Asst Prof @WeizmannScience. Studying how gene regulation has shaped human evolution. Especially fond of Neanderthals and Denisovans. david-gokhman.bsky.social
Israel
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And for more on the genetics of skeletal evolution, check out the wonderful recent work from the Capellini
lab lead by Alexander Okamoto pubmed.ncbi.nlm.nih.gov/4211…
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Co-led with the wonderful @TakaInoue5 , and spearheaded by the super talented Yizhi Yan (experiments) and
@nadavmishol
(analyses), together with a fantastic team of collaborators.
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This leaves some fascinating questions: why would such a costly change evolve instead of being purged? Was there an evolutionary trade-off? And what did this shift do in other organs where GAGs are important (brain, skin)?
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Our results suggest that all humans begin from a GAG-poor baseline that predisposes our joints to degeneration, on top of which aging, injury, and other risk factors act.
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This has a striking connection to disease. GAG loss is a hallmark of degenerative joint diseases, which are unusually common in humans. Remarkably, the evolutionary reduction we find is ~2x larger than the GAG depletion measured between diseased and healthy humans.
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So we measured them in tissue: 139 cartilage samples from 42 humans and 7 great apes, across 8 joint types. The result was surprising: human cartilage has lost ~2/3 of its GAG content.
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Why GAGs matter: after collagen, they are the most abundant biomolecule in cartilage. Their dense negative charge draws in water, giving joints their compressive resilience. They are also key regulators of skeletal development.
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Both methods converged on the same signal: extensive rewiring of our extracellular matrix, and specifically a coordinated suppression of glycosaminoglycan (GAG) biosynthesis, carrying strong signatures of selection.
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The hybrids tell us which genes changed. The MPRA tells us which variants cause it. Together, they turn 0.6M noncoding changes into a functional atlas of human regulatory evolution.
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Then, the human-gorilla hybrids let us determine which changes occurred specifically along the human lineage.
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Why make human–chimp hybrid cells? Gene expression differs for many reasons. But, in a hybrid cell, the human and chimp share one nucleus and one cellular environment. Any difference between the alleles is therefore genetic.
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We combined two powerful approaches: human–ape hybrid cells, and a systematic functional screen of all ~0.6M human-specific variants. Together, they let us study human evolution from both sides: gene expression and the DNA changes driving it.
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Humans are far more prone to degenerative skeletal diseases than other apes. Our new @Nature paper uncovers the genetic changes that shaped our skeleton and uncovers a major clue to why it is so vulnerable to degeneration.🧵👇
nature.com/articles/s41586-0…
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Such a fantastic resource by @MKuhlwilm's lab. We’re using this catalog in half our projects
nature.com/articles/s41597-0…
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It was a true pleasure to work on this with @nadavmishol , @lirancarmel , Gadi Herzlinger, Uzy Smilansky, and Yoel Rak.
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Our approach was based on gene regulatory phenotyping, which predicts the direction, rather than magnitude, of phenotypic difference - a much more attainable goal. If you're interested in why and how this approach works, see: nature.com/articles/s41467-0…
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Denisovans or their close relatives identified in the fossil record using a gene regulatory phenotyping method. Now out:
pnas.org/doi/10.1073/pnas.25…
ALT Credit: Maayan Harel
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Overall, we suggest that substantially more phenotypic information can be inferred from genetic data than previously appreciated @GiliGreenbaum @ShaiCarmi and Keith Harris
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Importantly, unlike quantitative phenotypic predictions (e.g., based on polygenic scores), we show that our qualitative approach circumvents one of the biggest problems in population genetics – the limited transferability of genotype-phenotype association data across populations
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