Insights into DNA repeat expansions among 900,000 biobank participants

Why it matters

Some parts of the genome are short DNA motifs repeated many times in a row. When these repeats grow too long they can cause inherited diseases such as Huntington's, and some keep growing inside the body's own cells during life. Until now nobody knew how common this kind of somatic growth is in ordinary people, or what controls its speed. This study answers those questions on a scale never reached before, linking DNA instability to aging, to inherited genes, and to new disease risks. Repeat growth is a kind of somatic mutation that standard tests often miss, because repeats are hard to measure with short sequencing reads.

What they did

The researchers analysed DNA sequencing data from more than 900,000 participants in the UK Biobank and the US All of Us programme. They developed computational methods to recognise and measure repeat instability from standard sequencing reads. They compared how readily different repeats mutate in the germline (passed to children) and in blood, ran genome-wide searches for inherited variants that change how fast repeats expand, and tested whether expanded repeats were linked to disease.

What they found

Repeats at different places in the genome varied widely in how likely they were to mutate, both between generations and in blood. Common repeat alleles in the genes TCF4 and ADGRE2 showed high rates of length mosaicism in blood, meaning most people carry repeat elements that expand as they age. The genome-wide search found 29 regions where inherited variants increased expansion of one or more repeats in blood. Together these modifiers had strong effects: at one repeat, expansion rates differed about fourfold between people in the top and bottom 5% of polygenic scores. Variants in several DNA-repair genes pushed the TCF4 repeat in the opposite direction from other repeats. Expanded repeats in the glutaminase gene (GLS) were linked to stage 5 chronic kidney disease (odds ratio 14.0) and to liver disease (odds ratio 3.0).

Limits

All measurements come from blood DNA, so the study cannot show what happens in brain, liver or other tissues. The disease links are associations, not proof that the repeats cause disease. Measuring repeat length from short sequencing reads is technically hard, and the authors note in the paper that biobank analyses of repeat instability have limitations.

Key terms

Tandem repeat

A short DNA motif repeated many times in a row, such as CAG CAG CAG.

Somatic expansion

A repeat getting longer within the body's own cells during life, rather than being inherited that way.

Mosaicism

Different cells in the same person carrying different versions of the DNA.

Genome-wide association study (GWAS)

A scan of the whole genome for inherited variants linked to a trait.

Polygenic score

A combined score of many small genetic effects.