Study maps 561,410 genetic variants behind human skeletal evolution

September 23, 2026 at 08:26 PM1 min

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Researchers assayed 561,410 single-nucleotide substitutions distinguishing humans from other great apes in human fetal chondrocytes. The study produced a genome-wide atlas of regulatory variants that became fixed or nearly fixed during human evolution. The work focuses on cis-regulatory elements, which are considered major drivers of skeletal morphological divergence.

Key Facts

The study assayed 561,410 single-nucleotide substitutions that distinguish humans from other great apes and fall within candidate cis-regulatory elements.
The variants were introduced into human fetal chondrocytes to quantify their transcriptional effects.
The analysis yielded a genome-wide atlas of functional effects for regulatory variants that arose and became fixed or nearly fixed in human evolution.
Cis-regulatory elements with higher activity showed greater overlap with chondrocyte active chromatin marks and open chromatin (ATAC-seq).

Experimental Design

The researchers synthesized the human (derived) and great ape (ancestral) allele of each candidate cis-regulatory element. Each sequence was cloned upstream of a transcribable DNA barcode, and RNA abundance of each barcode measured the expression driven by that sequence. The assay included positive controls (n = 1,404), negative controls (inactive, n = 961; scrambled, n = 1,051; non-SCREEN, n = 759), and candidate CRE test sequences (active, n = 87,704; non-active, n = 557,093).

Regulatory Activity Landscape

Candidate cis-regulatory elements with higher activity exhibited greater overlap with active chromatin features in chondrocytes. The study measured activity using median absolute deviation (MAD) and normalized RNA and DNA counts per million (CPM). RNA counts were capped at 300,000 and activity values were capped at 30 for visualization.