Biology subjects

Andirko, A.

Publications and source records attributed to Andirko, A..

7 recordsLinked to original sources

bioRxiv2021

Human-derived alleles in SOST and RUNX2 3'UTRs cause differential regulation in a bone cell-line model

The inquiry into the phenotypic features that set apart human species, such as a light, gracile skeleton and a rounded skull characteristic of Homo sapiens, can now benefit from the examination of ancient genomes. These have added a new layer of analysis allowing the identification of genetic differences between species like ours and our closest extinct relatives. Most of these genetic differences are non-coding changes with unknown functional consequences, and dissecting their putative regulatory effect remains challenging. Here we focus on the three prime untranslated regions (3UTR), known to play a critical role in messenger RNA regulation and a plausible locus for divergent regulation between Homo species. We report a set of genes with derived 3UTR changes in either the Homo sapiens or the Neanderthal/Denisovan lineages and experimentally evaluate the impact of 3UTR variants in four genes: E2F6, GLI3, RUNX2 and SOST. We performed a luciferase reporter assay in a bone cell-line model and found a statistically significant difference for the 3UTR variants of SOST (Homo sapiens-derived) and RUNX2 (Neanderthal/Denisovan-derived). The differential expression caused by these variants in our experimental model points to species differences in bone mineral density. Thus, this study adds insights into the functional effects of regulatory variants that emerged in recent human evolution.

evolutionary biology↗

bioRxiv2021

A distinct expression profile in the cerebellum and striatum for genes under selection within introgression deserts

Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of archaic haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, in particular the cerebellum, the striatum and the mediodorsal nucleus of the thalamus show the most divergent transcriptomic profiles when considering genes within large introgression deserts and under positive selection.

evolutionary biology↗

bioRxiv2021

Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution of Homo sapiens

As our knowledge about the history of the Homo sapiens lineage becomes increasingly complex, large-scale estimations of the time of emergence of derived variants become essential to be able to offer more precise answers to time-sensitive hypotheses concerning human evolution. Using an open repository of genetic variant age estimations recently made available, we offer here a temporal evaluation of various evolutionarily relevant datasets, such as Homo sapiens-specific variants, high-frequency variants found in genetic windows under positive selection, introgressed variants from extinct human species, as well as putative regulatory variants in various brain regions. We find a recurrent bimodal distribution of high-frequency variants, but also evidence for specific enrichments of gene categories in various time windows, which brings into prominence the 300-500k time slice. We also find evidence for very early mutations impacting the facial phenotype, and much more recent molecular events linked to specific brain regions such as the cerebellum or the precuneus. Additionally, we present a case study of an evolutionarily relevant gene, BAZ1B, and its targets, to emphasize the importance of applying temporal data to specific evolutionary questions. Overall, we present a unique resource that informs and complements our previous knowledge of Homo sapiens evolution using publicly available data, and reinforce the case for the mosaic, temporally very extended nature of the evolutionary trajectory of our species.

evolutionary biology↗

bioRxiv2020

An Agent-based model of the gradual emergence of modern linguistic complexity

A central question in the evolution of human language is whether it emerged as a result of one specific event or from a mosaic-like constellation of different phenomena and their interactions. Three potential processes have been identified by recent research as the potential primum mobile for the origins of modern linguistic complexity: Self-domestication, characterized by a reduction in reactive aggression and often associated with a gracilization of the face; changes in early brain development manifested by globularization of the skull; and demographic expansion of H. sapiens during the Middle Pleistocene. We developed an agent-based model to investigate how these three factors influence transmission of information within a population. Our model shows that there is an optimal degree of both hostility and mental capacity at which the amount of transmitted information is the largest. It also shows that linguistic communities formed within the population are strongest under circumstances where individuals have high levels of cognitive capacity available for information processing and there is at least a certain degree of hostility present. In contrast, we find no significant effects related to population size.

animal behavior and cognition↗

bioRxiv2019

Derived Homo sapiens cis-eQTL regulation: implications for brain evolution

The availability of high-coverage genomes of our extinct relatives, the Neanderthals and Denisovans, and the emergence of large, tissue-specific databases of modern human genetic variation, offer the possibility of probing the evolutionary trajectory of heterogenous structures of great interest, such as the brain. Using the GTEx cis-eQTL dataset and an extended catalog of Homo sapiens-specific alleles relative to Neanderthals and Denisovans, we generated a dataset of nearly fixed, Homo sapiens-derived alleles that affect the regulation of gene expression across 15 brain (and brain related) structures. The list of variants obtained reveals enrichments in regions of the modern human genome showing putative signals of positive selection relative to archaic humans, and bring out the highly derived status of the cerebellum. Additionally, we complement previous literature on the expression effects of ancestral alleles in the Homo sapiens brain by pointing at a downregulation bias caused by linkage disequilibrium.

genetics↗

bioRxiv2019

7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

Symmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face.\n\nOne Sentence SummaryBAZ1B dosage shapes the modern human face.

evolutionary biology↗

bioRxiv2018

Oxytocin and Vasopressin Receptor variants as a window onto the evolution of human prosociality

Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the full genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and that have associated literature. We performed variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency and selection analyses on data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, the OTR-rs6770632 was predicted to be the most functional. We found two sites where alleles (OTR: rs59190448 and rs237888)1 present only in modern humans and archaic humans are under positive selection in modern humans, with rs237888 predicted to be a highly functional site. We identified three sites of convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking very highly in terms of functionality and being under balancing selection in modern humans. Our findings shed light on evolutionary questions of modern human and hominid prosociality, as well as on similarities in the social behavior between modern humans and bonobos.

genetics↗