Hypermutable Genome Regions and Rapid Mutation Across Four Generations Revealed by Long-Read Sequencing

This video from Nature investigates how fast humans mutate by tracing four generations in a single Utah family using long‑read genome sequencing. It shows that each child carries new mutations not found in either parent, with typical numbers higher than previously thought, and that the hardest parts of the genome harbor most of these changes. The team also documents large structural changes that duplicate or delete DNA segments, especially in repetitive regions, and even accelerated mutation in duplicated genes. By reconstructing complete chromosomes, the researchers reveal that mutation rates are not uniform across the genome, and that hypermutable regions can drive rapid genetic novelty. The study depended on the family's generosity and could illuminate genetic diseases, chromosomal abnormalities, and cancer.

Introduction

The video from Nature asks how fast humans are mutating and why this matters for disease and evolution. It frames the question around the idea that human genomes differ by about 4 million differences on average, but that some regions mutate more rapidly than others, a concept researchers have pursued for years.

"When a child is born, they have new mutations that are not in either mom or dad." - Evan Eichler

Methods: Long-Read Sequencing and a Four-Generation Family

To study complex regions, the team used long-read sequencing that can reconstruct nearly full chromosomes, enabling accurate mutation discovery where short reads fall short. They partnered with Lynn Jordi, who assembled a multigenerational Utah family spanning four generations for complete sequencing.

"We had the good fortune of working with a colleague in Utah, Lynn Jordi, who had collected a very famous family." - Evan Eichler

Key Findings: Hypermutable Regions and Structural Variation

Compared with previous estimates, the data show many more new mutations per generation, with children carrying roughly 100 to 200 new mutations and rates being significantly higher in the genome’s most difficult regions. The team also observed large structural mutations that duplicate or remove chunks of DNA, especially in repetitive regions, and mutations in duplicated genes that evolve faster than unique genes, indicating a dynamic landscape for genomic novelty.

"The rate of new mutations was significantly higher, in some cases tenfold or even more higher than the other bits of the genome." - Evan Eichler

Implications: Disease, Cancer, and Future Research

The findings could improve understanding of genetic diseases, chromosomal abnormalities, and cancer, particularly if these techniques can be applied to other families. The study highlights the importance of broad, family‑level sequencing to reveal mutation patterns across the genome.

"The contribution of the family was critical." - Evan Eichler