation in dynamic contexts can enrich our understanding of primate evolution.

evolutionary biology↗

bioRxiv2021

An integrative skeletal and paleogenomic analysis of prehistoric stature variation suggests relatively reduced health for early European farmers

Human culture, biology, and health were shaped dramatically by the onset of agriculture ~12,000 years before present (BP). Subsistence shifts from hunting and gathering to agriculture are hypothesized to have resulted in increased individual fitness and population growth as evidenced by archaeological and population genomic data alongside a simultaneous decline in physiological health as inferred from paleopathological analyses and stature reconstructions of skeletal remains. A key component of the health decline inference is that relatively shorter statures observed for early farmers may (at least partly) reflect higher childhood disease burdens and poorer nutrition. However, while such stresses can indeed result in growth stunting, height is also highly heritable, and substantial inter-individual variation in the height genetic component within a population is typical. Moreover, extensive migration and gene flow were characteristics of multiple agricultural transitions worldwide. Here, we consider both osteological and ancient DNA data from the same prehistoric individuals to comprehensively study the trajectory of human stature variation as a proxy for health across a transition to agriculture. Specifically, we compared predicted genetic contributions to height from paleogenomic data and achieved adult osteological height estimated from long bone measurements on a per-individual basis for n=160 ancient Europeans from sites spanning the Upper Paleolithic to the Iron Age (~38,000-2,400 BP). We found that individuals from the Neolithic were shorter than expected (given their individual polygenic height scores) by an average of -4.47 cm relative to individuals from the Upper Paleolithic and Mesolithic (P=0.016). The average osteological vs. expected stature then increased relative to the Neolithic over the Copper (+2.67 cm, P=0.052), Bronze (+3.33 cm, P=0.032), and Iron Ages (+3.95 cm, P=0.094). These results were partly attenuated when we accounted for genome-wide genetic ancestry variation in our sample (which we note is partly duplicative with the individual polygenic score information). For example, in this secondary analysis Neolithic individuals were -3.48 cm shorter than expected on average relative to individuals from the Upper Paleolithic and Mesolithic (P=0.056). We also incorporated observations of paleopathological indicators of non-specific stress that can persist from childhood to adulthood in skeletal remains (linear enamel hypoplasia, cribra orbitalia, and porotic hyperostosis) into our model. Overall, our work highlights the potential of integrating disparate datasets to explore proxies of health in prehistory.

genomics↗

bioRxiv2020

A Minimally Destructive Protocol for DNA Extraction from Ancient Teeth

Ancient DNA sampling methods--although optimized for efficient DNA extraction--are destructive, relying on drilling or cutting and powdering (parts of) bones and teeth. As the field of ancient DNA has grown, so have concerns about the impact of destructive sampling of the skeletal remains from which ancient DNA is obtained. Due to a particularly high concentration of endogenous DNA, the cementum of tooth roots is often targeted for ancient DNA sampling, but standard destructive sampling methods often result in the loss of at least one entire root. Here, we present a minimally destructive method for extracting ancient DNA from dental cementum present on the surface of tooth roots. This method does not require destructive drilling or grinding, and, following extraction, the tooth remains safe to handle and suitable for most morphological studies, as well as other biochemical studies, such as radiocarbon dating. We extracted and sequenced ancient DNA from 30 teeth (and 9 corresponding petrous bones) using this minimally destructive extraction method in addition to a typical tooth sampling method. We find that the minimally destructive method can provide ancient DNA that is of comparable quality to extracts produced from teeth that have undergone destructive sampling processes. Further, we find that a rigorous cleaning of the tooth surface combining diluted bleach and UV light irradiation seems sufficient to minimize external contaminants usually removed through the physical removal of a superficial layer when sampling through regular powdering methods.

evolutionary biology↗

bioRxiv2018

Triple A patient cells suffering from mitotic defects fail to localize PGRMC1 to mitotic kinetochore fibers

HIGHLIGHT SUMMARYO_LIInvestigating cell division in human adrenal cells we show that proliferation is decreased upon overexpression of ALADIN, PGRMC1 or PGRMC2.\nC_LIO_LIIn immunofluorescence experiments using human adrenal cells and triple A patient fibroblasts we observed that during cell division PGRMC1 localizes to the microtubule kinetochore-fibers in metaphase and to the mid-body in telophase.\nC_LIO_LIDepletion of ALADIN results in mis-localization of Aurora A and PGRMC1 in metaphase cells of the human adrenal cell line and fibroblasts derived from patients with triple A syndrome.\nC_LIO_LIIn real time PCR using RNA of fibroblasts of triple A syndrome patients and healthy controls we measured an increased expression of PGRMC2 in cells with ALADIN mis-function compared to the control cells.\nC_LIO_LIWe hypothesize that a loss of the regulatory interaction between ALADIN and PGRMC2 leads to an over-regulation and over-expression of PGRMC2 and displaces PGRMC1 at the metaphase spindle. This diminishing of PGRMC1 concentration at kinetochore fibers may lead to mitotic errors and pro - liferation arrest.\nC_LI\n\nABSTRACTMembrane-associated progesterone receptors are restricted to the endoplasmic reticulum and are shown to regulate the activity of cytochrome P450 enzymes which are involved in steroidogenesis or drug detoxification. PGRMC1 and PGRMC2 belong to this group of microsomal receptors and are of interest due to their suspected role during cell cycle. PGRMC1 and PGRMC2 are thought to bind to each other thereby suppressing entry into mitosis. We could previously report that PGRMC2 interacts with the nucleoporin ALADIN which when mutated results in the autosomal recessive disorder triple A syndrome. ALADIN is a novel regulator of mitotic controller Aurora kinase A and depletion of this nucleoporin leads to microtubule instability. In the current study, we present that proliferation is decreased when ALADIN, PGRMC1 or PGRMC2 are over-expressed. Furthermore, we find that depletion of ALADIN results in mis-localization of Aurora kinase A and PGRMC1 in metaphase cells. Additionally, PGRMC2 is over-expressed in triple A patient fibroblasts. Our results emphasize the possibility that loss of the regulatory interaction between ALADIN and PGRMC2 gives rise to a depletion of PGRMC1 at kinetochore fibers and to mitotic errors. This observation may explain part of the symptoms seen in triple A syndrome patients.

cell biology↗