Molecular, Evolutionary and Stem Cell Biology

A differentiated chimpanzee cortical neurosphere from induced pluripotent stem cells. Photo by Andrew Field.

Neurodevelopment

The cerebral cortex has expanded in size and complexity in primates. We are taking experimental and computational approaches to understand the molecular innovations that enabled primate-specific brain attributes. We establish cerebral cortex organoids from human, chimpanzee, orangutan, and rhesus pluripotent stem cells to gain insight into how genomic differences influence gene expression, brain development and susceptibility to disease.

Human specific segmental duplications are an important source of new DNA in our genome and many of these “Seg Dups” are recurrently deleted and/or further duplicated in patients with neurodevelopmental disorders. We recently discovered a new family of NOTCH-related genes (NOTCH2NLA, -B, -C) in a disease-associated Seg Dup on human chromosome 1 and showed that altering the gene dosage of NOTCH2NL affects the balance between neural stem cell proliferation and neurogenesis using cerebral organoids. Ongoing research is aimed at understanding the genetic diversity of NOTCH2NL alleles in the human population and their association with neurological disorders as well as mechanistic exploration of the role of NOTCH2NL in cortical neurogenesis, neuronal subtype specification and neuronal function using pluripotent stem cell derived brain organoids.

We have also used transcriptional profiling of human and ape cerebral cortex organoids to identify primate-specific long non-coding (lnc) RNA that show exquisite cell type specificity. Ongoing work is aimed at further characterizing these lncRNAs and exploring their use in non-invasive monitoring of cerebral organoid differentiation and function in close collaboration with other Braingeneers researchers.

 

 

Notch2NL on the SciShow


Notch2NL Graphical abstract (from Fiddes et al. 2018)

Key Publications

Structurally conserved primate LncRNAs are transiently expressed during human cortical differentiation and influence cell-type-specific genes
AR Field, FMJ Jacobs, IT Fiddes, APR Phillips, AM Reyes-Ortiz, E LaMontagne, L Whitehead, V Meng, JL Rosenkrantz, M Olsen, M Hauessler, S Katzman, SR Salama, D Haussler
Stem cell reports 12 (2), 245-257

Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis
IT Fiddes, GA Lodewijk, M Mooring, CM Bosworth, AD Ewing, et al.
Cell 173 (6), 1356-1369. e22

Funding

National Human Genome Research Institute (NHGRI), NIH

The National Institute of Mental Health (NMH), NIH

Simons Foundation Autism Research Initiative (SFARI)

Retrotransposons

Retrotransposons are the family of mobile elements that is most active in the primate lineage. Mobile elements, in general, are a major source of new DNA in genomes. In humans, almost half of our genome can be identified as the relics of

Cartoon of a KRAB Zinc Finger Protein inactivating a transposon

transposition events with the vast majority of these insertions resulting from retrotransposons.

Retrotransposons mobilize by first utilizing host transcription machinery to make an RNA copy of themselves, which subsequently gets reverse transcribed and inserted at a new site in the genome. Not surprisingly, a major mechanism to prevent new retrotransposition events is to inhibit retroelement (RTE) transcription. Several years ago we discovered that a large and rapidly evolving family of transcription repressor proteins, the KRAB Zinc Finger proteins (KZNFs), plays an important role in repressing RTE in early embryonic cells and that the co-evolution of RTEs and KZNFs drives increased genomic complexity.

Current projects are aimed at 1) Tracing the evolutionary history of KZNF genes in the primate lineage, taking advantage of recent high quality human and primate genome assemblies. 2) Tracing the co-evolution of specific classes of retroelements and the KZNFs that regulate them using human and great ape pluripotent stem cells. 3) Exploring the consequences of these arms races in early embryonic gene expression networks and early embryonic development.

YouTube video: Dr. Salama presents KZNF research results at the October 2020 Stem Cell Club

Key Publications

An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons

FMJ Jacobs, D Greenberg, N Nguyen, M Haeussler, AD Ewing, S Katzman, B Paten, SR Salama, David Haussler

Nature (2014) 516 (7530), 242-245

The UCSC Repeat Browser allows discovery and visualization of evolutionary conflict across repeat families

JD Fernandes, A Zamudio-Hurtado, H Clawson, WJ Kent, D Haussler, SR. Salama, M Haeussler 

Mobile DNA (2020) 11, 1-12

Funding

National Human Genome Research Institute (NHGRI), NIH