Sagiv Shifman

Impact of intermittent lead exposure on hominid brain evolution Lead exposure, as influenced by NOVA1 expression, affected brain function in multiple hominid species.

“NOVA1 is a gene distinguishing modern humans from extinct hominids but evolutionary pressures that selected the modern allele remain elusive...Lead exposure on human brain organoids carrying the archaic NOVA1 variant disrupts FOXP2 expression, a gene crucial for human speech/language abilities.”🤔🧪

Beneath the surface of the sum When genetic interactions matter and when they don't

I wrote about gene-gene interactions (epistasis) and the implications for heritability, trait definitions, natural selection, and therapeutic interventions. Biology is clearly full of causal interactions, so why don't we see them in the data? A 🧵:

A brain-wide map of neural activity during complex behaviour - Nature The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task i...

The two key studies of the International Brain Laboratory @intlbrainlab.bsky.social are out today!

A brain-wide map of neural activity during complex behaviour
www.nature.com/articles/s41...

Brain-wide representations of prior information in mouse decision-making
www.nature.com/articles/s41...

A brain-wide map of neural activity during complex behaviour - Nature The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task i...

Extraordinary resource! "Comprehensive recordings from 621,733 neurons in 297 brain areas of 139 mice (12 labs) performing a decision-making task with sensory, motor & cognitive components: a public dataset to understand how computations distributed across & within brain areas drive behaviour."👇🧪

FOXP genes regulate Purkinje cell diversity and cerebellar morphogenesis - Nature Neuroscience The Li lab mapped molecularly distinct Purkinje cell (PC) subtypes in 3D and linked them to adult cerebellar architecture. They found that Foxp1/Foxp2 are essential for PC diversity and that Foxp1+ PC...

FOXP genes regulate Purkinje cell diversity and cerebellar morphogenesis

@nagham-farah.bsky.social

www.nature.com/articles/s41...

Selective interaction of the protein SMCHD1 with specific chromatin regions is governed by the loading factor LRIF1 and SMCHD1 ATPase activity The chromosomal protein SMCHD1 is a GHKL ATPase that plays important roles in epigenetic silencing, including on the inactive X chromosome (Xi) and at the D4Z4 macrosatellite linked to regulation of D...

Fresh preprint by @flavia-con.bsky.social from our lab uncovers how SMCHD1 finds & binds chromatin using live-cell single-molecule imaging🔬

She reveals how SMCHD1 dynamically engages chromatin, including the inactive X chromosome, to maintain gene silencing.

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

Focus on single gene effects limits discovery and interpretation of complex trait-associated variants Standard QTL mapping approaches consider variant effects on a single gene at a time, despite abundant evidence for allelic pleiotropy, where a single variant can affect multiple genes simultaneously. ...

“Focus on single gene effects limits discovery and interpretation of
complex trait-associated variants” Very interesting preprint by Kathryn Lawrence @tamigj.bsky.social @sbmontgom.bsky.social
good arguments to move beyond single-gene-at-a-time approaches 🧪🧬
www.biorxiv.org/content/10.1...

Role of X chromosome and dosage-compensation mechanisms in complex trait genetics We show that the X chromosome, understudied in genome-wide association studies, contributes to complex traits in a manner shaped by dosage-compensation mechanisms. We find near-full X inactivation bal...

Role of X chromosome and dosage-compensation mechanisms in complex trait genetics
www.cell.com/ajhg/fulltex...

Delighted to have our work on Polygenic Modifiers of #TelomereBiologyDisorders, led by Michael Poeschla, @sashagusevposts.bsky.social, @mitchiela.bsky.social, @sharonsavage.bsky.social, @tummalalab.bsky.social, + co, published in @jclinical-invest.bsky.social today: www.jci.org/articles/vie...

Maternal iron deficiency causes male-to-female sex reversal in mouse embryos - Nature Iron-deficient conditions in pregnant mice can cause XY mouse embryos to develop female rather than male genitalia, revealing that iron metabolism has a role in determining male sex in mice.

One of the coolest papers in the field of sex determination!

It is the first evidence that environmental aspects can affect mammalian sex determination!!

www.nature.com/articles/s41...

This seems to argue against the notion that girls are under-diagnosed because they express autistic symptoms differently, favoring a real sex difference in prevalence instead

Large-scale examination of early-age sex differences in neurotypical toddlers and those with autism spectrum disorder or other developmental conditions - Nature Human Behaviour Autism spectrum disorder (ASD) is clinically heterogeneous, with ongoing debates about phenotypic differences between boys and girls. Leveraging the Get SET Early programme, Pierce and colleagues find...

There is an ongoing debate about phenotypic differences in #autism spectrum disorder between girls and boys. In this study, Pierce et al found no significant sex differences in ASD toddlers across 17 of 18 measures.
www.nature.com/articles/s41...

Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X
www.nature.com/articles/s41...
@natcomms.nature.com @derubeislab.bsky.social

New publication!
We expand on our prior work demonstrating that pleiotropic effects of cognitive GWAS can provide biological insights into schizophrenia GWAS results. We differentiated "concordant" from "discordant" subsets of schizophrenia risk SNPs (1/3)

Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish - Genome Biology Background Parental experience can influence progeny behavior through gamete-mediated non-genetic inheritance, that is, mechanisms that do not involve changes in inherited DNA sequence. However, under...

Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish
genomebiology.biomedcentral.com/articles/10....

Scalable co-sequencing of RNA and DNA from individual nuclei - Nature Methods Building on a nucleosome-depletion strategy, DEFND-seq utilizes a droplet microfluidic platform to enable high-throughput co-profiling of DNA and RNA in single cells.

Scalable co-sequencing of RNA and DNA from individual nuclei www.nature.com/articles/s41...

Dissecting regulatory syntax in human development with scalable multiomics and deep learning Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expre...

Delighted to share our latest work deciphering the landscape of chromatin accessibility and modeling the DNA sequence syntax rules underlying gene regulation during human fetal development! www.biorxiv.org/content/10.1... Read on for more: 🧵 1/16 #GeneReg 🧬🖥️

Out today in AJHG, this work from my (recently graduated) student Teng Heng on recessive effects in 44k British South Asians from the Genes & Health project @genesandhealth.bsky.social . She found 185 independent hits of which >40% were novel. Worth looking for these in your own cohorts!

Delighted to share the latest preprint from the lab led by Janith Seneviratne

We reveal novel roles for #embryonic regulators DPPA2/4 in facilitating a H2AK119Ub primed #chromatin state when aberrantly up-regulated in non-small cell lung #cancers 🧬🔬 (1/6)

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

Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes - Nature Neuroscience Sznajder et al. identified a molecular link between autism and myotonic dystrophy, showing that a tandem repeat mutation in a single gene can disrupt splicing of multiple autism-related genes during b...

Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes
www.nature.com/articles/s41...

Brain circuits that regulate social behavior - Molecular Psychiatry Molecular Psychiatry - Brain circuits that regulate social behavior

Brain circuits that regulate social behavior
www.nature.com/articles/s41...

Human de novo mutation rates from a four-generation pedigree reference - Nature Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a truth set t...

Human de novo mutation rates from a four-generation pedigree reference
www.nature.com/articles/s41...

Distinct synaptic plasticity rules operate across dendritic compartments in vivo during learning Synaptic plasticity underlies learning by modifying specific synaptic inputs to reshape neural activity and behavior. However, the rules governing which synapses will undergo different forms of plasti...

Distinct synaptic plasticity rules operate across dendritic compartments in vivo during learning
www.science.org/doi/10.1126/...

Low overlap of transcription factor DNA binding and regulatory targets - Nature A near-complete survey of transcription factor activities in Saccharomyces cerevisiae reveals that most transcription factors have both activator and repressor activities and limited overlap between t...

Low overlap of transcription factor DNA binding and regulatory targets
www.nature.com/articles/s41...

bioRxiv Genomics on X: "Exonic enhancers are a widespread class of dual-function regulatory elements https://t.co/Ho0TdalAsu #biorxiv_genomic" / X Exonic enhancers are a widespread class of dual-function regulatory elements https://t.co/Ho0TdalAsu #biorxiv_genomic

Exonic enhancers are a widespread class of dual-function regulatory elements

x.com/biorxiv_geno...

I am honored to receive this grant. I am hopeful that it will allow us to learn more about the mechanisms involved in the increased risk of autism among boys.

Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions This study investigates gene expression variability in human neurodevelopmental conditions. Using single-cell analyses of brain cell types, we identify a significant increase in gene expression variability driven by trisomy 21 as well as CHD8 haploinsufficiency. Additional analyses ascertain core features of highly and least variable genes across independent datasets.

Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions
www.cell.com/ajhg/fulltex...

What an amazing discovery from Scott Kennedy's lab! A new splicing system that recognizes transposons and removes them from mRNAs! t.co/3p3wyxkYXX

Constrained roads to complex brains Neural development and brain circuit evolution converged in birds and mammals

Constrained roads to complex brains
Neural development and brain circuit evolution converged in birds and mammals

www.science.org/doi/10.1126/...

The KRAB-Zinc Finger protein ZKSCAN3 represses enhancers via embedded retrotransposons Gene cis -regulatory sequences are increasingly recognised as containing “domesticated” transposable elements that impact their function. The KRAB Zinc Finger Protein (KZFP) family of transcription fa...

Our new #preprint has:
✅ A KRAB Zinc Finger (the SCAN domain-containing kind)
✅ #transposon sequences (the SINE kind)
✅ #epigenetic regulation (the #enhancer kind)
✅ lineage specification (the neural kind)
❌ and NO heterochromatin!

All by PhD student Daniel Moore 🚀

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