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A single-nucleotide mutation within the TBX3 enhancer increased body size in Chinese horses.

ABSTRACT: Chinese ponies are endemic to the mountainous areas of southwestern China and were first reported in the archaeological record at the Royal Tomb of Zhongshan King, Mancheng, dated to approximately ∼2,100 YBP.¹ Previous work has started uncovering the genetic basis of size variation in western ponies and horses, revealing a limited number of loci, including HMGA2,²LCORL/NCAPG,³ZFAT, and LASP1.⁴^,⁵ Whether the same genetic pathways also drive the small body size of Chinese ponies, which show striking anatomical differences to Shetland ponies,⁶ remains unclear.²^,⁷ To test this, we combined whole-genome sequences of 187 horses across China. Statistical analyses revealed top association between genetic variation at the T-box transcription factor 3 (TBX3) and the body size. Fine-scale analysis across an extended population of 189 ponies and 574 horses narrowed down the association to one A/G SNP at an enhancer region upstream of the TBX3 (ECA8:20,644,555, p = 2.34e-39). Luciferase assays confirmed the single-nucleotide G mutation upregulating TBX3 expression, and enhancer-knockout mice exhibited shorter limbs than wild-type littermates (p < 0.01). Re-analysis of ancient DNA data showed that the G allele, which is most frequent in modern horses, first occurred some ∼2,300 years ago and rose in frequency since. This supports selection for larger size in Asia from approximately the beginning of the Chinese Empire. Overall, this study characterized the causal regulatory mutation underlying small body size in Chinese ponies and revealed size as one of the main selection targets of past Chinese breeders.

SUBMITTER: Liu X

PROVIDER: S-EPMC8796118 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleThe development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined.ObjectiveIdentification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation.Methods and resultsWe performed Assay for Transposase-Accessible Chromatin using sequencing on human pluripotent stem cell-derived SAN-like pacemaker cells and ventricle-like cells and identified thousands of putative REs specific for either human cell type. We validated pacemaker cell-specific elements in the SHOX2 and TBX3 loci. CRISPR-mediated homozygous deletion of the mouse ortholog of a noncoding region with candidate pacemaker-specific REs in the SHOX2 locus resulted in selective loss of Shox2 expression from the developing SAN and embryonic lethality. Putative pacemaker-specific REs were identified up to 1 Mbp upstream of TBX3 in a region close to MED13L harboring variants associated with heart rate recovery after exercise. The orthologous region was deleted in mice, which resulted in selective loss of expression of Tbx3 from the SAN and (cardiac) ganglia and in neonatal lethality. Expression of Tbx3 was maintained in other tissues including the atrioventricular conduction system, lungs, and liver. Heterozygous adult mice showed increased SAN recovery times after pacing. The human REs harboring the associated variants robustly drove expression in the SAN of transgenic mouse embryos.ConclusionsWe provided a genome-wide collection of candidate human pacemaker-specific REs, including the loci of SHOX2, TBX3, and ISL1, and identified a link between human genetic variants influencing heart rate recovery after exercise and a variant RE with highly conserved function, driving SAN expression of TBX3.

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A single-nucleotide mutation within the TBX3 enhancer increased body size in Chinese horses.

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