Long Read Sequencing Uncovers Telomere Length Variation Across Chromosomes

In a new proof-of-concept study published in Nature Communications, researchers at the University of Chicago analyzed genomic data from more than 2,500 participants in the national All of Us research program to estimate chromosome-specific telomere length (csTL). They found that telomere length varies across different chromosome arms, and that this variation is influenced by factors such as age and individual differences. 

Telomeres are protective ends of chromosomes composed of repetitive DNA sequences (TTAGGG). Each time a cell divides, telomeres progressively shorten, eventually leading to cell death or senescence-a state in which they lose their ability to divide. Maintaining telomere length is therefore critical for normal cell function.

Telomere length can differ among 23 pairs of chromosomes in a cell-some have longer ends, while others are shorter. Telomere length has long been used as biomarker for aging and disease risk. However, most previous research studies measured only the average telomere length across all chromosomes, making it difficult to determine which specific chromosome ends may be linked to disease. 

Long-Read Sequences Enable Chromosome-Specific Insights

Niyati Jain, first author of the study and a graduate student in the laboratory of Brandon Pierce, PhD, Professor in the Departments of Public Health Sciences and Human Genetics and the senior author, leveraged long-read whole genome sequencing (lrWGS) data from the National Institutes of Health-All of Us program to study the variations in telomeres at chromosomal level. Long-read sequences are the continuous stretches of DNA data available from whole genome sequencing, which allow researchers to study telomeres in greater detail. She used a computational tool called Telogator2 to identify telomere sequences in lrWGS. 

This is the largest study of telomere length conducted to date using human long-read sequencing, with well over 2,500 samples, and the data resource will continue to grow."

Brandon Pierce, PhD, Professor in the Departments of Public Health Sciences and Human Genetics and senior author

Long-read sequencing captures DNA fragments that are about 10,000 to 30,000 base pairs long, often spanning both the telomeres and nearby regions of the chromosome. This enables accurate assignment of telomeres to specific chromosome ends. In contrast, traditional or more commonly used short-read sequencing produces much smaller fragments (about 150 to 300 base pairs), which lack sufficient information to determine their chromosomal origin. 

Variations in Telomere Length

The All of Us research program is a large U.S.-based population study that has genetic data, health records, and demographic information from a diverse group of participants including historically underrepresented individuals. Although short-read sequencing data is available for about 400,000 individuals, long-read data are currently available for only around 2,800 participants. 

"As telomeres shorten, cells become less able to divide and as this happens in stem cells, tissues lose their ability to regenerate, increasing the risk of cardiovascular disease and other age-related conditions," Pierce said. "Understanding how telomere length varies across chromosome arms is important for understanding aging-related health issues."

The researchers identified clear patterns in telomere length across chromosome arms. Some chromosome ends consistently had longer telomeres, whereas others were shorter across participants. 

"As expected, we found an association between telomere length and age across all arms – younger individuals tend to have longer lengths compared to older participants," Jain said. 

Telomere Length and Aging

The study's findings support the hypothesis that telomere length status is established early in life. Some individuals start with shorter telomeres and maintain relatively shorter lengths over time, while others begin with longer telomeres and carry long ends throughout life. 

"We found that longer telomeres tend to shorten faster than shorter ones. The relationship with age is stronger for chromosome arms that start out longer," Pierce added.

Although researchers did not find strong links between chromosome-specific telomere length and diseases such as diabetes and cardiovascular disease, future studies with larger datasets may provide deeper insights into these conditions. 

The team is also exploring how epigenetics-changes in gene activity without altering DNA sequence-may influence aging. Long-read sequencing can detect DNA methylation, an epigenetic marker, across millions of sites in the genome.

"We are working to build epigenetic aging clocks using methylation data from long-read sequencing," Pierce said. "Because we can measure methylation at so many sites, we may gain new insights into how the epigenome changes with age."

The study, "Determinants of chromosome-specific telomere lengths among 2,573 All of Us participants" was supported by funding from the National Institutes of Health. Additional authors include Yuqing Yang, Habibul Ahsan, Briseis Aschebrook-Kilfoy, and Lin Chen from the University of Chicago; Jiajun Luofrom the University of Macau, SAR Macau; and Kathryn Demanelis from the University of Pittsburgh, Pittsburgh.