Zoonomia Papers Released in Science
Members of the Reilly Lab were part of three papers being released today in a special issue of Science.
The Zoonomia Project is an international collaboration sequencing the genomes of hundreds of mammals. This database will be used to understand the genomic basis of specialized traits in mammals, inform our understand of human disease, and aid in genetic. conservation effort . The data is all freely available here.
In flagship paper 1, “Evolutionary constraint and innovation across hundreds of placental mammals”, the sequencing effort is introduced, along the vast technological effort needed to build evolutionary trees of this many species.
The second flagship, “Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease”, dives into how we can use knowledge of which bases have been unchanged over millions of years of evolution, to identify human genetic changes linked to health and disease.
Human Conserved Deletions
In a paper led by the Reilly Lab, we sought to uncover "The functional and evolutionary impacts of human-specific deletions in conserved elements”. Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits.
We identified 10,032 hCONDELs by examining conserved regions across diverse vertebrate genomes and overlapping with confidently annotated, human-specific fixed deletions. We found that these hCONDELs are enriched to delete conserved sequences originating from stem amniotes. Overlap with transcriptional, epigenomic, and phenotypic datasets all implicate neuronal and cognitive functional impacts. We characterized these hCONDELs using massively parallel reporter assays (MPRA) in six different human cell types, including induced pluripotent stem cell–derived neural progenitor cells. We found that 800 hCONDELs displayed species-specific regulatory effect effects. Although many hCONDELs perturb transcription factor binding sites in active enhancers, we estimate that 30% create or improve binding sites, including activators and repressors.
Some hCONDELs exhibit molecular functions that affect core neurodevelopmental genes. One hCONDEL removes a single base in an active enhancer in the neurogenesis gene HDAC5, and another deletes six bases in an alternative promoter of PPP2CA, a gene that regulates neuronal signaling. We deeply characterized an hCONDEL in a putative regulatory element of LOXL2, a gene that controls neuronal differentiation. Using genome engineering to reintroduce the conserved chimpanzee sequence into human cells, we confirmed that the human deletion alters transcriptional output of LOXL2. Single-cell RNA sequencing of these cells uncovered a cascade of myelination and synaptic function related transcriptional changes induced by the hCONDEL.
Our identification of hundreds of hCONDELs with functional impacts reveals new molecular changes that may have shaped our unique biological lineage. These hCONDELs display predicted functions in a variety of biological systems but are especially enriched for function in neuronal tissue. Many hCONDELs induced gains of regulatory activity, a surprising discovery given that deletions of conserved bases are commonly thought to abrogate function. Our work provides a paradigm for the characterization of nucleotide changes shaping species.
