About

Dr. Janet Song is an Assistant Professor in the Department of Human Evolutionary Biology at Harvard University. Her research focuses on identifying and characterizing the genetic variants that contributed to human-specific traits, with a particular emphasis on the evolution of the human brain. Her work aims to understand how human-specific changes to the brain impact neurodevelopmental and neuropsychiatric diseases in modern humans. She is associated with the Song Lab at Harvard University, which investigates the genetic basis of human evolution and brain development.

Research topics

• Biology
• Neuroscience
• Genetics

Selected publications

• Linked origins but distinct roles for extreme length and sequence variation at a tandem repeat in <i>CACNA1C</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-23

  articleOpen access1st authorCorresponding

  Abstract Length variation in tandem repeats is a well-established driver of disease risk and is commonly assumed to arise from persistent genomic instability. Here, we characterize TRACT, a 30-bp variable number tandem repeat (VNTR) intronic to the calcium channel gene CACNA1C . TRACT exhibits extreme length variation (3-30+ kb) and has been previously linked to risk for bipolar disorder and schizophrenia. By examining multiple human cohorts, we find that TRACT alleles are strikingly bimodal in both length and sequence composition. Short alleles (TRACT S , ∼6 kb) and long alleles (TRACT L , ∼24 kb) are enriched for distinct 30-bp variants and are found on separate haplotypes that arose prior to the human migration out of Africa. Our data suggest that these ancient alleles expanded via perfect repeat tracts that were disrupted by accumulated mutations to result in relative length stability in extant humans, where there is no evidence for overt germline or somatic instability. Interestingly, neuropsychiatric disease risk is associated with specific 30-bp variants within TRACT S alleles, but not with overall TRACT length or with 30-bp variants enriched in TRACT L alleles. Instead, TRACT L alleles are associated with decreased gene expression in fibroblasts and testis. Together, these findings motivate joint examination of both sequence composition and length variation to fully understand the effects of VNTRs on evolution, trait variation, and disease risk.

  PublisherOA PDFDOI

• Genomic approaches for understanding the evolution of the human brain

  Nature Neuroscience · 2026-04-21

  article1st authorCorresponding
  PublisherDOI

• Human-specific tandem repeat in <i>CACNA1C</i> modulates responses to neuronal stimulation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-16 · 2 citations

  preprintOpen access1st author

  Abstract The recent development of long-read sequencing has made it possible to catalog variable number tandem repeats (VNTRs) in the human genome. However, little is known about their functional consequences. Here, we characterized the effect of TRACT, a VNTR that is unique to humans and that has sequence variants linked to risk for bipolar disorder and schizophrenia. By adding or removing this VNTR in both mouse models and human neural organoids, we find that TRACT, which is intronic to the L-type voltage-gated calcium channel gene CACNA1C , increases intracellular calcium after neuronal stimulation and leads to widespread changes in activity-dependent transcription programs in neurons. TRACT-dependent changes are enriched for genes associated with synapse formation and plasticity, and partially recapitulate evolutionary changes in activity-dependent transcription between species. These findings demonstrate that a single, human-specific, non-coding element can strongly affect the neuronal response to stimulation, and motivate the study of VNTRs as a genetic source of phenotypic variation in both evolution and disease.

  PublisherOA PDFDOI

• FOS binding sites are a hub for the evolution of activity-dependent gene regulatory programs in human neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-01 · 4 citations

  preprintOpen access

  After birth, sensory inputs to neurons trigger the induction of activity-dependent genes (ADGs) that mediate many aspects of neuronal maturation and plasticity. To identify human-specific ADGs, we characterized these genes in human-chimpanzee tetraploid neurons. We identified 235 ADGs that are differentially expressed between human and chimpanzee neurons and found that their nearby regulatory sites are species-biased in their binding of the transcription factor FOS. An assessment of these sites revealed that many are enriched for single nucleotide variants that promote or eliminate FOS binding in human neurons. Disrupting the function of individual species-biased FOS-bound enhancers diminishes expression of nearby genes and affects the firing dynamics of human neurons. Our findings indicate that FOS-bound enhancers are frequent sites of evolution and that they regulate human-specific ADGs that may contribute to the unusually protracted and complex process of postnatal human brain development.

