INTERSPECIES ORGANOIDS REVEAL HUMAN-SPECIFIC MOLECULAR FEATURES OF DOPAMINERGIC NEURON DEVELOPMENT AND VULNERABILITY.

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release.

Mapping - and -regulatory target genes of human-specific deletions.

Deletion of functional sequence is predicted to represent a fundamental mechanism of molecular evolution. Comparative genetic studies of primates have identified thousands of human-specific deletions (hDels), and the -regulatory potential of short (≤31 base pairs) hDels has been assessed using reporter assays. However, how structural variant-sized (≥50 base pairs) hDels influence molecular and cellular processes in their native genomic contexts remains unexplored.

Comparative landscape of genetic dependencies in human and chimpanzee stem cells.

Comparative studies of great apes provide a window into our evolutionary past, but the extent and identity of cellular differences that emerged during hominin evolution remain largely unexplored. We established a comparative loss-of-function approach to evaluate whether human cells exhibit distinct genetic dependencies. By performing genome-wide CRISPR interference screens in human and chimpanzee pluripotent stem cells, we identified 75 genes with species-specific effects on cellular proliferation.

Comparative landscape of genetic dependencies in human and chimpanzee stem cells.

Comparative studies of great apes provide a window into our evolutionary past, but the extent and identity of cellular differences that emerged during hominin evolution remain largely unexplored. We established a comparative loss-of-function approach to evaluate whether changes in human cells alter requirements for essential genes. By performing genome-wide CRISPR interference screens in human and chimpanzee pluripotent stem cells, we identified 75 genes with species-specific effects on cellular proliferation.

Rethinking nomenclature for interspecies cell fusions.

Cell fusions have a long history of supporting biomedical research. These experimental models, historically referred to as 'somatic cell hybrids', involve combining the plasma membranes of two cells and merging their nuclei within a single cytoplasm. Cell fusion studies involving human and chimpanzee pluripotent stem cells, rather than somatic cells, highlight the need for responsible communication and a revised nomenclature.

An ancestral recombination graph of human, Neanderthal, and Denisovan genomes.

Many humans carry genes from Neanderthals, a legacy of past admixture. Existing methods detect this archaic hominin ancestry within human genomes using patterns of linkage disequilibrium or direct comparison to Neanderthal genomes. Each of these methods is limited in sensitivity and scalability.

A novel NGS library preparation method to characterize native termini of fragmented DNA.

Biological and chemical DNA fragmentation generates DNA molecules with a variety of termini, including blunt ends and single-stranded overhangs. We have developed a Next Generation Sequencing (NGS) assay, XACTLY, to interrogate the termini of fragmented DNA, information traditionally lost in standard NGS library preparation methods. Here we describe the XACTLY method, showcase its sensitivity and specificity, and demonstrate its utility in in vitro experiments.

AD-LIBS: inferring ancestry across hybrid genomes using low-coverage sequence data.

Background: Inferring the ancestry of each region of admixed individuals' genomes is useful in studies ranging from disease gene mapping to speciation genetics. Current methods require high-coverage genotype data and phased reference panels, and are therefore inappropriate for many data sets. We present a software application, AD-LIBS, that uses a hidden Markov model to infer ancestry across hybrid genomes without requiring variant calling or phasing.

Detecting hybridization using ancient DNA.

It is well established that related species hybridize and that this can have varied but significant effects on speciation and environmental adaptation. It should therefore come as no surprise that hybridization is not limited to species that are alive today. In the last several decades, advances in technologies for recovering and sequencing DNA from fossil remains have enabled the assembly of high-coverage genome sequences for a growing diversity of organisms, including many that are extinct.