A high-resolution map of human evolutionary constraint using 29 mammals

TLDR

Comparing related genomes provides a powerful lens for genome interpretation. The study reports sequencing and comparative analysis of 29 eutherian genomes. The authors sequenced 29 eutherian genomes and used evolutionary signatures and experimental data comparisons to assign candidate functions to ~60 % of constrained bases. They find that 5.5 % of the human genome is under purifying selection, with constrained elements covering ~4.2 %, including new coding exons, stop‑codon readthrough, 10,000 overlapping synonymous constraints, 220 RNA structural families, nearly a million regulatory elements, positively selected residues, 280,000 mobile‑element exaptations, over 1,000 accelerated elements, and overlap with disease‑associated variants.

Abstract

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.