  PublisherOA PDFDOI

• Transcriptomic Convergence and the Female Protective Effect in Autism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-22 · 6 citations

  preprintOpen access

  ABSTRACT Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by deficits in social communication as well as restricted and/or repetitive behaviors. ASD is highly heritable 1 , with a complex genetic architecture: large-scale studies have identified dosage-altering copy number variants (CNV) and single nucleotide variants (SNV) that implicate hundreds of genes as individually rare causes of ASD (ASD genes) 2–4 , with common variation at multiple loci also contributing substantially to risk 5 . Understanding how disruptions to these functionally diverse genes lead to the shared core features of ASD remains a major challenge 6 . Moreover, ASD is three- to four-fold more common in males than females 7,8 , and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males 9–13 , but the biological basis of this “female protective effect” (FPE) is unknown 14,15 . Here we show that individual perturbations of 18 ASD genes converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST , that drive this transcriptomic convergence in ASD. Furthermore, the X-linked transcription factor ZFX , which is expressed from both the active and the “inactive” X chromosomes in females 16 , emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.

  PublisherDOI

• 236 SCOPE-KIDS: feasibility study of a collaborative care model for delivering youth urgent mental health care

  2025-05-01

  articleOpen access
  PublisherOA PDFDOI

• Human-chimpanzee tetraploid system defines mechanisms of species-specific neural gene regulation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-31 · 7 citations

  preprintOpen access1st author

  Abstract A major challenge in human evolutionary biology is to pinpoint genetic differences that underlie human-specific traits, such as increased neuron number and differences in cognitive behaviors. We used human-chimpanzee tetraploid cells to distinguish gene expression changes due to cis -acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment. In neural progenitor cells, examination of both cis and trans changes — combined with CRISPR inhibition and transcription factor motif analyses — identified cis -acting, species-specific gene regulatory changes, including to TNIK, FOSL2 , and MAZ , with widespread trans effects on neurogenesis-related gene programs. In excitatory neurons, we identified POU3F2 as a key cis -regulated gene with trans effects on synaptic gene expression and neuronal firing. This study identifies cis -acting genomic changes that cause cascading trans gene regulatory effects to contribute to human neural specializations, and provides a general framework for discovering genetic differences underlying human traits.

  PublisherOA PDFDOI

• Pretraining Improves Prediction of Genomic Datasets Across Species

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-24

  preprintOpen access

  Recent studies suggest that deep neural network models trained on thousands of human genomic datasets can accurately predict genomic features, including gene expression and chromatin accessibility. However, training these models is computation- and time-intensive, and datasets of comparable size do not exist for most other organisms. Here, we identify modifications to an existing state-of-the-art model that improve model accuracy while reducing training time and computational cost. Using this stream-lined model architecture, we investigate the ability of models pretrained on human genomic datasets to transfer performance to a variety of different tasks. Models pretrained on human data but fine-tuned on genomic datasets from diverse tissues and species achieved significantly higher prediction accuracy while significantly reducing training time compared to models trained from scratch, with Pearson correlation coefficients between experimental results and predictions as high as 0.8. Further, we found that including excessive training tasks decreased model performance and that this compromised performance could be partially but not completely rescued by fine-tuning. Thus, simplifying model architecture, applying pretrained models, and carefully considering the number of training tasks may be effective and economical techniques for building new models across data types, tissues, and species.

  PublisherOA PDFDOI

• Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk

  Cell Genomics · 2024-07-16 · 31 citations

  articleOpen access

  Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.

  PublisherOA PDFDOI

• Geospatial investigations in Colombia reveal variations in the distribution of mood and psychotic disorders

  Communications Medicine · 2024-02-21 · 8 citations

  articleOpen access1st authorCorresponding

  BACKGROUND: Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas. METHODS: We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters. RESULTS: We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval [0.71, 0.89], p = 5.67E-05). We find nine clusters/hotspots of inpatients. CONCLUSIONS: Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.

  PublisherOA PDFDOI

Frequent coauthors

• Christopher A. Walsh

  Mount Sinai Hospital

  77 shared

• Taehwan Shin

  Howard Hughes Medical Institute

  52 shared

• Xuyu Qian

  Howard Hughes Medical Institute

  48 shared

• Connor Kenny

  Boston Children's Museum

  40 shared

• Dilenny M. Gonzalez

  Howard Hughes Medical Institute

  36 shared

• Ellen M. DeGennaro

  Boston Children's Hospital

  36 shared

• Ryan N. Doan

  Harvard University

  36 shared

• Samantha G. Beck

  Harvard University

  32 shared

Labs

• SONG LABPI

Education

• Ph.D., Genetics

  Stanford University

  2020

• A.B. in Chemical and Physical Biology, Secondary in Computer Science

  Harvard University

  2013