David Gokhman

🧵 Excited to share a new preprint from our lab looking into signals of disease-burden in aDNA (doi.org/10.1101/2025...)! It has long been speculated that transition to sedentary, agricultural and urbanized lifestyle increases disease burden, but can we see this in aDNA?

Overall, we suggest that substantially more phenotypic information can be inferred from genetic data than previously appreciated. Had a great time working on this with @gilig.bsky.social @shaicarmi.bsky.social and Keith Harris

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

This estimator can be applied to comparisons of individuals from the same family, same population, different populations, or even different species

Our method works even when genotype-to-phenotype information is limited. For example, we show that even in phenotypes where known SNPs explain only 3% of phenotypic variation, you can often predict with >90% accuracy who has the higher phenotypic value

Predicting the direction of phenotypic difference Nature Communications - Here authors reveal a method to predict key information on phenotypes - their direction. This is achievable even for phenotypes with incomplete genotype-to-phenotype...

Given two genomes, can you tell who’s taller or more prone to a disease? How confident can you be? A fresh take on phenotypic inference, now out:
rdcu.be/exW4f
See thread🧵👇:

For additional specimens we think likely belong to Denisovans, see Nadav Mishol's beautiful preprint, in collaboration with
@lirancarmel.bsky.social www.biorxiv.org/content/10.1...

Although a Denisovan pinky bone has been discovered, testing our pinky-related prediction also requires the proximal and intermediate phalanges. Once those are found, we’ll also be able to test whether Denisovan phalanges exhibit the predicted tapering from proximal to distal

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: www.biorxiv.org/content/10.1...

Interestingly, our Denisovan trait prediction accuracy now stands at 89% - matching the accuracy we estimated using Neanderthal and chimpanzee data. Always nice when the model does what it says on the tin.

Overall 25/28 of our predictions have been confirmed. Not too shabby for profiling an extinct species from DNA methylation maps!

6 years ago, we predicted what Denisovans probably looked like. Since then, every new Denisovan specimen💀 - Harbin, Penghu, Xiahe - matched it beautifully.
☑️ Xiahe: 4/4 features match the profile
☑️ Penghu: 5/6
☑️ and now: Harbin with 16/18!
See 🧵
pubmed.ncbi.nlm.nih.gov/31539495/

The proteome of the late Middle Pleistocene Harbin individual Denisovans are a hominin group primarily known through genomes or proteins, but the precise morphological features of Denisovans remain elusive due to the fragmentary nature of discovered fossils. Her...

Correct links here:
www.science.org/doi/10.1126/...
and
www.cell.com/cell/fulltex...

And the first genetic evidence supporting this was posted last year: www.biorxiv.org/content/10.1...

First genetic evidence that Harbin was likely a Denisovan was here: www.biorxiv.org/content/10.1...

We showed it first: www.biorxiv.org/content/10.1...

Last year, we posted a preprint providing the first genetic evidence that the Harbin skull likely belonged to a Denisovan: www.biorxiv.org/content/10.1... Today, DNA evidence provided the final proof: www-sciencedirect-com.ezproxy.weizmann.ac.il/science/arti...

It is! And yes, we’re going to have brain-related data soon and I’m super curious to see if the variants we report played a role in human brain evo too!

Find out about other potential Denisovan specimens here, in a beautiful work led by Nadav Mishol: www.biorxiv.org/content/10.1... @lirancarmel.bsky.social

A common mistake when evaluating the profile is normalizing features (e.g., by breadth). But since the profile includes independent predictions affecting length, height, and breadth, normalization cancels out key signals. Absolute values are the way to go here, and they align with our predictions.

Condyle is shorter but much broader, giving it a larger area than in humans or Neanderthals (see. Ishwarkumar et al. 2016). Symphyseal height is 31 mm in Penghu vs. 32 mm in humans.

Technical details: anterior width (I1–I2 alveolar length) is 13 mm in Penghu vs. 11 mm median in modern humans. Prognathism (superior mandibular length) is 104 mm vs. 101 mm. Dental arch wasn’t directly measured, but Penghu is broader with a higher length/breadth ratio, indicating greater length.

Compared to Neanderthals, we predicted a longer dental arch and a larger condyle. Except for mandibular height, all check out!

Just like the Xiahe jaw, most of our Denisovan predictions hold up in Penghu—5 out of 6 anatomical predictions matched! 🦴✨ Compared to modern humans, Denisovans were predicted to have a wider anterior mandible, a more prognathic and taller mandible, a longer dental arch, and a larger condyle.

Super exciting to see the Penghu jaw confirmed as Denisovan— its features line up beautifully with what we predicted Denisovan mandibles to look like! More in the thread 🧵 pubmed.ncbi.nlm.nih.gov/31539495/

A structured coalescent model reveals deep ancestral structure shared by all modern humans - Nature Genetics The cobraa model extends the pairwise sequentially Markovian coalescent to identify structured population history by examination of the model transition matrix. Applied to human polymorphism data, cob...

Fascinating, really thought-provoking work by Trevor Cousins, @aylwyn-scally.bsky.social and Richard Durbin, now out in @naturegenet.bsky.social 🧪🧬
Deep ancestral structure shared by all modern humans
www.nature.com/articles/s41...

Haha you’re right! Old habits…

Interested in discovering the genetic changes that made us human? Our lab is looking for students and postdocs! 👩‍🔬👨‍🔬 gokhmanlab.com
please RT!