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Summary: DMM is launching a new Subject Focus on genetic variance in human disease. Here, we discuss this ongoing series of invited articles and reflect on advances in understanding the genotype–phenotype complexities in disease.



Summary: The alcohol flushing-associated ALDH2*2 variant is one of the most common genetic polymorphisms in humans. This variant exhibits complex pleiotropic effects associated with alcohol consumption and aldehyde toxicity, which diversely impact human health.


Summary: Variant effect predictors (VEPs) are algorithms that aim to predict the likelihood that a genetic or protein variant will be pathogenic. Herein, we review benchmarking procedures and deep mutational scanning as methods for validating VEPs.

Summary: The functionally replaced human genes in yeast generate humanized yeast, providing a simple growth-based readout for the functions of hundreds of critical human genes and allowing researchers to study them in a simplified organismal context.

Summary: This Review discusses challenges in neurodegenerative disease research and how deep phenotyping and genomics, alongside machine learning, can help the progress towards precision medicine.


Summary: This study shows, for the first time, a neuroprotective role of chaperone Hsp40 in suppressing circadian dysfunction associated with Huntington's disease in a Drosophila model.

Editor's choice: This study describes the genomic structures of two common sickle cell disease mouse models, illustrates their limitations for analyzing some genetic therapies and confirms the importance of distal DNA elements in human globin gene regulation.

Summary: We used a caspase-1 reporter mouse model to measure spatiotemporal dynamics of inflammation in obese mice, identifying tissue- and sex-specific caspase-1 activation patterns and inflammatory phenotypes, indicating mechanisms underlying the dynamics of inflammation.

Summary: We identified two types of cancer stem cell (CSC)-like populations in triple-negative breast cancer xenografts and patients. These CSC-like populations could potentially make tumors more drug resistant and thus more difficult to treat.

Summary: We report the first mouse model for cerebrocostomandibular syndrome, showing that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations.

Summary: Transcriptome analysis of zebrafish slc39a14−/− mutants demonstrates that loss of slc39a14 leads to concurrent manganese neurotoxicity and deficiency, both of which are associated with Ca2+ dyshomeostasis.

Summary: A series of physiological, histochemical and molecular analyses reveal that enriched environment decreases inflammation in adipose tissue and in hypothalamus, re-establishing glucose metabolism in metabolically compromised mice.

Summary: Conditional ablation of Lrp6 in dorsal neural folds causes spinal neural tube defects that can be rescued by genetic activation of β-catenin or maternal supplementation of Wnt signaling agonists.

Summary: Automated meiotic mapping, which allows rapid discovery of induced germline disease modifier mutations, reveals influential loci in mice with an autoimmune diabetes phenotype, identifying genes that may influence type 1 diabetes susceptibility in humans.

Summary: AMPK inhibition in conjunction with regular chemotherapy is likely to reduce the stem cell pool and improve chemosensitivity and therapeutic outcomes in breast cancers.

Summary: Phenotyping data for two novel mouse models combining glucocerebrosidase (GCase) deficiencies and alpha-synuclein pathology reveal the extent to which alpha-synuclein pathology is exacerbated by GCase deficiency.

Summary: Chronic unpredictable mild stress, a putative model of depression, reduced PPP4R3A expression in mice. PPP4R3A deficiency in mice leads to depression-like behaviors by inhibiting mTORC1-mediated synthesis of synaptic proteins.


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